336 results on '"Cell cycle checkpoint"'
Search Results
2. The Combination of ATM and Chk1 Inhibitors Induces Synthetic Lethality in Colorectal Cancer Cells
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Yuri Tozaki, Hiromasa Aoki, Rina Kato, Kohki Toriuchi, Saki Arame, Yasumichi Inoue, Hidetoshi Hayashi, Eiji Kubota, Hiromi Kataoka, and Mineyoshi Aoyama
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ATM ,Chk1 ,CDK1 ,cancer therapies ,cell cycle checkpoint ,synthetic lethality ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Genetic abnormalities induce the DNA damage response (DDR), which enables DNA repair at cell cycle checkpoints. Although the DDR is thought to function in preventing the onset and progression of cancer, DDR-related proteins are also thought to contribute to tumorigenesis, tumor progression, and drug resistance by preventing irreparable genomic abnormalities from inducing cell death. In the present study, the combination of ataxia telangiectasia-mutated serine/threonine kinase (ATM) and checkpoint kinase 1 (Chk1) inhibition exhibited synergistic antitumor effects and induced synergistic lethality in colorectal cancer cells at a low dose. The ATM and Chk1 inhibitors synergistically promoted the activation of cyclin-dependent kinase 1 by decreasing the phosphorylation levels of T14 and Y15. Furthermore, the combined treatment increased the number of sub-G1-stage cells, phospho-histone H2A.X-positive cells, and TdT-mediated dUTP nick-end labeling-positive cells among colon cancer cells, suggesting that the therapy induces apoptosis. Finally, the combined treatment exhibited a robust antitumor activity in syngeneic tumor model mice. These findings should contribute to the development of new treatments for colorectal cancer that directly exploit the genomic instability of cancer cells.
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- 2023
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3. Cell Signaling Pathways That Promote Radioresistance of Cancer Cells
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Michel M. Ouellette, Sumin Zhou, and Ying Yan
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radiation therapy ,cell signaling pathways ,cell cycle checkpoint ,DNA repair ,apoptosis ,autophagy ,Medicine (General) ,R5-920 - Abstract
Radiation therapy (RT) is a standard treatment for solid tumors and about 50% of patients with cancer, including pediatric cancer, receive RT. While RT has significantly improved the overall survival and quality of life of cancer patients, its efficacy has still been markedly limited by radioresistance in a significant number of cancer patients (intrinsic or acquired), resulting in failure of the RT control of the disease. Radiation eradicates cancer cells mainly by causing DNA damage. However, radiation also concomitantly activates multiple prosurvival signaling pathways, which include those mediated by ATM, ATR, AKT, ERK, and NF-κB that promote DNA damage checkpoint activation/DNA repair, autophagy induction, and/or inhibition of apoptosis. Furthermore, emerging data support the role of YAP signaling in promoting the intrinsic radioresistance of cancer cells, which occurs through its activation of the transcription of many essential genes that support cell survival, DNA repair, proliferation, and the stemness of cancer stem cells. Together, these signaling pathways protect cancer cells by reducing the magnitude of radiation-induced cytotoxicity and promoting radioresistance. Thus, targeting these prosurvival signaling pathways could potentially improve the radiosensitivity of cancer cells. In this review, we summarize the contribution of these pathways to the radioresistance of cancer cells.
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- 2022
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4. A Mutation in DNA Polymerase α Rescues WEE1KO Sensitivity to HU
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Thomas Eekhout, José Antonio Pedroza-Garcia, Pooneh Kalhorzadeh, Geert De Jaeger, and Lieven De Veylder
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replication stress ,DNA damage ,cell cycle checkpoint ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
During DNA replication, the WEE1 kinase is responsible for safeguarding genomic integrity by phosphorylating and thus inhibiting cyclin-dependent kinases (CDKs), which are the driving force of the cell cycle. Consequentially, wee1 mutant plants fail to respond properly to problems arising during DNA replication and are hypersensitive to replication stress. Here, we report the identification of the polα-2 mutant, mutated in the catalytic subunit of DNA polymerase α, as a suppressor mutant of wee1. The mutated protein appears to be less stable, causing a loss of interaction with its subunits and resulting in a prolonged S-phase.
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- 2021
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5. Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach
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Samuele Lodovichi, Tiziana Cervelli, Achille Pellicioli, and Alvaro Galli
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cell cycle checkpoint ,DNA repair ,cancer therapy ,DNA repair inhibitors ,synthetic lethality ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.
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- 2020
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6. Cell Cycle-Dependent Control and Roles of DNA Topoisomerase II
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Joyce H. Lee and James M. Berger
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topoisomerase ii ,cell cycle ,mitosis ,dna replication ,decatenation ,cell cycle checkpoint ,cancer ,Genetics ,QH426-470 - Abstract
Type II topoisomerases are ubiquitous enzymes in all branches of life that can alter DNA superhelicity and unlink double-stranded DNA segments during processes such as replication and transcription. In cells, type II topoisomerases are particularly useful for their ability to disentangle newly-replicated sister chromosomes. Growing lines of evidence indicate that eukaryotic topoisomerase II (topo II) activity is monitored and regulated throughout the cell cycle. Here, we discuss the various roles of topo II throughout the cell cycle, as well as mechanisms that have been found to govern and/or respond to topo II function and dysfunction. Knowledge of how topo II activity is controlled during cell cycle progression is important for understanding how its misregulation can contribute to genetic instability and how modulatory pathways may be exploited to advance chemotherapeutic development.
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- 2019
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7. AMPK Is the Crucial Target for the CDK4/6 Inhibitors Mediated Therapeutic Responses in PANC-1 and MIA PaCa-2 Pancreatic Cancer Cell Lines
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Ajda Coker-Gurkan, Pınar Obakan-Yerlikaya, Elif Damla Arisan, Merve Nur Coban, Ozge Rencuzogullari, Pinar Uysal Onganer, and Bortecine Sevgin
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0301 basic medicine ,Tumor microenvironment ,Cell cycle checkpoint ,LY2835219 ,pancreatic ductal adenocarcinoma ,AMPK ,Cancer ,PI3K/AKT/mTOR and AMPK signaling axis ,Cell cycle ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pancreatic cancer ,PD-0332991 ,Cancer research ,medicine ,cell cycle ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
The survival rate of pancreatic ductal adenocarcinoma (PDAC) patients is short, and PDAC is a cancer type that ranks fourth in the statistics regarding death due to cancer. Mutation in the KRAS gene, which plays a role in pancreatic cancer development, activates the PI3K/AKT/mTOR signaling pathway. The activity of the AMPK as a cellular energy sensor is one of the fundamental mechanisms that can induce effective therapeutic responses against CDK4/6 inhibitors via adjusting the cellular and tumor microenvironment stress management. The phosphorylation of AMPKα at the different phosphorylation residues such as Thr172 and Ser 377 causes metabolic differentiation in the cells following CDK4/6 inhibitor treatment in accordance with an increased cell cycle arrest and senescence under the control of different cellular players. In this study, we examined the competencies of the CDK4/6 inhibitors LY2835219 and PD-0332991 on the mechanism of cell survival and death based on AMPK signaling. Both CDK4/6 inhibitors LY2835219 and PD-0332991 modulated different molecular players on the PI3K/AKT/mTOR and AMPK signaling axis in different ways to reduce cell survival in a cell type dependent manner. These drugs are potential inducers of apoptosis and senescence that can alter the therapeutic efficacy cells.
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- 2021
8. S-Adenosyl-l-Methionine Overcomes uL3-Mediated Drug Resistance in p53 Deleted Colon Cancer Cells
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Annapina Russo, Annalisa Pecoraro, Martina Pagano, Luigi Borzacchiello, Giovanna Cacciapuoti, Giulia Russo, Luigi Mele, Marina Porcelli, Laura Mosca, Mosca, Laura, Pagano, Martina, Pecoraro, Annalisa, Borzacchiello, Luigi, Mele, Luigi, Cacciapuoti, Giovanna, Porcelli, Marina, Russo, Giulia, Russo, Annapina, Osca, L, Pagano, M, Pecoraro, A, Borzachiello, L, Mele, L, Cacciapuoti, G, Porcelli, M, Russo, G, and Russo, A
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Ribosomal Proteins ,S-Adenosylmethionine ,autophagy ,Cell cycle checkpoint ,Colorectal cancer ,Ribosomal Protein L3 ,Drug resistance ,Article ,Catalysis ,AdoMet ,Inorganic Chemistry ,lcsh:Chemistry ,chemistry.chemical_compound ,uL3 ,medicine ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Methionine ,drug resistance ,Chemistry ,Organic Chemistry ,Autophagy ,apoptosis ,General Medicine ,HCT116 Cells ,medicine.disease ,apoptosi ,Computer Science Applications ,colon cancer ,lcsh:Biology (General) ,lcsh:QD1-999 ,Drug Resistance, Neoplasm ,Apoptosis ,Methionine Adenosyltransferase ,Colonic Neoplasms ,Cancer cell ,Cancer research ,Tumor Suppressor Protein p53 ,Gene Deletion - Abstract
Purpose: In order to study novel therapeutic approaches taking advantage of natural compounds showing anticancer and anti-proliferative effects, we focused our interest on S-adenosyl-l-methionine, a naturally occurring sulfur-containing nucleoside synthesized from adenosine triphosphate and methionine by methionine adenosyltransferase, and its potential in overcoming drug resistance in colon cancer cells devoid of p53. Results: In the present study, we demonstrated that S-adenosyl-l-methionine overcomes uL3-mediated drug resistance in p53 deleted colon cancer cells. In particular, we demonstrated that S-adenosyl-l-methionine causes cell cycle arrest at the S phase, inhibits autophagy, augments reactive oxygen species, and induces apoptosis in these cancer cells. Conclusions: Results reported in this paper led us to propose S-adenosyl-l-methionine as a potential promising agent for cancer therapy by examining p53 and uL3 profiles in tumors to yield a better clinical outcomes.
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- 2021
9. The Effect of Novel Oleanolic Acid Oximes Conjugated with Indomethacin on the Nrf2-ARE And NF-κB Signaling Pathways in Normal Hepatocytes and Human Hepatocellular Cancer Cells
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Robert Kleszcz, Jacek Kujawski, Barbara Bednarczyk-Cwynar, Violetta Krajka-Kuźniak, Wanda Baer-Dubowska, and Maria Narożna
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indomethacin conjugates ,Cell cycle checkpoint ,Pharmaceutical Science ,lcsh:Medicine ,lcsh:RS1-441 ,Article ,NF-κB ,Nrf2 ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Drug Discovery ,Oleanolic acid ,HepG2 cells ,030304 developmental biology ,0303 health sciences ,oleanolic acid oxime derivatives ,lcsh:R ,Cell cycle ,chemistry ,Apoptosis ,Cell culture ,THLE-2 cells ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Molecular Medicine - Abstract
Nrf2 and NF-&kappa, B play a key role in inflammation-driven cancers. Conjugation of anti-inflammatory drugs with oleanolic acid oxime (OAO) may enhance their therapeutic potential as a result of downregulation of these pathways. Novel OAO derivatives conjugated with indomethacin (IND) were synthesized, and their effect on the activation and expression of Nrf2 and NF-&kappa, B in HepG2 hepatoma cells and THLE-2 immortalized normal hepatocytes was evaluated in relation to cell cycle arrest and apoptosis. Treatment with OAO&ndash, IND conjugates reduced the activation of Nrf2 and NF-&kappa, B and the expression of their active forms in HepG2 cells, while in normal hepatocytes, the activation of Nrf2 was increased and NF-&kappa, B diminished. Compounds 3d, 3-indomethacinoxyiminoolean-12-en-28-oic acid morpholide, and 3c, 3-indomethacinoxyiminoolean-12-en-28-oic acid benzyl ester, were the most efficient. In THLE-2 cells, as opposed to HepG2 cells, the expressions of SOD-1 and NQO1 were significantly enhanced after treatment with these compounds. The COX-2 expression was diminished in both cell lines. OAO&ndash, IND derivatives affected the cell cycle arrest at G2/M, leading to increased apoptosis and increased number of resting HepG2 cells. Therefore, the conjugation of IND with OAO derivatives may preserve cancer cells against chemoresistance through the inhibition of the Nrf2-ARE pathway and NF-&kappa, B and, at the same time, exert a chemopreventive effect in normal hepatocytes.
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- 2021
10. CKAP2L Knockdown Exerts Antitumor Effects by Increasing miR-4496 in Glioblastoma Cell Lines
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Dueng-Yuan Hueng, Shih-Ming Huang, Wen-Chiuan Tsai, Li-Chun Huang, Chung-Hsing Chou, Yao-Feng Li, and Chia-Kuang Tsai
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Male ,Cell cycle checkpoint ,Central Nervous System Neoplasms ,lcsh:Chemistry ,Cell Movement ,glioma ,Databases, Genetic ,lcsh:QH301-705.5 ,Spectroscopy ,Gene knockdown ,miR-4496 ,Brain Neoplasms ,General Medicine ,Middle Aged ,Immunohistochemistry ,Phenotype ,Computer Science Applications ,G2 Phase Cell Cycle Checkpoints ,Gene Expression Regulation, Neoplastic ,Gene Knockdown Techniques ,CGGA ,Female ,Epithelial-Mesenchymal Transition ,Biology ,Article ,Catalysis ,Inorganic Chemistry ,CKAP2L ,Cell Line, Tumor ,Glioma ,medicine ,Humans ,UCSC Xena ,Neoplasm Invasiveness ,Physical and Theoretical Chemistry ,Progenitor cell ,Lung cancer ,E2F ,Molecular Biology ,Mitosis ,Cell Proliferation ,Organic Chemistry ,glioblastoma ,TCGA ,medicine.disease ,E2F Transcription Factors ,Cytoskeletal Proteins ,MicroRNAs ,lcsh:Biology (General) ,lcsh:QD1-999 ,Tissue Array Analysis ,Cancer research ,prognosis ,Neoplasm Grading - Abstract
Despite advances in the diagnosis and treatment of the central nervous system malignancy glioma, overall survival remains poor. Cytoskeleton-associated protein 2-like (CKAP2L), which plays key roles in neural progenitor cell division, has also been linked to poor prognosis in lung cancer. In the present study, we investigated the role of CKAP2L in glioma. From bioinformatics analyses of datasets from The Cancer Gene Atlas and the Chinese Glioma Genome Atlas, we found that CKAP2L expression correlates with tumor grade and overall survival. Gene set enrichment analysis (GSEA) showed that MITOTIC_SPINDLE, G2M_CHECKPOINT, and E2F_TARGETS are crucially enriched phenotypes associated with high CKAP2L expression. Using U87MG, U118MG, and LNZ308 human glioma cells, we confirmed that CKAP2L knockdown with siCKAP2L inhibits glioma cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Interestingly, CKAP2L knockdown also induced cell cycle arrest at G2/M phase, which is consistent with the GSEA finding. Finally, we observed that CKAP2L knockdown led to significant increases in miR-4496. Treating cells with exogenous miR-4496 mimicked the effect of CKAP2L knockdown, and the effects of CKAP2L knockdown could be suppressed by miR-4496 inhibition. These findings suggest that CKAP2L is a vital regulator of miR-4496 activity and that CKAP2L is a potentially useful prognostic marker in glioma.
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- 2021
11. DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond
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Donald T. Fox and Delisa E. Clay
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Cell cycle checkpoint ,ved/biology ,DNA repair ,DNA damage ,ved/biology.organism_classification_rank.species ,Cell Cycle Stage ,Cell Cycle Checkpoints ,Review ,Cell cycle ,Biology ,QH426-470 ,Genome ,model organisms ,Evolutionary biology ,Genetics ,Animals ,Humans ,cell cycle ,Model organism ,Genetics (clinical) ,Organism ,Signal Transduction - Abstract
Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected.
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- 2021
12. Bad Smells and Broken DNA: A Tale of Sulfur-Nucleic Acid Cooperation
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Ghali E. Ghali, Yan Li, Christopher G. Kevil, and Rodney E. Shackelford
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autophagy ,Cell cycle checkpoint ,Physiology ,DNA damage ,DNA repair ,Clinical Biochemistry ,hydrogen sulfide ,Review ,RM1-950 ,Biology ,Biochemistry ,MEK1 ,medicine ,Molecular Biology ,cystathionine γ-lyase ,3-mercaptopyruvate sulfurtransferase ,chemistry.chemical_classification ,Autophagy ,Cancer ,cystathionine β-synthase ,Cell Biology ,medicine.disease ,equipment and supplies ,Cell biology ,Enzyme ,ATR ,chemistry ,Nucleic acid ,Therapeutics. Pharmacology ,Function (biology) - Abstract
Hydrogen sulfide (H2S) is a gasotransmitter that exerts numerous physiologic and pathophysiologic effects. Recently, a role for H2S in DNA repair has been identified, where H2S modulates cell cycle checkpoint responses, the DNA damage response (DDR), and mitochondrial and nuclear genomic stability. In addition, several DNA repair proteins modulate cellular H2S concentrations and cellular sulfur metabolism and, in turn, are regulated by cellular H2S concentrations. Many DDR proteins are now pharmacologically inhibited in targeted cancer therapies. As H2S and the enzymes that synthesize it are increased in many human malignancies, it is likely that H2S synthesis inhibition by these therapies is an underappreciated aspect of these cancer treatments. Moreover, both H2S and DDR protein activities in cancer and cardiovascular diseases are becoming increasingly apparent, implicating a DDR–H2S signaling axis in these pathophysiologic processes. Taken together, H2S and DNA repair likely play a central and presently poorly understood role in both normal cellular function and a wide array of human pathophysiologic processes. Here, we review the role of H2S in DNA repair.
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- 2021
13. Autophagic Activation and Decrease of Plasma Membrane Cholesterol Contribute to Anticancer Activities in Non-Small Cell Lung Cancer
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Jih-Hwa Guh, Wohn-Jenn Leu, Jui-Ling Hsu, and Nan-Shan Zhong
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autophagy ,Cell cycle checkpoint ,Lung Neoplasms ,Pharmaceutical Science ,Organic chemistry ,Antineoplastic Agents ,para-toluenesulfonamide ,Article ,Analytical Chemistry ,QD241-441 ,Lysosome ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Drug Discovery ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Physical and Theoretical Chemistry ,Lipid raft ,Protein kinase B ,PI3K/AKT/mTOR pathway ,non-small cell lung cancer ,Sulfonamides ,plasma membrane cholesterol ,Chemistry ,TOR Serine-Threonine Kinases ,Akt/mTOR/p70S6K pathway ,Autophagy ,Cell Membrane ,Ribosomal Protein S6 Kinases, 70-kDa ,Gefitinib ,Cell cycle ,medicine.anatomical_structure ,Cholesterol ,Chemistry (miscellaneous) ,Apoptosis ,Cancer research ,Molecular Medicine ,Lysosomes ,Proto-Oncogene Proteins c-akt ,Toluene - Abstract
Non-small cell lung cancer (NSCLC), an aggressive subtype of pulmonary carcinomas with high mortality, accounts for 85% of all lung cancers. Drug resistance and high recurrence rates impede the chemotherapeutic effect, making it urgent to develop new anti-NSCLC agents. Recently, we have demonstrated that para-toluenesulfonamide is a potential anti-tumor agent in human castration-resistant prostate cancer (CRPC) through inhibition of Akt/mTOR/p70S6 kinase pathway and lipid raft disruption. In the current study, we further addressed the critical role of cholesterol-enriched membrane microdomain and autophagic activation to para-toluenesulfonamide action in killing NSCLC. Similar in CRPC, para-toluenesulfonamide inhibited the Akt/mTOR/p70S6K pathway in NSCLC cell lines NCI-H460 and A549, leading to G1 arrest of the cell cycle and apoptosis. Para-toluenesulfonamide significantly decreased the cholesterol levels of plasma membrane. External cholesterol supplement rescued para-toluenesulfonamide-mediated effects. Para-toluenesulfonamide induced a profound increase of LC3-II protein expression and a significant decrease of p62 expression. Double staining of lysosomes and cellular cholesterol showed para-toluenesulfonamide-induced lysosomal transportation of cholesterol, which was validated using flow cytometric analysis of lysosome staining. Moreover, autophagy inhibitors could blunt para-toluenesulfonamide-induced effect, indicating autophagy induction. In conclusion, the data suggest that para-toluenesulfonamide is an effective anticancer agent against NSCLC through G1 checkpoint arrest and apoptotic cell death. The disturbance of membrane cholesterol levels and autophagic activation may play a crucial role to para-toluenesulfonamide action.
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- 2021
14. Synthetic Tryptanthrin Derivatives Induce Cell Cycle Arrest and Apoptosis via Akt and MAPKs in Human Hepatocellular Carcinoma Cells
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Chih-Shiang Chang, Ting-Wei Chen, Jin-Cherng Lien, Jing-Lan Hu, Jing-Yan Gao, and Jing-Ru Weng
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Cell cycle checkpoint ,biology ,Kinase ,Chemistry ,QH301-705.5 ,Cyclin-dependent kinase 2 ,apoptosis ,Medicine (miscellaneous) ,ROS ,hepatocellular carcinoma ,Article ,General Biochemistry, Genetics and Molecular Biology ,Apoptosis ,cell cycle arrest ,Cancer cell ,Cancer research ,biology.protein ,Phosphorylation ,Biology (General) ,Protein kinase B ,Cyclin A1 ,tryptanthrin - Abstract
Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.
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- 2021
15. A Nitrocarbazole as a New Microtubule-Targeting Agent in Breast Cancer Treatment
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Marco Ponassi, Jessica Ceramella, Lara Bianchi, Domenico Spinelli, Alexia Barbarossa, Giovanni Petrillo, Maria Stefania Sinicropi, Domenico Iacopetta, Alice Benzi, Cinzia Tavani, Camillo Rosano, and Massimo Maccagno
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Programmed cell death ,Technology ,Cell cycle checkpoint ,QH301-705.5 ,QC1-999 ,Context (language use) ,breast cancer ,Microtubule ,medicine ,General Materials Science ,Biology (General) ,carbazoles, ellipticine, tubulin, breast cancer, apoptosis, docking simulations ,Instrumentation ,QD1-999 ,Fluid Flow and Transfer Processes ,docking simulations ,biology ,Chemistry ,Process Chemistry and Technology ,Physics ,General Engineering ,apoptosis ,Engineering (General). Civil engineering (General) ,In vitro ,Computer Science Applications ,Vinblastine ,carbazoles ,Tubulin ,tubulin ,Apoptosis ,Cancer research ,biology.protein ,TA1-2040 ,ellipticine ,medicine.drug - Abstract
Breast cancer is still considered a high-incidence disease, and numerous are the research efforts for the development of new useful and effective therapies. Among anticancer drugs, carbazole compounds are largely studied for their anticancer properties and their ability to interfere with specific targets, such as microtubule components. The latter are involved in vital cellular functions, and the perturbation of their dynamics leads to cell cycle arrest and subsequent apoptosis. In this context, we report the anticancer activity of a series of carbazole analogues 1–8. Among them, 2-nitrocarbazole 1 exhibited the best cytotoxic profile, showing good anticancer activity against two breast cancer cell lines, namely MCF-7 and MDA-MB-231, with IC50 values of 7 ± 1.0 and 11.6 ± 0.8 μM, respectively. Furthermore, compound 1 did not interfere with the growth of the normal cell line MCF-10A, contrarily to Ellipticine, a well-known carbazole derivative used as a reference molecule. Finally, in vitro immunofluorescence analysis and in silico studies allowed us to demonstrate the ability of compound 1 to interfere with tubulin organization, similarly to vinblastine: a feature that results in triggering MCF-7 cell death by apoptosis, as demonstrated using a TUNEL assay.
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- 2021
16. RTA404, an Activator of Nrf2, Activates the Checkpoint Kinases and Induces Apoptosis through Intrinsic Apoptotic Pathway in Malignant Glioma
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Tzuu-Yuan Huang, Ann-Shung Lieu, Chih-Lung Lin, Aij-Lie Kwan, Yi-Chiang Hsu, and Tai-Hsin Tsai
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RTA404 ,Cell cycle checkpoint ,business.industry ,apoptosis ,General Medicine ,malignant glioma ,G2-M DNA damage checkpoint ,Cell cycle ,medicine.disease ,medicine.disease_cause ,Article ,Apoptosis ,checkpoint kinase ,Glioma ,Cancer cell ,Cancer research ,Medicine ,Viability assay ,business ,Carcinogenesis - Abstract
Background: Malignant glioma (MG) is an aggressive malignant brain tumor. Despite advances in multidisciplinary treatment, overall survival rates remain low. A trifluoroethyl amide derivative of 2-cyano-3-,12-dioxoolean-1,9-dien-28-oic acid (CDDO), CDDO–trifluoroethyl amide (CDDO–TFEA) is a nuclear erythroid 2-related factor 2/antioxidant response element pathway activator. RTA404 is used to inhibit proliferation and induce apoptosis in cancer cells. However, its effect on tumorigenesis in glioma is unclear. Methods: This in vitro study evaluated the effects of RTA404 on MG cells. We treated U87MG cell lines with RTA404 and performed assessments of apoptosis and cell cycle distributions. DNA content and apoptosis induction were subjected to flow cytometry analysis. The mitotic index was assessed based on MPM-2 expression. Protein expression was analyzed through Western blotting. Results: RTA404 significantly inhibited the cell viability and induced cell apoptosis on the U87MG cell line. The Annexin-FITC/PI assay revealed significant changes in the percentage of apoptotic cells. Treatment with RTA404 led to a significant reduction in the U87MG cells’ mitochondrial membrane potential. A significant rise in the percentage of caspase-3 activity was detected in the treated cells. In addition, these results suggest that cells pass the G2 checkpoint without cell cycle arrest by RTA404 treatment in the MPM-2 staining. An analysis of CHK1, CHK2, and p-CHK2 expression suggested that the DNA damage checkpoint system seems also to be activated by RTA404 treatment in established U87MG cells. Therefore, RTA404 may not only activate the DNA damage checkpoint system, it may also exert apoptosis in established U87MG cells. Conclusions: RTA404 inhibits the cell viability of gliomas and induces cancer cell apoptosis through intrinsic apoptotic pathway in Malignant glioma. In addition, the DNA damage checkpoint system seems also to be activated by RTA404. Taken together, RTA404 activated the DNA damage checkpoint system and induced apoptosis through intrinsic apoptotic pathways in established U87MG cells.
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- 2021
17. Developmental Acquisition of p53 Functions
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Sonam Raj, Sushil Kumar Jaiswal, and Melvin L. DePamphilis
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Pluripotent Stem Cells ,Cell cycle checkpoint ,DNA damage ,embryo ,Review ,Biology ,QH426-470 ,Regenerative Medicine ,Regenerative medicine ,Genomic Instability ,Mice ,pluripotent ,stem cells ,Genetics ,cancer ,Animals ,Humans ,Induced pluripotent stem cell ,Transcription factor ,Embryonic Stem Cells ,Genetics (clinical) ,Mammals ,apoptosis ,Gene Expression Regulation, Developmental ,Cell Differentiation ,differentiation ,Cell cycle ,genomic stability ,Embryonic stem cell ,Cell biology ,cell_developmental_biology ,cell cycle ,Tumor Suppressor Protein p53 ,Stem cell ,DNA Damage - Abstract
Remarkably, the p53 transcription factor, referred to as “the guardian of the genome”, is not essential for mammalian development. Moreover, efforts to identify p53-dependent developmental events have produced contradictory conclusions. Given the importance of pluripotent stem cells as models of mammalian development, and their applications in regenerative medicine and disease, resolving these conflicts is essential. Here we attempt to reconcile disparate data into justifiable conclusions predicated on reports that p53-dependent transcription is first detected in late mouse blastocysts, that p53 activity first becomes potentially lethal during gastrulation, and that apoptosis does not depend on p53. Furthermore, p53 does not regulate expression of genes required for pluripotency in embryonic stem cells (ESCs); it contributes to ESC genomic stability and differentiation. Depending on conditions, p53 accelerates initiation of apoptosis in ESCs in response to DNA damage, but cell cycle arrest as well as the rate and extent of apoptosis in ESCs are p53-independent. In embryonic fibroblasts, p53 induces cell cycle arrest to allow repair of DNA damage, and cell senescence to prevent proliferation of cells with extensive damage.
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- 2021
18. Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways
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Robert H. Whitaker and Jeanette Gowen Cook
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MAPK/ERK pathway ,Cell signaling ,Cell cycle checkpoint ,Cell division ,DNA Repair ,DNA repair ,kinase ,Review ,Cell fate determination ,Biology ,chemotherapy ,Biochemistry ,p38 Mitogen-Activated Protein Kinases ,Microbiology ,cell stress ,Humans ,cell signaling ,Protein Interaction Maps ,Phosphorylation ,Molecular Biology ,Mitosis ,mitosis ,protein networks ,apoptosis ,Cell Cycle Checkpoints ,Cell cycle ,QR1-502 ,Cell biology ,Proto-Oncogene Proteins c-bcl-2 ,DNA damage ,cell cycle ,Protein Processing, Post-Translational ,Signal Transduction - Abstract
Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways.
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- 2021
19. Inhibition of UBA5 Expression and Induction of Autophagy in Breast Cancer Cells by Usenamine A
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Bo Fang, Zijun Li, Namki Cho, Hee Min Yoo, and Yinda Qiu
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autophagy ,Cell cycle checkpoint ,Apoptosis ,Breast Neoplasms ,Ubiquitin-Activating Enzymes ,Biology ,Biochemistry ,Microbiology ,Article ,Flow cytometry ,Breast cancer ,breast cancer ,Downregulation and upregulation ,UBA5 ,Cell Line, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Protein Interaction Maps ,RNA, Messenger ,Lung cancer ,Molecular Biology ,Cell Proliferation ,medicine.diagnostic_test ,Autophagy ,Cancer ,Reproducibility of Results ,Cell Cycle Checkpoints ,medicine.disease ,Endoplasmic Reticulum Stress ,Prognosis ,Survival Analysis ,QR1-502 ,Gene Expression Regulation, Neoplastic ,Molecular Docking Simulation ,Gene Ontology ,Cancer research ,usenamine A ,Female ,ER stress - Abstract
Breast cancer is now the most common type of cancer worldwide, surpassing lung cancer. This issue is further worsened by the lack of effective therapies for the disease. Recent reports indicate that the inhibition of ubiquitin-like modifier-activating enzyme 5 (UBA5) can impede tumor development. However, there have been few reports regarding UBA5-inhibiting compounds. This work studied usenamine A, a natural product from the lichen Usnea longissimi that exhibits UBA5-inhibitory effects. Bioinformatics analysis was performed using public databases, and the anti-proliferative ability of usenamine A in breast cancer cells was examined through MTS and colony formation assays. Flow cytometry and western blot analysis were also conducted to examine and analyze cell cycle arrest and apoptosis. In addition, LC3B-RFP and UBA5 expression plasmids were used for the analysis of usenamine A-induced autophagy. According to the bioinformatics analysis results, UBA5 was upregulated in breast cancer. According to in vitro studies, usenamine A displayed prominent anti-proliferative activity and resulted in G2/M phase arrest in MDA-MB-231 cells. Moreover, usenamine A induced autophagy and endoplasmic reticulum stress in MDA-MB-231 cells. In conclusion, the findings support the potential of usenamine A as an agent that can attenuate the development and progression of breast cancer.
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- 2021
20. Playing on the Dark Side: SMYD3 Acts as a Cancer Genome Keeper in Gastrointestinal Malignancies
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Cristiano Simone, Paola Sanese, and Candida Fasano
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Cancer Research ,SMYD3 ,Cell cycle checkpoint ,gastrointestinal tumors ,Cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Synthetic lethality ,Review ,Cell cycle ,Biology ,medicine.disease_cause ,medicine.disease ,DNA damage response ,synthetic lethality ,homologous recombination repair ,PARP1 ,Oncology ,Tumor progression ,Cancer cell ,medicine ,Cancer research ,SMYD3 inhibition ,Carcinogenesis ,cell cycle checkpoints ,RC254-282 - Abstract
Simple Summary The activity of SMYD3 in promoting carcinogenesis is currently under debate. Growing evidence seems to confirm that SMYD3 overexpression correlates with poor prognosis, cancer growth and invasion, especially in gastrointestinal tumors. In this review, we dissect the emerging role played by SMYD3 in the regulation of cell cycle and DNA damage response by promoting homologous recombination (HR) repair and hence cancer cell genomic stability. Considering the crucial role of PARP1 in other DNA repair mechanisms, we also discuss a recently evaluated synthetic lethality approach based on the combined use of SMYD3 and PARP inhibitors. Interestingly, a significant proportion of HR-proficient gastrointestinal tumors expressing high levels of SMYD3 from the PanCanAtlas dataset seem to be eligible for this innovative strategy. This promising approach could be taken advantage of for therapeutic applications of SMYD3 inhibitors in cancer treatment. Abstract The SMYD3 methyltransferase has been found overexpressed in several types of cancers of the gastrointestinal (GI) tract. While high levels of SMYD3 have been positively correlated with cancer progression in cellular and advanced mice models, suggesting it as a potential risk and prognosis factor, its activity seems dispensable for autonomous in vitro cancer cell proliferation. Here, we present an in-depth analysis of SMYD3 functional role in the regulation of GI cancer progression. We first describe the oncogenic activity of SMYD3 as a transcriptional activator of genes involved in tumorigenesis, cancer development and transformation and as a co-regulator of key cancer-related pathways. Then, we dissect its role in orchestrating cell cycle regulation and DNA damage response (DDR) to genotoxic stress by promoting homologous recombination (HR) repair, thereby sustaining cancer cell genomic stability and tumor progression. Based on this evidence and on the involvement of PARP1 in other DDR mechanisms, we also outline a synthetic lethality approach consisting of the combined use of SMYD3 and PARP inhibitors, which recently showed promising therapeutic potential in HR-proficient GI tumors expressing high levels of SMYD3. Overall, these findings identify SMYD3 as a promising target for drug discovery.
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- 2021
21. Aza-Reversine Promotes Reprogramming of Lung (MRC-5) and Differentiation of Mesenchymal Cells into Osteoblasts
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Fani Tsitouroudi, Maria Pitou, Theodora Choli-Papadopoulou, Vasiliki Sarli, Dimitrios Poulcharidis, and Alexandros Katranidis
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Mesoderm ,Technology ,Cell cycle checkpoint ,MRC-5 cells ,PMMA-HEMA surfaces ,aza-reversine ,Article ,chemistry.chemical_compound ,medicine ,General Materials Science ,Microscopy ,QC120-168.85 ,mesenchymal cells ,cell reprogramming ,Mesenchymal stem cell ,QH201-278.5 ,Engineering (General). Civil engineering (General) ,Cell biology ,TK1-9971 ,medicine.anatomical_structure ,chemistry ,Descriptive and experimental mechanics ,Cancer cell ,immobilization of aza-reversine ,Electrical engineering. Electronics. Nuclear engineering ,Endoderm ,TA1-2040 ,C2C12 ,Reprogramming ,ddc:600 ,Reversine - Abstract
Reversine or 2-(4-morpholinoanilino)-N6-cyclohexyladenine was originally identified as a small organic molecule that induces dedifferentiation of lineage-committed mouse myoblasts, C2C12, and redirects them into lipocytes or osteoblasts under lineage-specific conditions (LISCs). Further, it was proven that this small molecule can induce cell cycle arrest and apoptosis and thus selectively lead cancer cells to cell death. Further studies demonstrated that reversine, and more specifically the C2 position of the purine ring, can tolerate a wide range of substitutions without activity loss. In this study, a piperazine analog of reversine, also known as aza-reversine, and a biotinylated derivative of aza-reversine were synthesized, and their potential medical applications were investigated by transforming the endoderm originates fetal lung cells (MRC-5) into the mesoderm originated osteoblasts and by differentiating mesenchymal cells into osteoblasts. Moreover, the reprogramming capacity of aza-reversine and biotinylated aza-reversine was investigated against MRC-5 cells and mesenchymal cells after the immobilization on PMMA/HEMA polymeric surfaces. The results showed that both aza-reversine and the biofunctionalized, biotinylated analog induced the reprogramming of MRC-5 cells to a more primitive, pluripotent state and can further transform them into osteoblasts under osteogenic culture conditions. These molecules also induced the differentiation of dental and adipose mesenchymal cells to osteoblasts. Thus, the possibility to load a small molecule with useful “information” for delivering that into specific cell targets opens new therapeutic personalized applications.
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- 2021
22. Potential Roles of Iridoid Glycosides and Their Underlying Mechanisms against Diverse Cancer Growth and Metastasis: Do They Have an Inhibitory Effect on Cancer Progression?
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Cho-Won Kim and Kyung-Chul Choi
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Iridoid Glycosides ,Cell cycle checkpoint ,iridoids ,Angiogenesis ,Apoptosis ,Review ,Biology ,anticancer ,Metastasis ,angiogenesis ,Neoplasms ,medicine ,Humans ,metastasis ,TX341-641 ,Epithelial–mesenchymal transition ,Neoplasm Metastasis ,chemistry.chemical_classification ,Nutrition and Dietetics ,Nutrition. Foods and food supply ,Cancer ,Glycoside ,Cell Cycle Checkpoints ,medicine.disease ,phytochemicals ,invasion ,chemistry ,Disease Progression ,Cancer research ,Signal transduction ,Food Science - Abstract
Iridoids are glycosides found in plants, having inherent roles in defending them against infection by viruses and microorganisms, and in the rapid repair of damaged areas. The emerging roles of iridoid glycosides on pharmacological properties have aroused the curiosity of many researchers, and studies undertaken indicate that iridoid glycosides exert inhibitory effects in numerous cancers. This review focuses on the roles and the potential mechanism of iridoid glycosides at each stage of cancer development such as proliferation, epithelial mesenchymal transition (EMT), migration, invasion and angiogenesis. Overall, the reviewed literature indicates that iridoid glycosides inhibit cancer growth by inducing cell cycle arrest or by regulating apoptosis-related signaling pathways. In addition, iridoid glycosides suppress the expression and activity of matrix metalloproteinases (MMPs), resulting in reduced cancer cell migration and invasiveness. The antiangiogenic mechanism of iridoid glycosides was found to be closely related to the transcriptional regulation of pro-angiogenic factors, i.e., vascular endothelial growth factors (VEGFs) and cluster of differentiation 31 (CD31). Taken together, these results indicate the therapeutic potential of iridoid glycosides to alleviate or prevent rapid cancer progression and metastasis.
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- 2021
23. Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells
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Mohamed M. Tawfik, Eman Fayad, Nourhan Eissa, Ali H. Abu Almaaty, and Fayez Althobaiti
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HepG2 ,Cell cycle checkpoint ,Carcinoma, Hepatocellular ,Scyphozoa ,Rhopilema nomadica ,Pharmaceutical Science ,Down-Regulation ,Organic chemistry ,Venom ,Article ,Analytical Chemistry ,Cnidarian Venoms ,QD241-441 ,Annexin ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,MTT assay ,Physical and Theoretical Chemistry ,Cytotoxicity ,Cell Proliferation ,biology ,Cell Death ,Chemistry ,Liver Neoplasms ,apoptosis ,Cell Cycle Checkpoints ,Hep G2 Cells ,biology.organism_classification ,Molecular biology ,Chemistry (miscellaneous) ,Apoptosis ,cell cycle arrest ,Molecular Medicine ,DNA fragmentation ,Apoptosis Regulatory Proteins - Abstract
Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 μg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors’ knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom.
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- 2021
24. Farrerol Induces Cancer Cell Death via ERK Activation in SKOV3 Cells and Attenuates TNF-α-Mediated Lipolysis
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Ju-Ock Nam, Jongbeom Chae, Seok Tae Choi, Jin Soo Kim, Seul Gi Lee, Youngjin Kang, Oyindamola Vivian Ojulari, and Taeg Kyu Kwon
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MAPK/ERK pathway ,Cell cycle checkpoint ,antitumor effect ,QH301-705.5 ,Poly ADP ribose polymerase ,Lipolysis ,Apoptosis ,cachexia ,Catalysis ,Article ,adipogenesis ,Inorganic Chemistry ,Cyclin-dependent kinase ,Tumor Cells, Cultured ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Extracellular Signal-Regulated MAP Kinases ,Molecular Biology ,QD1-999 ,Spectroscopy ,Cell Proliferation ,Ovarian Neoplasms ,biology ,Chemistry ,Kinase ,Tumor Necrosis Factor-alpha ,Organic Chemistry ,Cell Cycle ,General Medicine ,farrerol ,Cell cycle ,Molecular biology ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,ovarian cancer ,Chromones ,cell cycle arrest ,Cancer cell ,biology.protein ,Female - Abstract
Farrerol (FA) is a flavanone isolated from the Chinese herbal medicine “Man-shan-hong” (Rhododendron dauricum L.). In the present study, FA decreased the viability of SKOV3 cells in a dose- and time-dependent manner, and it induced G2/M cell cycle arrest and cell apoptosis. Cell cycle distribution analysis via flow cytometry showed that FA decreased G1 populations and increased G2/M populations in SKOV3 cells. Additionally, Western blotting confirmed an increase in the expression level of proteins involved in the cell cycle, e.g., CDK and cyclins. FA-induced apoptosis in SKOV3 cells was also investigated using a TUNEL assay, and increased expression levels of proapoptotic factors, including Caspase-3 and poly ADP ribose polymerase (PARP), through the Extracellular signal-regulated kinase (ERK)/MAPK pathway were investigated. Proinflammatory cytokines (e.g., IL-6, TNF-α, and IL-1) have been identified as a driver of the pathological mechanisms underlying involuntary weight loss and impaired physical function, i.e., cachexia, during cancer, in the present study, we showed that farrerol attenuates TNF-α-induced lipolysis and increases adipogenic differentiation in 3T3-L1 cells. Thus, farrerol could potentially be used as an anticancer agent or anticachetic drug.
- Published
- 2021
25. Antitumor Mechanism of Hydroxycamptothecin via the Metabolic Perturbation of Ribonucleotide and Deoxyribonucleotide in Human Colorectal Carcinoma Cells
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Wendi Luo, Caiyuan Yu, Zhi-Hong Jiang, Huixia Zhang, Cai-Yun Wang, Wei Zhang, and Yan Li
- Subjects
Ribonucleotide ,Cell cycle checkpoint ,Ribonucleoside Diphosphate Reductase ,DNA damage ,Cell Survival ,perturbation ,Pharmaceutical Science ,Organic chemistry ,Cell Cycle Proteins ,Irinotecan ,Article ,Analytical Chemistry ,Deoxyribonucleotide ,chemistry.chemical_compound ,hydroxycamptothecin ,QD241-441 ,Drug Discovery ,Ribonucleotide Reductases ,Humans ,Viability assay ,Physical and Theoretical Chemistry ,chemistry.chemical_classification ,deoxyribonucleotide ,DNA synthesis ,ribonucleotide ,Cell Cycle Checkpoints ,DNA ,Ribonucleotides ,HCT116 Cells ,Antineoplastic Agents, Phytogenic ,Deoxyribonucleoside ,Enzyme ,chemistry ,Chemistry (miscellaneous) ,Cancer research ,Molecular Medicine ,Camptothecin ,Colorectal Neoplasms ,DNA Damage - Abstract
Hydroxycamptothecin (SN38) is a natural plant extract isolated from Camptotheca acuminate. It has a broad spectrum of anticancer activity through inhibition of DNA topoisomerase I, which could affect DNA synthesis and lead to DNA damage. Thus, the action of SN38 against cancers could inevitably affect endogenous levels of ribonucleotide (RNs) and deoxyribonucleotide (dRNs) that play critical roles in many biological processes, especially in DNA synthesis and repair. However, the exact impact of SN38 on RNs and dRNs is yet to be fully elucidated. In this study, we evaluated the anticancer effect and associated mechanism of SN38 in human colorectal carcinoma HCT 116 cells. As a result, SN38 could decrease the cell viability and induce DNA damage in a concentration-dependent manner. Furthermore, cell cycle arrest and intracellular nucleotide metabolism were perturbed due to DNA damage response, of which ATP, UTP, dATP, and TTP may be the critical metabolites during the whole process. Combined with the expression of deoxyribonucleoside triphosphates synthesis enzymes, our results demonstrated that the alteration and imbalance of deoxyribonucleoside triphosphates caused by SN38 was mainly due to the de novo nucleotide synthesis at 24 h, and subsequently the salvage pathways at 48 h. The unique features of SN38 suggested that it might be recommended as an effective supplementary drug with an anticancer effect.
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- 2021
26. ClbG in Avian Pathogenic Escherichia coli Contributes to Meningitis Development in a Mouse Model
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Jiaxiang Zhang, Pengpeng Xia, Peili Wang, Yanfei Chen, Junsheng Dong, Guoqiang Zhu, Jun Li, Xia Meng, Luying Cui, Haoran Zhong, Qingqing Gao, Jianji Li, and Heng Wang
- Subjects
Cell cycle checkpoint ,animal structures ,Health, Toxicology and Mutagenesis ,APEC ,clbG ,Biology ,Cell cycle ,Toxicology ,medicine.disease ,biology.organism_classification ,Occludin ,Article ,In vitro ,Microbiology ,Sepsis ,Escherichia coli meningitis ,In vivo ,Pathogenic Escherichia coli ,medicine ,Medicine ,colibactin ,Meningitis - Abstract
Colibactin is a complex secondary metabolite that leads to genotoxicity that interferes with the eukaryotic cell cycle. It plays an important role in many diseases, including neonatal mouse sepsis and meningitis. Avian pathogenic Escherichia coli (APEC) is responsible for several diseases in the poultry industry and may threaten human health due to its potential zoonosis. In this study, we confirmed that clbG was necessary for the APEC XM strain to produce colibactin. The deletion of clbG on APEC XM contributed to lowered γH2AX expression, no megalocytosis, and no cell cycle arrest in vitro. None of the 4-week Institute of Cancer Research mice infected with the APEC XM ΔclbG contracted meningitis or displayed weakened clinical symptoms. Fewer histopathological lesions were observed in the APEC XM ΔclbG group. The bacterial colonization of tissues and the relative expression of cytokines (IL-1β, IL-6, and TNF-α) in the brains decreased significantly in the APEC XM ΔclbG group compared to those in the APEC XM group. The tight junction proteins (claudin-5, occludin, and ZO-1) were not significantly destroyed in APEC XM ΔclbG group in vivo and in vitro. In conclusion, clbG is necessary for the synthesis of the genotoxin colibactin and affects the development of APEC meningitis in mice.
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- 2021
27. Alternative Splicing of Pericentrin Contributes to Cell Cycle Control in Cardiomyocytes
- Author
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Silvia Vergarajauregui, Felix B. Engel, Robert Becker, and Jakob Steinfeldt
- Subjects
0301 basic medicine ,heart regeneration ,Cell cycle checkpoint ,Centriole ,cardiomyocyte ,030204 cardiovascular system & hematology ,Biology ,Article ,centriole splitting ,03 medical and health sciences ,0302 clinical medicine ,PCNT ,Diseases of the circulatory (Cardiovascular) system ,Pharmacology (medical) ,General Pharmacology, Toxicology and Pharmaceutics ,Mitosis ,non-centrosomal microtubule organizing center ,pericentrin ,Cell cycle ,Cell biology ,030104 developmental biology ,centrosome ,Centrosome ,RC666-701 ,Ectopic expression ,cell cycle ,C2C12 - Abstract
Induction of cardiomyocyte proliferation is a promising option to regenerate the heart. Thus, it is important to elucidate mechanisms that contribute to the cell cycle arrest of mammalian cardiomyocytes. Here, we assessed the contribution of the pericentrin (Pcnt) S isoform to the cell cycle arrest in postnatal cardiomyocytes. Immunofluorescence staining of Pcnt isoforms combined with siRNA-mediated depletion indicates that Pcnt S preferentially localizes to the nuclear envelope, while the Pcnt B isoform is enriched at centrosomes. This is further supported by the localization of ectopically expressed FLAG-tagged Pcnt S and Pcnt B in postnatal cardiomyocytes. Analysis of centriole configuration upon Pcnt depletion revealed that Pcnt B but not Pcnt S is required for centriole cohesion. Importantly, ectopic expression of Pcnt S induced centriole splitting in a heterologous system, ARPE-19 cells, and was sufficient to impair DNA synthesis in C2C12 myoblasts. Moreover, Pcnt S depletion enhanced serum-induced cell cycle re-entry in postnatal cardiomyocytes. Analysis of mitosis, binucleation rate, and cell number suggests that Pcnt S depletion promotes progression of postnatal cardiomyocytes through the cell cycle resulting in cell division. Collectively, our data indicate that alternative splicing of Pcnt contributes to the establishment of cardiomyocyte cell cycle arrest shortly after birth.
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- 2021
28. Selective Inhibition of Aurora Kinase A by AK-01/LY3295668 Attenuates MCC Tumor Growth by Inducing MCC Cell Cycle Arrest and Apoptosis
- Author
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Aarthi Kannan, Ling Gao, Quy H. Nguyen, Haibo Zhao, Bhaba K Das, and Jyoti Gogoi
- Subjects
0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,neuroendocrine skin cancer ,Article ,03 medical and health sciences ,0302 clinical medicine ,Aurora kinase ,Merkel cell carcinoma ,aurora kinase ,In vivo ,medicine ,RC254-282 ,business.industry ,food and beverages ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,030104 developmental biology ,Oncology ,Cell culture ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Aurora Kinase A ,Skin cancer ,business ,LY3295668 ,AK-01 - Abstract
Simple Summary Merkel cell carcinoma is a deadly skin cancer with few treatment options. When the tumor has spread, less than 18% of patients survive past five years, and the mortality rate is 3-times higher than melanoma. Cancer immunotherapy is a promising field, harnessing the patient’s immune system to fight cancer and offering hope to many patients. However, ineligibility or resistance to immunotherapy is a critical challenge; half of all MCC patients are ineligible, and many treated patients either stop responding after an initial positive response or don’t respond at all. In this study, we tested a promising drug based on genomic information from MCC patient tumors. We found that it was highly effective in killing MCC cells and MCC tumors grown in mice; we also observed that MCC genetic characteristics partly predicted how well the drug worked. These results provide strong evidence for its potential clinical application in MCC patients. Abstract Merkel cell carcinoma (MCC) is an often-lethal skin cancer with increasing incidence and limited treatment options. Although immune checkpoint inhibitors (ICI) have become the standard of care in advanced MCC, 50% of all MCC patients are ineligible for ICIs, and amongst those treated, many patients develop resistance. There is no therapeutic alternative for these patients, highlighting the urgent clinical need for alternative therapeutic strategies. Using patient-derived genetic insights and data generated in our lab, we identified aurora kinase as a promising therapeutic target for MCC. In this study, we examined the efficacy of the recently developed and highly selective AURKA inhibitor, AK-01 (LY3295668), in six patient-derived MCC cell lines and two MCC cell-line-derived xenograft mouse models. We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.
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- 2021
29. Hydroxyurea—The Good, the Bad and the Ugly
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Dorota Rybaczek and Marcelina W. Musiałek
- Subjects
DNA Replication ,0301 basic medicine ,Cell cycle checkpoint ,DNA damage ,replication stress ,Review ,QH426-470 ,medicine.disease_cause ,ribonucleotide reductase ,hydroxyurea ,S Phase ,03 medical and health sciences ,0302 clinical medicine ,Ribonucleotide Reductases ,medicine ,Genetics ,Animals ,Humans ,Cognitive decline ,Genetics (clinical) ,business.industry ,Cell cycle ,medicine.disease ,DNA replication checkpoint ,030104 developmental biology ,Ribonucleotide reductase ,cell cycle arrest ,030220 oncology & carcinogenesis ,Cancer research ,Skin cancer ,business ,Oxidative stress - Abstract
Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and—recently—a promising factor in preventing cognitive decline in Alzheimer’s disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.
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- 2021
30. 3′,4′-Dihydroxyflavonol Modulates the Cell Cycle in Cancer Cells: Implication as a Potential Combination Drug in Osteosarcoma
- Author
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Joana Almeida, Conceição Santos, Maria João Martins, Carina Proença, Helena Oliveira, José Miguel P. Ferreira de Oliveira, and Eduarda Fernandes
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,Pharmaceutical Science ,bone sarcoma ,anthracycline ,doxorubicin ,Article ,03 medical and health sciences ,0302 clinical medicine ,Pharmacy and materia medica ,Cyclin-dependent kinase ,Drug Discovery ,medicine ,Doxorubicin ,flavonoid ,Viability assay ,drug dose reduction ,biology ,Cell growth ,Chemistry ,Cell cycle ,RS1-441 ,030104 developmental biology ,Apoptosis ,cell cycle arrest ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Molecular Medicine ,Medicine ,cyclin-dependent kinases ,cyclins ,medicine.drug - Abstract
New agents are demanded to increase the therapeutic options for osteosarcoma (OS). Although OS is the most common bone cancer in children and adolescents, it is considered a rare disorder. Therefore, finding adjuvant drugs has potential to advance therapy for this disease. In this study, 3′,4′-dihydroxyflavonol (DiOHF) was investigated to assess the effects in OS cellular models in combination with doxorubicin (Dox). MG-63 and U2OS human OS cells were exposed to DiOHF and Dox and tested for cell viability and growth. To elucidate the inhibitory effects of DiOHF, additional studies were conducted to assess apoptosis and cell cycle distribution, gene expression quantification of cell cycle regulators, and cytokinesis-block cytome assay to determine nuclear division rate. DiOHF decreased OS cell growth and viability in a concentration-dependent manner. Its combination with Dox enabled Dox dose reduction in both cell lines, with synergistic interactions in U2OS cells. Although no significant apoptotic effects were detected at low concentrations, cytostatic effects were demonstrated in both cell lines. Incubation with DiOHF altered cell cycle dynamics and resulted in differential cyclin and cyclin-dependent kinase expression. Overall, this study presents an antiproliferative action of DiOHF in OS combination therapy via modulation of the cell cycle and nuclear division.
- Published
- 2021
31. Ceramide Metabolism Enzymes—Therapeutic Targets against Cancer
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Alberto Ouro, Antía Custodia, Marta Aramburu-Nuñez, Upasana Das Adhikari, and Ana Gomez-Larrauri
- Subjects
0301 basic medicine ,Ceramide ,Programmed cell death ,Medicine (General) ,Cell cycle checkpoint ,shingosine 1-phosphate (S1P) ,ceramide 1-phosphate (C1P) ,Cell ,Antineoplastic Agents ,Review ,Biology ,Ceramides ,medicine.disease_cause ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,R5-920 ,Neoplasms ,medicine ,Humans ,cancer ,Inflammation ,Sphingolipids ,Cell growth ,ceramide (Cer) ,apoptosis ,sphingolipids (Sphs) ,General Medicine ,Sphingolipid ,Cell biology ,carbohydrates (lipids) ,cell proliferation ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Second messenger system ,lipids (amino acids, peptides, and proteins) ,deoxy-sphingolipids ,Carcinogenesis - Abstract
Sphingolipids are both structural molecules that are essential for cell architecture and second messengers that are involved in numerous cell functions. Ceramide is the central hub of sphingolipid metabolism. In addition to being the precursor of complex sphingolipids, ceramides induce cell cycle arrest and promote cell death and inflammation. At least some of the enzymes involved in the regulation of sphingolipid metabolism are altered in carcinogenesis, and some are targets for anticancer drugs. A number of scientific reports have shown how alterations in sphingolipid pools can affect cell proliferation, survival and migration. Determination of sphingolipid levels and the regulation of the enzymes that are implicated in their metabolism is a key factor for developing novel therapeutic strategies or improving conventional therapies. The present review highlights the importance of bioactive sphingolipids and their regulatory enzymes as targets for therapeutic interventions with especial emphasis in carcinogenesis and cancer dissemination.
- Published
- 2021
32. Interleukin-32θ Triggers Cellular Senescence and Reduces Sensitivity to Doxorubicin-Mediated Cytotoxicity in MDA-MB-231 Cells
- Author
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Jinju Kim, Thu-Huyen Pham, Jin-Tae Hong, Hyo-Min Park, and Do-Young Yoon
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,senescence ,Apoptosis ,0302 clinical medicine ,Biology (General) ,skin and connective tissue diseases ,Cellular Senescence ,Spectroscopy ,Cell Death ,Interleukin ,General Medicine ,Transfection ,interleukin-32θ ,Metastatic breast cancer ,Computer Science Applications ,Chemistry ,Phenotype ,cell cycle arrest ,030220 oncology & carcinogenesis ,Female ,Senescence ,Cell Nucleus Shape ,QH301-705.5 ,Breast Neoplasms ,Biology ,Article ,Genomic Instability ,Catalysis ,Inorganic Chemistry ,03 medical and health sciences ,Breast cancer ,breast cancer ,Cell Line, Tumor ,Autophagy ,medicine ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Mitosis ,QD1-999 ,Cell Proliferation ,Ploidies ,drug resistance ,Interleukins ,Organic Chemistry ,medicine.disease ,G1 Phase Cell Cycle Checkpoints ,030104 developmental biology ,Doxorubicin ,Cancer cell ,Cancer research - Abstract
The recently discovered interleukin (IL)- 32 isoform IL-32θ exerts anti-metastatic effects in the breast tumor microenvironment. However, the involvement of IL-32θ in breast cancer cell proliferation is not yet fully understood, therefore, the current study aimed to determine how IL-32θ affects cancer cell growth and evaluated the responses of IL-32θ-expressing cells to other cancer therapy. We compared the functions of IL-32θ in triple-negative breast cancer MDA-MB-231 cells that stably express IL-32θ, with MDA-MB-231 cells transfected with a mock vector. Slower growth was observed in cells expressing IL-32θ than in control cells, and changes were noted in nuclear morphology, mitotic division, and nucleolar size between the two groups of cells. Interleukin-32θ significantly reduced the colony-forming ability of MDA-MB-231 cells and induced permanent cell cycle arrest at the G1 phase. Long-term IL-32θ accumulation triggered permanent senescence and chromosomal instability in MDA-MB-231 cells. Genotoxic drug doxorubicin (DR) reduced the viability of MDA-MB-231 cells not expressing IL-32θ more than in cells expressing IL-32θ. Overall, these findings suggest that IL-32θ exerts antiproliferative effects in breast cancer cells and initiates senescence, which may cause DR resistance. Therefore, targeting IL-32θ in combination with DR treatment may not be suitable for treating metastatic breast cancer.
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- 2021
33. Fucoxanthin Exerts Anti-Tumor Activity on Canine Mammary Tumor Cells via Tumor Cell Apoptosis Induction and Angiogenesis Inhibition
- Author
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Jeong-ki Park, Gayeon Won, Jae-Won Seol, Jawun Choi, and Hyuk Jang
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,Angiogenesis ,Veterinary medicine ,Article ,fucoxanthin ,03 medical and health sciences ,chemistry.chemical_compound ,angiogenesis ,0302 clinical medicine ,SF600-1100 ,Fucoxanthin ,Viability assay ,Tube formation ,Mammary tumor ,General Veterinary ,Chemistry ,apoptosis ,canine mammary gland tumor ,Endothelial stem cell ,030104 developmental biology ,QL1-991 ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Animal Science and Zoology ,angiopoietin-2 ,Zoology - Abstract
Simple Summary Fucoxanthin is a carotenoid that reportedly exhibits anticancer activity against different types of cancer cells. However, the activity of fucoxanthin in canine mammary gland tumors has not been extensively investigated. In this study, we evaluated fucoxanthin against canine mammary tumor cells (CMT-U27) and human umbilical vein endothelial cells (HUVECs). Our results indicated that fucoxanthin induced apoptosis via caspase activation and suppressed angiogenesis in CMT-U27 cells. Moreover, fucoxanthin inhibited tube formation and cell migration in HUVECs and CMT-U27 cells, indicating that it possessed anti-angiogenic potential. In conclusion, fucoxanthin induced tumor cell death and inhibited angiogenesis. Therefore, we propose that fucoxanthin can be considered a prospective therapeutic agent for canine mammary gland tumors. Abstract Fucoxanthin is a carotenoid derived from brown algae. It is known to exhibit anticancer activity, including the promotion of apoptosis and cell cycle arrest in several tumors. However, it remains unclear whether fucoxanthin exhibits anticancer activity against mammary gland tumors. In this study, we evaluated fucoxanthin activity against canine mammary tumor cells (CMT-U27) and human umbilical vein endothelial cells (HUVECs) to investigate its effect on cell viability, migration, tube formation, and angiopoietin 2 (Ang2) expression. Our results showed that fucoxanthin induced apoptosis via caspase activation in CMT-U27 cells. In rat aortic ring assay, fucoxanthin suppressed endothelial cell sprouting. Furthermore, fucoxanthin inhibited tube formation and migration in HUVECs. The number of migrated cells was assessed using CMT-U27 cells. The results demonstrated that fucoxanthin exerted anti-angiogenic activity on HUVECs and CMT-U27 cells by promoting Ang2 expression. In conclusion, our results demonstrated that fucoxanthin induced tumor cell death and inhibited angiogenesis, suggesting that fucoxanthin could be considered as a promising therapeutic agent for canine mammary gland tumors.
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- 2021
34. Sorghum Phenolic Compounds Are Associated with Cell Growth Inhibition through Cell Cycle Arrest and Apoptosis in Human Hepatocarcinoma and Colorectal Adenocarcinoma Cells
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Ramasamy Perumal, Dmitriy Smolensky, Jiamin Shen, Xi Chen, Jingwen Xu, Weiqun Wang, and Thomas J. Herald
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HepG2 ,Health (social science) ,Cell cycle checkpoint ,030309 nutrition & dietetics ,Plant Science ,phenolic compounds ,TP1-1185 ,Health Professions (miscellaneous) ,Microbiology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Functional food ,Cytotoxic T cell ,Food science ,IC50 ,cell growth inhibition ,cell cycle analysis ,0303 health sciences ,biology ,Cell growth ,Chemistry ,Chemical technology ,apoptosis ,food and beverages ,Caco-2 ,Sorghum ,biology.organism_classification ,Apoptosis ,030220 oncology & carcinogenesis ,sorghum ,Food Science - Abstract
Phenolic compounds in some specialty sorghums have been associated with cancer prevention. However, direct evidence and the underlying mechanisms for this are mostly unknown. In this study, phenolics were extracted from 13 selected sorghum accessions with black pericarp while F10000 hybrid with white pericarp was used as a control, and cell growth inhibition was studied in hepatocarcinoma HepG2 and colorectal adenocarcinoma Caco-2 cells. Total phenolic contents of the 13 high phenolic grains, as determined by Folin–Ciocalteu, were 30–64 mg GAE/g DW in the phenolic extracts of various accessions compared with the control F10000 at 2 mg GAE/g DW. Treatment of HepG2 with the extracted phenolics at 0–200 μM GAE up to 72 h resulted in a dose- and time-dependent reduction in cell numbers. The values of IC50 varied from 85 to 221 mg DW/mL while the control of F10000 was 1275 mg DW/mL. The underlying mechanisms were further examined using the highest phenolic content of PI329694 and the lowest IC50 of PI570481, resulting in a non-cytotoxic decrease in cell number that was significantly correlated with increased cell cycle arrest at G2/M and apoptotic cells in both HepG2 and Caco-2 cells. Taken together, these results indicated, for the first time, that inhibition of either HepG2 or Caco-2 cell growth by phenolic extracts from 13 selected sorghum accessions was due to cytostatic and apoptotic but not cytotoxic mechanisms, suggesting some specialty sorghums are a valuable, functional food, providing sustainable phenolics for potential cancer prevention.
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- 2021
35. The Therapeutic Potential of the Anticancer Activity of Fucoidan: Current Advances and Hurdles
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Ananta Prasad Arukha, Dhananjay Yadav, Pallavi Singh Chauhan, Jun-O Jin, Anuj Dubey, and Vishal Chavda
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Drug ,Cell cycle checkpoint ,QH301-705.5 ,media_common.quotation_subject ,Anti-Inflammatory Agents ,Pharmaceutical Science ,Antineoplastic Agents ,Apoptosis ,Review ,brown algae ,Fucose ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,fucoidan ,Polysaccharides ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Medicine ,Cytotoxic T cell ,Tumor growth ,Biology (General) ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,030304 developmental biology ,media_common ,0303 health sciences ,Fucoidan ,business.industry ,Cell Cycle ,cytotoxic effects ,anticancer activity ,tumor growth ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,business - Abstract
Several types of cancers share cellular and molecular behaviors. Although many chemotherapy drugs have been designed to weaken the defenses of cancer cells, these drugs may also have cytotoxic effects on healthy tissues. Fucoidan, a sulfated fucose-based polysaccharide from brown algae, has gained much attention as an antitumor drug owing to its anticancer effects against multiple cancer types. Among the anticancer mechanisms of fucoidan are cell cycle arrest, apoptosis evocation, and stimulation of cytotoxic natural killer cells and macrophages. Fucoidan also protects against toxicity associated with chemotherapeutic drugs and radiation-induced damage. The synergistic effect of fucoidan with existing anticancer drugs has prompted researchers to explore its therapeutic potential. This review compiles the mechanisms through which fucoidan slows tumor growth, kills cancer cells, and interacts with cancer chemotherapy drugs. The obstacles involved in developing fucoidan as an anticancer agent are also discussed in this review.
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- 2021
36. A Phenylacetamide Resveratrol Derivative Exerts Inhibitory Effects on Breast Cancer Cell Growth
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Carmela Saturnino, Adele Chimento, Anna Santarsiero, Jessica Ceramella, Arianna De Luca, Vincenzo Pezzi, Vittoria Infantino, Maria Stefania Sinicropi, Paola Avena, Maria Grazia Bonomo, Domenico Iacopetta, and Ortensia Ilaria Parisi
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antiproliferative activity ,Programmed cell death ,Cell cycle checkpoint ,QH301-705.5 ,Estrogen receptor ,Biological Availability ,Apoptosis ,Breast Neoplasms ,Cell Cycle Proteins ,Resveratrol ,resveratrol ,Catalysis ,Article ,Inorganic Chemistry ,chemistry.chemical_compound ,Breast cancer ,Cell Line, Tumor ,medicine ,Humans ,Secretion ,MTT assay ,Breast ,Physical and Theoretical Chemistry ,Biology (General) ,anti-inflammatory activity ,Molecular Biology ,QD1-999 ,Spectroscopy ,Cell Proliferation ,Organic Chemistry ,Cell Cycle ,G1 Phase ,phenylacetamide RSV derivatives ,General Medicine ,Cell Cycle Checkpoints ,medicine.disease ,breast cancer cell lines ,Computer Science Applications ,Bioavailability ,Gene Expression Regulation, Neoplastic ,Chemistry ,cell death ,chemistry ,cell cycle arrest ,Cancer research ,MCF-7 Cells - Abstract
Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.
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- 2021
37. Insight into Bortezomib Focusing on Its Efficacy against P-gp-Positive MDR Leukemia Cells
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Albert Breier, Alexandra Poturnayova, Tomáš Kyca, Zdena Sulova, Anton Misak, Lucia Pavlikova, Viera Bohacova, and Mário Šereš
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0301 basic medicine ,Cell cycle checkpoint ,Transcription, Genetic ,Mice ,0302 clinical medicine ,RNA, Neoplasm ,Biology (General) ,26S proteasome ,Spectroscopy ,P-glycoprotein ,Deubiquitinating Enzymes ,biology ,Bortezomib ,Chemistry ,Cell Cycle ,bortezomib ,General Medicine ,Transfection ,Fluoresceins ,Ubiquitinated Proteins ,Drug Resistance, Multiple ,Recombinant Proteins ,Neoplasm Proteins ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Leukemia ,Vincristine ,030220 oncology & carcinogenesis ,cyclins ,CDK inhibitors ,Cell Division ,medicine.drug ,Proteasome Endopeptidase Complex ,QH301-705.5 ,Antineoplastic Agents ,ubiquitination ,Article ,Catalysis ,Inorganic Chemistry ,Inhibitory Concentration 50 ,03 medical and health sciences ,Cyclin-dependent kinase ,Cell Line, Tumor ,medicine ,Animals ,Humans ,HSP90 ,Protease Inhibitors ,deubiquitinases ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,RNA, Messenger ,Physical and Theoretical Chemistry ,Molecular Biology ,QD1-999 ,L1210 cells ,Organic Chemistry ,medicine.disease ,Molecular biology ,Leukemia, Lymphoid ,Genes, cdc ,030104 developmental biology ,Proteasome ,Drug Resistance, Neoplasm ,biology.protein ,cyclin-dependent kinases - Abstract
In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. We also observed an increase in the level of polyubiquitinated proteins (via K48-linkage) and a decrease in the gene expression of some deubiquitinases after treatment with bortezomib. Resistant cells expressed higher levels of genes encoding 26S proteasome components and the chaperone HSP90, which is involved in 26S proteasome assembly. After 4 h of preincubation, bortezomib induced a more pronounced depression of proteasome activity in S cells than in R or T cells. However, none of these changes alone or in combination sufficiently suppressed the sensitivity of R or T cells to bortezomib, which remained at a level similar to that of S cells.
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- 2021
38. Decursinol Angelate Arrest Melanoma Cell Proliferation by Initiating Cell Death and Tumor Shrinkage via Induction of Apoptosis
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Jae Gyu Park, Buyng Su Hwang, Dong Kyu Choi, Imran Khan, Heejin Lee, Sun Chul Kang, Chang Geon Kim, Seon Min Park, and Sukkum Ngullie Chang
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Male ,Skin Neoplasms ,Cell cycle checkpoint ,Melanoma, Experimental ,lcsh:Chemistry ,Melanoma ,lcsh:QH301-705.5 ,Spectroscopy ,Mice, Inbred BALB C ,decursinol angelate (DA) ,B16F10 murine melanoma cells ,Chemistry ,apoptosis ,General Medicine ,Cell cycle ,Mitochondria ,Computer Science Applications ,Butyrates ,Mitochondrial Membranes ,cell cycle ,Programmed cell death ,Mice, Nude ,Antineoplastic Agents ,Caspase 3 ,reactive oxygen species (ROS) ,Models, Biological ,Catalysis ,Article ,Inorganic Chemistry ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Benzopyrans ,Physical and Theoretical Chemistry ,Molecular Biology ,Cell Proliferation ,Cell growth ,Organic Chemistry ,Autophagosomes ,Cell Cycle Checkpoints ,medicine.disease ,Acetylcysteine ,lcsh:Biology (General) ,lcsh:QD1-999 ,Apoptosis ,Cancer research ,Reactive Oxygen Species - Abstract
Melanoma is known to aggressively metastasize and is one of the prominent causes of skin cancer mortality. This study was designed to assess the molecular mechanism of decursinol angelate (DA) against murine melanoma cell line (B16F10 cells). Treatment of DA resulted in growth inhibition and cell cycle arrest at G0/G1 (p < 0.001) phase, evaluated through immunoblotting. Moreover, autophagy-related proteins such as ATG-5 (p < 0.0001), ATG-7 (p < 0.0001), beclin-1 (p < 0.0001) and transition of LC3-I to LC3-II (p < 0.0001) were markedly decreased, indicating autophagosome inhibition. Additionally, DA treatment triggered apoptotic events which were corroborated by the occurrence of distorted nuclei, elevated reactive oxygen species (ROS) levels and reduction in the mitochondrial membrane potential. Subsequently, there was an increase in the expression of pro-apoptotic protein Bax in a dose-dependent manner, with the corresponding downregulation of Bcl-2 expression and cytochrome C expression following 24 h DA treatment in A375.SM and B16F10 cells. We substantiated our results for apoptotic occurrence through flow cytometry in B16F10 cells. Furthermore, we treated B16F10 cells with N-acetyl-L-cysteine (NAC). NAC treatment upregulated ATG-5 (p < 0.0001), beclin-1 (p < 0.0001) and LC3-I to LC3-II (p < 0.0001) conversion, which was inhibited in the DA treatment group. We also noticed a systematic upregulation of important markers for progression of G1 cell phase such as CDK-2 (p < 0.029), CDK-4 (p < 0.036), cyclin D1 (p < 0.0003) and cyclin E (p < 0.020) upon NAC treatment. In addition, we also observed a significant fold reduction (p < 0.05) in ROS fluorescent intensity and the expression of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase-9 (p > 0.010) and cleaved caspase-3 (p < 0.0001). NAC treatment was able to ameliorate DA-induced apoptosis and cell cycle arrest to support our finding. Our in vivo xenograft model also revealed similar findings, such as downregulation of CDK-2 (p < 0.0001) and CDK-4 (p < 0.0142) and upregulation of Bax (p < 0.0001), cytochrome C (p < 0.0001), cleaved caspase 3 (p < 0.0001) and cleaved caspase 9 (p < 0.0001). In summary, our study revealed that DA is an effective treatment against B16F10 melanoma cells and xenograft mice model.
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- 2021
39. Palmitoylethanolamide Reduces Colon Cancer Cell Proliferation and Migration, Influences Tumor Cell Cycle and Exerts In Vivo Chemopreventive Effects
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Barbara Romano, Vincenzo Brancaleone, Francesca Borrelli, M Francesca Nanì, Ester Pagano, Giuseppe Lucariello, Donatella Cicia, Angelo A. Izzo, Tommaso Venneri, Raffaele Capasso, Nunzio Antonio Cacciola, Pagano, E., Venneri, T., Lucariello, G., Cicia, D., Brancaleone, V., Nani, M. F., Cacciola, N. A., Capasso, R., Izzo, A. A., Borrelli, F., and Romano, B.
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0301 basic medicine ,Cancer Research ,Cell cycle checkpoint ,Colorectal cancer ,Article ,acylethanolamides ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,endocannabinoid system ,RC254-282 ,Cyclin-dependent kinase 1 ,Palmitoylethanolamide ,Acylethanolamide ,Chemistry ,Azoxymethane ,food and beverages ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell cycle ,medicine.disease ,Endocannabinoid system ,030104 developmental biology ,Oncology ,colon cancer ,030220 oncology & carcinogenesis ,Cancer research - Abstract
Simple Summary Treatment of colon cancer remains a significant unmet need. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide also present in food sources. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. Here, we found that ultramicronized PEA inhibited tumor cell proliferation mediated by PPAR-α and GPR55, induced cell cycle arrest in the G2/M phase and DNA fragmentation, reduced cell migration and exerted beneficial effects in the azoxymethane model of colonic tumors. Collectively, these data provide evidence on the beneficial effects of PEA in colon carcinogenesis. Abstract Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the endocannabinoid anandamide. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. We deepened this aspect by studying the effects of PEA (ultramicronized PEA, um-PEA) on colon cancer cell proliferation, migration and cell cycle as well as its effects in a murine model of colon cancer. Results showed that um-PEA inhibited tumor cell proliferation via peroxisome proliferator-activated receptor α and G protein-coupled receptor 55, induced cell cycle arrest in the G2/M phase, possibly through cyclin B1/CDK1 upregulation, and induced DNA fragmentation. Furthermore, um-PEA reduced tumor cell migration by reducing MMP2 and TIMP1 expression. In vivo administration of um-PEA exerted beneficial effects in the azoxymethane model of colonic tumors, by reducing the number of preneoplastic lesions and tumors. Collectively, our findings provide novel proofs on the effects of um-PEA in colon carcinogenesis.
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- 2021
40. Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer
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Roman Nawroth, Per Sonne Holm, Florian Gerhard Klein, Zhichao Tong, Qi Pan, Yuling Zhao, Charlène Granier, and Jürgen E. Gschwend
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Cell cycle checkpoint ,Combination therapy ,Talazoparib ,Medicine (miscellaneous) ,Palbociclib ,Article ,Olaparib ,combination therapy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chorioallantoic membrane model ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Kinase ,Retinoblastoma protein ,apoptosis ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,bladder cancer ,Medicine - Abstract
The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecular factors conferring resistance to CDK4/6 inhibition in bladder cancer (BLCA) that also included components within the DNA repair pathway. In this study, we validated whether a combinatory treatment approach of the CDK4/6 inhibitor Palbociclib with Poly-(ADP-Ribose) Polymerase (PARP) inhibitors improves therapy response in BLCA. First, a comparison of PARP inhibitors Talazoparib and Olaparib showed superior efficacy of Talazoparib in vitro and displayed high antitumor activity in xenografts in the chicken chorioallantoic membrane (CAM) model. Moreover, the combination of Talazoparib and the CDK4/6 inhibitor Palbociclib synergistically reduced tumor growth in Retinoblastoma protein (RB)-positive BLCA in vitro and in a CAM model, an effect that relies on Palbociclib-induced cell cycle arrest in G0/G1-phase complemented by a G2 arrest induced by Talazoparib. Interestingly, Talazoparib-induced apoptosis was reduced by Palbociclib. The combination of Palbociclib and Talazoparib effectively enhances BLCA therapy, and RB is a molecular biomarker of response to this treatment regimen.
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- 2021
41. Ginsenoside Rh1 Induces MCF-7 Cell Apoptosis and Autophagic Cell Death through ROS-Mediated Akt Signaling
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Chang-Seon Myung, Yujin Jin, Diem Thi Ngoc Huynh, and Kyung-Sun Heo
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0301 basic medicine ,Cancer Research ,Programmed cell death ,autophagy ,Cell cycle checkpoint ,lcsh:RC254-282 ,Article ,ginsenoside Rh1 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Propidium iodide ,Clonogenic assay ,Protein kinase B ,PI3K/AKT/mTOR pathway ,reactive oxygen species ,Akt ,apoptosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,Oncology ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research - Abstract
Simple Summary Breast cancer (BC) is the most common cause of cancer-related deaths among women worldwide, and its incidence has been increasing. However, current therapeutic approaches, such as chemotherapy, radiation, and hormonal therapy, have become increasingly ineffective because of their severe adverse effects and multidrug resistance. Therefore, the discovery of new potential candidates for BC therapy is essential. Here, we investigated whether ginsenoside Rh1 exhibits anticancer effects on BC. We found that this ginsenoside effectively inhibited the growth of BC cells in both cell cultures and mice. Therefore, ginsenoside Rh1 is a promising candidate for BC treatment. Abstract Breast cancer (BC) is the leading cause of cancer-related deaths among women worldwide. Ginsenosides exhibit anticancer activity against various cancer cells. However, the effects of ginsenoside Rh1 on BC and the underlying mechanisms remain unknown. Here, we investigated the anticancer effects of Rh1 on human BC MCF-7 and HCC1428 cells and the underlying signaling pathways. The anticancer effects of Rh1 in vitro were evaluated using sulforhodamine B (SRB), 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), clonogenic assay, propidium iodide (PI)/Hoechst staining, Western blotting, flow cytometry, and immunofluorescence analysis. The in vivo effects of Rh1 were determined using a xenograft model via hematoxylin and eosin and the immunohistochemistry staining of tumor tissues. We found that Rh1 exerted cytotoxicity in the cells by increasing cell apoptosis, autophagy, and cell cycle arrest. These effects were further enhanced by a phosphatidylinositol 3-kinase (PI3K) inhibitor but were rescued by the inhibition of reactive oxygen species (ROS). Moreover, enhanced ROS generation by Rh1 inhibited the activation of the PI3K/Akt pathway. Consistently, Rh1 treatment significantly reduced tumor growth in vivo and increased the ROS production and protein expression of LC3B and cleaved caspase-3 but decreased the phosphorylation of Akt and retinoblastoma (Rb) in tumor tissues. Taken together, Rh1 exerted a potential anticancer effect on BC cells by inducing cell cycle arrest, apoptosis, and autophagy via inhibition of the ROS-mediated PI3K/Akt pathway.
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- 2021
42. Ampelopsin Inhibits Cell Proliferation and Induces Apoptosis in HL60 and K562 Leukemia Cells by Downregulating AKT and NF-κB Signaling Pathways
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Jang Mi Han, Hye Jin Jung, and Hong Lae Kim
- Subjects
cancer stemness ,Cell cycle checkpoint ,HL60 ,Cell Survival ,QH301-705.5 ,proliferation ,Antineoplastic Agents ,HL-60 Cells ,Catalysis ,Article ,Inorganic Chemistry ,chemistry.chemical_compound ,Cyclin-dependent kinase ,hemic and lymphatic diseases ,medicine ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,Protein kinase B ,QD1-999 ,Spectroscopy ,Cell Proliferation ,Flavonoids ,Membrane Potential, Mitochondrial ,biology ,Cell growth ,Organic Chemistry ,NF-kappa B ,leukemia ,apoptosis ,General Medicine ,medicine.disease ,Computer Science Applications ,Ampelopsin ,Leukemia ,Chemistry ,ampelopsin ,chemistry ,biology.protein ,Cancer research ,K562 Cells ,Proto-Oncogene Proteins c-akt ,K562 cells ,Signal Transduction - Abstract
Leukemia is a type of blood cancer caused by the rapid proliferation of abnormal white blood cells. Currently, several treatment options, including chemotherapy, radiation therapy, and bone marrow transplantation, are used to treat leukemia, but the morbidity and mortality rates of patients with leukemia are still high. Therefore, there is still a need to develop more selective and less toxic drugs for the effective treatment of leukemia. Ampelopsin, also known as dihydromyricetin, is a plant-derived flavonoid that possesses multiple pharmacological functions, including antibacterial, anti-inflammatory, antioxidative, antiangiogenic, and anticancer activities. However, the anticancer effect and mechanism of action of ampelopsin in leukemia remain unclear. In this study, we evaluated the antileukemic effect of ampelopsin against acute promyelocytic HL60 and chronic myelogenous K562 leukemia cells. Ampelopsin significantly inhibited the proliferation of both leukemia cell lines at concentrations that did not affect normal cell viability. Ampelopsin induced cell cycle arrest at the sub-G1 phase in HL60 cells but the S phase in K562 cells. In addition, ampelopsin regulated the expression of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors differently in each leukemia cell. Ampelopsin also induced apoptosis in both leukemia cell lines through nuclear condensation, loss of mitochondrial membrane potential, increase in reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP), and regulation of Bcl-2 family members. Furthermore, the antileukemic effect of ampelopsin was associated with the downregulation of AKT and NF-κB signaling pathways. Moreover, ampelopsin suppressed the expression levels of leukemia stemness markers, such as Oct4, Sox2, CD44, and CD133. Taken together, our findings suggest that ampelopsin may be an attractive chemotherapeutic agent against leukemia.
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- 2021
43. New Amides and Phosphoramidates Containing Selenium: Studies on Their Cytotoxicity and Antioxidant Activities in Breast Cancer
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Carlos Aydillo, Mikel Etxebeste-Mitxeltorena, Nora Astrain-Redín, Daniel Plano, Ignacio Encío, Cristina Morán-Serradilla, Carmen Sanmartín, Socorro Espuelas, and Esther Moreno
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0301 basic medicine ,Amide ,Programmed cell death ,Cell cycle checkpoint ,Antioxidant ,Physiology ,DPPH ,phosphoramidate ,medicine.medical_treatment ,Cytotoxicity ,Clinical Biochemistry ,chemistry.chemical_element ,Phosphoramidate ,Pharmacology ,Biochemistry ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Molecular Biology ,diselenide ,ABTS ,Selenocyanate ,lcsh:RM1-950 ,selenocyanate ,Cell Biology ,Diselenide ,amide ,030104 developmental biology ,lcsh:Therapeutics. Pharmacology ,chemistry ,Apoptosis ,030220 oncology & carcinogenesis ,cytotoxicity ,Selenium - Abstract
Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines (MCF-7, CCRF-CEM, HT-29, HTB-54 and PC-3) and two nonmalignant cell lines (184B5 and BEAS-2B). MCF-7 cells were the most sensitive and the selenoamides I.1f and I.2f and the selenium phosphoramidate II.2d, with GI50 values ranging from 0.08 to 0.93 µM, were chosen for further studies. Additionally, radical scavenging activity for all the compounds was determined using DPPH and ABTS colorimetric assays. Phosphoramidates turned out to be inactive as radical scavengers. No correlation was observed for the antioxidant activity and the cytotoxic effect, except for compounds I.1e and I.2f, which showed dual antioxidant and antitumor activity. The type of programmed cell death and cell cycle arrest were determined, and the results provided evidence that I.1f and I.2f induced cell death via autophagy, while the derivative II.2d provoked apoptosis. In addition, Western blot analysis corroborated these mechanisms with an increase in Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels for I.1f and I.2f, as well as an increase in BAX, p21 and p53 accompanied by a decrease in BCL-2 levels for derivative II.2d.
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- 2021
44. Mechanisms Governing DDK Regulation of the Initiation of DNA Replication
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Larasati and Bernard P. Duncker
- Subjects
DNA replication ,DDK ,Dbf4 ,Cdc7 ,MCM ,Rad53 ,cell cycle checkpoint ,Rif1 ,Sld3 ,Genetics ,QH426-470 - Abstract
The budding yeast Dbf4-dependent kinase (DDK) complex—comprised of cell division cycle (Cdc7) kinase and its regulatory subunit dumbbell former 4 (Dbf4)—is required to trigger the initiation of DNA replication through the phosphorylation of multiple minichromosome maintenance complex subunits 2-7 (Mcm2-7). DDK is also a target of the radiation sensitive 53 (Rad53) checkpoint kinase in response to replication stress. Numerous investigations have determined mechanistic details, including the regions of Mcm2, Mcm4, and Mcm6 phosphorylated by DDK, and a number of DDK docking sites. Similarly, the way in which the Rad53 forkhead-associated 1 (FHA1) domain binds to DDK—involving both canonical and non-canonical interactions—has been elucidated. Recent work has revealed mutual promotion of DDK and synthetic lethal with dpb11-1 3 (Sld3) roles. While DDK phosphorylation of Mcm2-7 subunits facilitates their interaction with Sld3 at origins, Sld3 in turn stimulates DDK phosphorylation of Mcm2. Details of a mutually antagonistic relationship between DDK and Rap1-interacting factor 1 (Rif1) have also recently come to light. While Rif1 is able to reverse DDK-mediated Mcm2-7 complex phosphorylation by targeting the protein phosphatase glycogen 7 (Glc7) to origins, there is evidence to suggest that DDK can counteract this activity by binding to and phosphorylating Rif1.
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- 2016
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45. 5-Aryl-1-Arylideneamino-1H-Imidazole-2(3H)-Thiones: Synthesis and in Vitro Anticancer Evaluation
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Islam Zaki, Ali H. Abu Almaaty, Elsherbiny H. El-Sayed, Eman Fayad, Eslam E M Toson, Ola A. Abu Ali, and Mohamed A. Tantawy
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Cell cycle checkpoint ,synthesis ,Pharmaceutical Science ,01 natural sciences ,Annexin V ,Analytical Chemistry ,chemistry.chemical_compound ,Drug Discovery ,Cytotoxic T cell ,Imidazole ,Cytotoxicity ,cell cycle analysis ,0303 health sciences ,Chemistry ,Imidazoles ,apoptosis ,Hep G2 Cells ,G2 Phase Cell Cycle Checkpoints ,Molecular Docking Simulation ,Biochemistry ,Chemistry (miscellaneous) ,MCF-7 Cells ,Molecular Medicine ,cytotoxicity ,Erlotinib ,medicine.drug ,Proto-Oncogene Proteins B-raf ,Cell Survival ,Antineoplastic Agents ,In Vitro Techniques ,Article ,imidazole ,lcsh:QD241-441 ,Erlotinib Hydrochloride ,Structure-Activity Relationship ,03 medical and health sciences ,lcsh:Organic chemistry ,medicine ,Humans ,Physical and Theoretical Chemistry ,030304 developmental biology ,Organic Chemistry ,Thiones ,HCT116 Cells ,Vascular Endothelial Growth Factor Receptor-2 ,In vitro ,0104 chemical sciences ,VEGFR-2 ,010404 medicinal & biomolecular chemistry ,Apoptosis ,Cell culture ,Drug Screening Assays, Antitumor - Abstract
A novel series of N-1 arylidene amino imidazole-2-thiones were synthesized, identified using IR, 1H-NMR, and 13C-NMR spectral data. Cytotoxic effect of the prepared compounds was carried out utilizing three cancer cell lines, MCF-7 breast cancer, HepG2 liver cancer, and HCT-116 colon cancer cell lines. Imidazole derivative 5 was the most potent of all against three cell lines. DNA flow cytometric analysis showed that, imidazoles 4d and 5 exhibit pre-G1 apoptosis and cell cycle arrest at G2/M phase. The results of the VEGFR-2 and B-Raf kinase inhibition assay revealed that compounds 4d and 5 displayed good inhibitory activity compared with reference drug erlotinib.
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- 2021
46. The MEK1/2 Pathway as a Therapeutic Target in High-Grade Serous Ovarian Carcinoma
- Author
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Abdelrahman Yousif, Ronald J. Buckanovich, Geeta Mehta, Imran Khan, Yeonjung Park, Akimasa Takahashi, Mikhail Chesnokov, Linda J. Hong, Jessica Ezell, and Ilana Chefetz
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,cancer stem-like cells ,Cancer Research ,Cell cycle checkpoint ,proliferation ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Ovarian carcinoma ,Medicine ,Trametinib ,Cisplatin ,MEK1/2 ,trametinib ,business.industry ,Cell growth ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Serous fluid ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,business ,Ovarian cancer ,high-grade serous ovarian carcinoma ,medicine.drug - Abstract
Simple Summary High-grade serous ovarian carcinoma (HGSOC) has poor prognosis for patients due to its high rate of recurrence and acquired resistance to therapy. MEK1/2-ERK1/2 signaling pathway that controls cell proliferation and survival is active in the majority of HGSOC cases, but its functional impact is unclear. We suggest that inhibition of MEK1/2 with specific inhibitor trametinib may exert anti-cancer effects upon HGSOC cells. Here we demonstrate that trametinib treatment of HGSOC cells indeed prominently inhibits cell proliferation and tumor growth, and that cisplatin-resistant cells displaying high MEK1/2 activity are particularly sensitive to trametinib. However, we also discovered that trametinib treatment of HGSOC cells has no cytotoxic effects and promotes cancer stem-like characteristics. We therefore suggest to use MEK1/2 inhibitors with other treatment strategies targeting cancer stem-like cells, like aldehyde dehydrogenase 1 inhibition that might show together strong synergy. Abstract High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to its high recurrence rate and acquired chemoresistance. RAS/MEK/ERK pathway activation is linked to cell proliferation and therapeutic resistance, but the role of MEK1/2-ERK1/2 pathway in HGSOC is poorly investigated. We evaluated MEK1/2 pathway activity in clinical HGSOC samples and ovarian cancer cell lines using immunohistochemistry, immunoblotting, and RT-qPCR. HGSOC cell lines were used to assess immediate and lasting effects of MEK1/2 inhibition with trametinib in vitro. Trametinib effect on tumor growth in vivo was investigated using mouse xenografts. MEK1/2 pathway is hyperactivated in HGSOC and is further stimulated by cisplatin treatment. Trametinib treatment causes cell cycle arrest in G1/0-phase and reduces tumor growth rate in vivo but does not induce cell death or reduce fraction of CD133+ stem-like cells, while increasing expression of stemness-associated genes instead. Transient trametinib treatment causes long-term increase in a subpopulation of cells with high aldehyde dehydrogenase (ALDH)1 activity that can survive and grow in non-adherent conditions. We conclude that MEK1/2 inhibition may be a promising approach to suppress ovarian cancer growth as a maintenance therapy. Promotion of stem-like properties upon MEK1/2 inhibition suggests a possible mechanism of resistance, so a combination with CSC-targeting drugs should be considered.
- Published
- 2021
47. Adlay Testa (Coix lachryma-jobi L. var. Ma-yuen Stapf.) Ethanolic Extract and Its Active Components Exert Anti-Proliferative Effects on Endometrial Cancer Cells via Cell Cycle Arrest
- Author
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Yun Ya Wang, Mohamed Ali, Kai Lee Wang, Tzong-Ming Shieh, Yun Ju Huang, Yin Hwa Shih, Wen Chang Chiang, Chih Chao Chang, and Shih Min Hsia
- Subjects
Cell cycle checkpoint ,phytosterols ,Pharmaceutical Science ,Pharmacology ,adlay ,01 natural sciences ,Article ,Protocatechuic acid ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Phenols ,lcsh:Organic chemistry ,Cell Line, Tumor ,Drug Discovery ,medicine ,Caffeic acid ,Humans ,Physical and Theoretical Chemistry ,Coix ,Cell Proliferation ,biology ,Plant Extracts ,010405 organic chemistry ,Cell growth ,Chemistry ,inhibitory effects ,Endometrial cancer ,Organic Chemistry ,Cell Cycle Checkpoints ,medicine.disease ,biology.organism_classification ,Endometrial Neoplasms ,0104 chemical sciences ,polyphenol ,Phytochemical ,Chemistry (miscellaneous) ,Polyphenol ,030220 oncology & carcinogenesis ,flavonoids ,Molecular Medicine ,Female ,Steroids - Abstract
Endometrial cancer is the most common malignant tumors of gynecologic neoplasms in Western society. In recent years, the incidence of endometrial cancer has increased, and it has become the third most common female gynecological cancer (after ovarian and cervical cancer) in Taiwan. Adlay (Coix lachryma-jobi L. var. Ma-yuen Stapf.) has been demonstrated to have bioactive polyphenols, flavonoids, phytosterols, and essential nutrients for health benefits, including anticancer effects in humans. However, little is known about the effect of adlay seeds on endometrial cancer. Our study aimed to investigate the potential growth inhibitory effects of several adlay seed fractions, including ethyl acetate (ATE-EA) and its bioactive constituents, separately on endometrial cancer cells—HEC-1A (phosphatase and tensin homolog-positive) and RL95-2 (phosphatase and tensin homolog-negative)—and identify related active ingredients. In addition, the potential active fractions and the phytochemical compounds were elucidated. The results demonstrate superior activity of ATE-EA with significant in vitro cell proliferation inhibitory capacity, particularly its C.D.E.F-subfraction. Moreover, HPLC- and GC/FID-based quantification of ATE-EA subfractions showed that phenolic compounds (caffeic acid, protocatechuic acid, and p-hydroxybenzaldehyde), flavonoids, steroids, and fatty acid compounds exert anti-proliferative effects in the cell model. Finally, it was shown that cell growth and cell cycle arrest most significantly occurred in the in G1 or G2/M phase under ATE-EA treatment. Collectively, our results demonstrate an antiproliferative effect of ATE-EA on endometrial cancer cells that suggest a positive health outcome for women from consumption of these compounds.
- Published
- 2021
48. Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction
- Author
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Hong Jiang, Ye Zhang, Xian-Li Ma, Jian-Hua Wei, Haoran Wang, and Cai-Na Jiang
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Magnetic Resonance Spectroscopy ,Cell cycle checkpoint ,DNA damage ,Pharmaceutical Science ,Antineoplastic Agents ,010402 general chemistry ,01 natural sciences ,Piperazines ,Ruthenium ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,Mice ,dithiocarbamate ,Downregulation and upregulation ,lcsh:Organic chemistry ,Coordination Complexes ,Thiocarbamates ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,antitumor activity ,Physical and Theoretical Chemistry ,chemistry.chemical_classification ,Cisplatin ,Reactive oxygen species ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,apoptosis ,ruthenium polypyridyl complexes ,Cell Cycle Checkpoints ,Cell cycle ,Xenograft Model Antitumor Assays ,0104 chemical sciences ,Drug Resistance, Neoplasm ,Chemistry (miscellaneous) ,Cell culture ,Apoptosis ,cell cycle arrest ,Cancer research ,Molecular Medicine ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.
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- 2021
49. Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1H)-thiones
- Author
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Tomasz J. Idzik, Jacek G. Sośnicki, Marek Droździk, Gabriela Maciejewska, Katarzyna Piotrowska, Łukasz Skalski, Magdalena Perużyńska, Łukasz Struk, Aleksandra Borzyszkowska-Ledwig, Mateusz Kurzawski, and Paweł Łukasik
- Subjects
0301 basic medicine ,Cell cycle checkpoint ,dihydropyridine ,colchicine-binding site ,01 natural sciences ,tubulin inhibitors ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,anticancer agents ,Therapeutic index ,medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Mitosis ,IC50 ,lcsh:QH301-705.5 ,Spectroscopy ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Dihydropyridine ,General Medicine ,0104 chemical sciences ,Computer Science Applications ,Spindle apparatus ,030104 developmental biology ,Biochemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Apoptosis ,mitotic spindle ,Cancer cell ,medicine.drug - Abstract
Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog (S1) were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1H)-thione (S22) with promising antiproliferative activity (IC50 equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely S1, S19 and S22 showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.
- Published
- 2021
50. Synthesis of MeON-Glycoside Derivatives of Oleanolic Acid by Neoglycosylation and Evaluation of Their Cytotoxicity Against Selected Cancer Cell Lines
- Author
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Xiaoyang Zhou, Jian Zhang, Zhichao Du, and Guolong Li
- Subjects
Glycosylation ,Cell cycle checkpoint ,antiproliferation ,Pharmaceutical Science ,Antineoplastic Agents ,Chemistry Techniques, Synthetic ,anticancer ,Resting Phase, Cell Cycle ,01 natural sciences ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,oleanolic acid ,lcsh:Organic chemistry ,Drug Discovery ,neoglycosides ,Humans ,Glycosides ,Physical and Theoretical Chemistry ,Cytotoxicity ,Oleanolic acid ,Cell Proliferation ,chemistry.chemical_classification ,010405 organic chemistry ,Organic Chemistry ,apoptosis ,Glycoside ,Hep G2 Cells ,G1 Phase Cell Cycle Checkpoints ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,chemistry ,Chemistry (miscellaneous) ,Apoptosis ,Cell culture ,Cancer cell ,Cancer research ,Molecular Medicine - Abstract
A series of C-3 and C-28 MeON-neoglycosides of oleanolic acid were designed and synthesized by neoglycosylation as potential antiproliferative agents. Their cytotoxicity was evaluated in vitro against five human cancer cell lines: human non-small cell lung cancer cell line (A549), human melanoma cell line (A375), human colon cancer cell line (HCT116), human liver carcinoma cell line (HepG2), human breast adenocarcinoma cell line (MCF-7) by the Cell Counting Kit-8 (CCK-8) assay. Most of C-3 and C-28 MeON-neoglycosides of oleanolic acid exhibited notably inhibitory effects against the tested cancer cells and more sensitive to HepG2 cells than 5-Fluorouracil (5-FU). Structure-activities relationship (SAR) analysis revealed that sugar types and the d/l configuration of sugars would significantly affect their antiproliferative activities of neoglycosides. Among them, compound 8a (28-N-methoxyaminooleanane-β-d-glucoside) exhibited the most potent antiproliferative activities against HepG2 cells with IC50 values of 2.1 µM. Further pharmacological experiments revealed that compound 8a could cause morphological changes and cell cycle arrest at G0/G1 phase and induce apoptosis in HepG2 cells. These results suggested that neoglycosylation could provide a rapid strategy for the discovery of potential antiproliferative agents and their possible pharmacological mechanisms need more further research.
- Published
- 2021
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