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Chinese hamster ovary (CHO) cells represent the most preferential host cell system for therapeutic monoclonal antibody (mAb) production. Enhancing mAb production in CHO cells can be achieved by adding chemical compounds that regulate the cell cycle and cell survival pathways. This study investigated the impact of ectoine supplementation on mAb production in CHO cells. The results showed that adding ectoine at a concentration of 100 mM on the 3 rd day of cultivation improved mAb production by improving cell viability and extending the culture duration. RNA sequencing analysis revealed differentially expressed genes associated with cell cycle regulation, cell proliferation, and cellular homeostasis, in particular promotion of cell cycle arrest, which was then confirmed by flow cytometry analysis. Ectoine-treated CHO cells exhibited an increase in the number of cells in the G0/G1 phase. In addition, the cell diameter was also increased. These findings support the hypothesis that ectoine enhances mAb production in CHO cells through mechanisms involving cell cycle arrest and cellular homeostasis. Overall, this study highlights the potential of ectoine as a promising supplementation strategy to enhance mAb production not only in CHO cells but also in other cell lines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A series of novel 4-alkylthio-2-chloro-5-[(2-arylmethylidene)hydrazinecarbonyl]benzenesulfonamide derivatives 3-22 were synthesized and evaluated for their inhibitory activity against human carbonic anhydrase isozymes hCA I, hCA II, hCA IX, and hCA XII. These compounds showed varying degrees of activity against the studied isoenzymes. However, the importance of substituent choice in designing potent carbonic anhydrase inhibitors is highlighted by the strong inhibition profiles of compounds 3 and 10 against hCA IX and the low average K I values for compounds 9 and 10 (134 nM and 77 nM, respectively). All the synthesized compounds were evaluated for their antiproliferative activity toward HeLa, HCT-116, and MCF-7 cell lines. Compounds 9 and 19 exhibited significant activity, particularly against the MCF-7 cell line (IC 50 values of 4 μM and 6 μM, respectively). Notably, compound 9 demonstrated a high selectivity index (SI = 8.2) for MCF-7 cells. The antiproliferative effects of compounds 9 and 19 were linked to the induction of cell cycle arrest and apoptosis via the mitochondrial pathway and involved the activation of the MAPK/ERK signaling pathway. Inhibition of MAPK/ERK activity reduced the compounds' ability to induce cell cycle arrest and apoptosis, indicating the critical role of this pathway. These findings suggest that compounds 9 and 19 are promising candidates for further development as specific and potent anticancer agents targeting the MAPK/ERK pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Medical University of Gdansk. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options. This study explores the potential of novel 5-nitro-thiophene-thiosemicarbazone derivatives as therapeutic agents for PDAC., Methods: We evaluated the cytotoxicity of seven derivatives in peripheral blood mononuclear cells (PBMCs) and PDAC cell lines. Promising candidates (PR12 and PR17) were further analyzed for their effects on colony formation, cell cycle progression, and reactive oxygen species (ROS) production. PR17, the most promising derivative, was subjected to additional investigation, including analysis of autophagy-related genes and protein kinase inhibition., Results: Three derivatives (PR16, PR19, and PR20) displayed cytotoxicity towards PBMCs. PR12 reduced colony formation and G0/G1 cell cycle arrest in PDAC cells. Notably, PR17 exhibited potent activity in MIA PaCa-2 cells, inducing S-phase cell cycle arrest, downregulating autophagy genes, and inhibiting key protein kinases., Conclusion: PR17, a 5-nitro-thiophene-thiosemicarbazone derivative, demonstrates promising antineoplastic activity against PDAC cells by potentially modulating cell cycle progression, autophagy, and protein kinase signaling. Further studies are warranted to elucidate the detailed mechanism of action and explore its efficacy in vivo., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Recent research found artesunate could inhibit ocular fibrosis; however, the underlying mechanisms are not fully known. Since the ocular fibroblast is the main effector cell in fibrosis, we hypothesized that artesunate may exert its protective effects by inhibiting the fibroblasts proliferation. TGF-β1-induced ocular fibroblasts and glaucoma filtration surgery (GFS)-treated rabbits were used as ocular fibrotic models. Firstly, we analyzed fibrosis levels by assessing the expression of fibrotic marker proteins, and used Ki67 immunofluorescence, EdU staining, flow cytometry to determine cell cycle status, and SA-β-gal staining to assess cellular senescence levels. Then to predict target genes and pathways of artesunate, we analyzed the differentially expressed genes and enriched pathways through RNA-seq. Western blot and immunohistochemistry were used to detect the pathway-related proteins. Additionally, we validated the dependence of artesunate's effects on HO-1 expression through HO-1 siRNA. Moreover, DCFDA and MitoSOX fluorescence staining were used to examine ROS level. We found artesunate significantly inhibits the expression of fibrosis-related proteins, induces cell cycle arrest and cellular senescence. Knocking down HO-1 in fibroblasts with siRNA reverses these regulatory effects of artesunate. Mechanistic studies show that artesunate significantly inhibits the activation of the Cyclin D1/CDK4-pRB pathway, induces an increase in cellular and mitochondrial ROS levels and activates the Nrf2/HO-1 pathway. In conclusion, the present study identifies that artesunate induces HO-1 expression through ROS to activate the antioxidant Nrf2/HO-1 pathway, subsequently inhibits the cell cycle regulation pathway Cyclin D1/CDK4-pRB in an HO-1-dependent way, induces cell cycle arrest and senescence, and thereby resists periorbital fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background/aim: Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Standard treatment options include surgery, radiation therapy, chemotherapy, and targeted therapies. Despite advancements over the past 25 years, the prognosis of patients with lung cancer remains poor. This study evaluated the synergistic anticancer effects of fenbendazole (FZ) and diisopropylamine dichloroacetate (DADA) on A549 lung cancer cells., Materials and Methods: Fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is a broad-spectrum benzimidazole anthelmintic commonly used in veterinary medicine. Diisopropylamine Dichloroacetate (DADA), an over-the-counter treatment for chronic liver disease, has demonstrated anti-tumor properties as an inhibitor of pyruvate dehydrogenase kinase., Results: The combination of FZ and DADA exhibited a synergistic effect on inhibiting the proliferation of A549 lung cancer cells. After 48 h of treatment, the FZ-DADA combination produced reactive oxygen species (ROS) and promoted apoptosis by down-regulating Bcl2 and up-regulating BAX protein expression. The combination activated caspase-3, caspase-7, and PARP, further driving apoptosis in A549 cells. The FZ-DADA treatment also induced cell cycle arrest, as evidenced by the inhibition of Cyclin A and Cyclin E proteins., Conclusion: The synergistic anticancer effects of the FZ-DADA combination were confirmed at both cellular and protein levels in A549 lung cancer cells. The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production, suggesting a promising approach for lung cancer treatment that warrants further investigation and development., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Breast cancer is the most prevalent cancer among women worldwide, characterized by a high mortality rate and propensity for metastasis. Although surgery is the standard treatment for breast cancer, there is still no effective method to inhibit tumor metastasis and improve the prognosis of patients with breast cancer after surgery. Propofol, one of the most widely used intravenous anesthetics in surgery, has exhibited a positive association with improved survival outcomes in patients with breast cancer post‑surgery. However, the underlying molecular mechanism remains to be elucidated. The present study revealed that triple negative breast cancer cells, MDA‑MB‑231 and 4T1, exposed to propofol exhibited a significant decrease in cell viability. Notably, propofol exhibited minimal cytotoxic effects on HUVECs under the same conditions. Furthermore, propofol significantly inhibited the migration and invasion ability of MDA‑MB‑231 and 4T1 cells. Propofol promoted apoptosis in 4T1 cells through upregulation of Bax and cleaved caspase 3, while downregulating B‑cell lymphoma‑extra large. Concomitantly, propofol induced cell cycle arrest of 4T1 cells by downregulating cyclin E2 and phosphorylated cell division cycle 6. Furthermore, propofol exhibited excellent anticancer efficacy in a 4T1 breast cancer allograft mouse model. The present study sheds light on the potential of propofol as an old medicine with a novel use for breast cancer treatment.

Four lanthanide complexes with 8-hydroxyquinoline-2-aldehyde-2-hydrazinopyridine (H-L 1 ), 8-hydroxyquinoline-2-aldehyde-2-hydrazimidazole (H-L 2 ): [Sm(L 1 ) 2 ][Sm(L 1 )(NO 3 ) 3 ]·CHCl 3 ·2CH 3 OH (1), [Gd(L 1 ) 2 ][Gd(L 1 )(NO 3 ) 3 ]·CHCl 3 ·2CH 3 OH (2), [Sm(L 2 )(NO 3 ) 2 ] 2 ·CH 3 OH (3), and [Eu(L 2 )(NO 3 ) 2 ] 2 ·CH 3 OH (4) were synthesized and characterized. In vitro cytotoxicity evaluation showed that the ligands and four lanthanide complexes exhibited cytotoxicity to the five tested tumor cell lines. Among them, complex 1 showed the best antiproliferative activity against NCI-H460 tumor cells. Mechanistic studies demonstrated that complex 1 arrested the cell cycle of NCI-H460 cells in G1 phase and induced mitochondria-mediated apoptosis, which resulted in the loss of mitochondrial membrane potential, enhanced intracellular Ca 2+ levels and reactive oxygen species generation. In addition, complex 1 affected the expression levels of intracellular apoptosis-related proteins and activated the caspase-3/9 in NCI-H460 cells. Therefore, complex 1 is a potential anticancer agent., (© 2024 Wiley Periodicals LLC.)

Ginkgolic acid (GA), isolated from the leaves and seed coats of Ginkgo biloba , exerts several biological effects, including antitumor, antibacterial, anti‑HIV and anti‑inflammatory effects. However, the effects of GA on C2C12 myoblasts remain unclear. The present study assessed cell viability with the MTT assay and evaluated colony formation through crystal violet staining. Flow cytometry was used to analyze apoptosis with Annexin V/7‑AAD staining, proliferation with Ki67 staining and cell cycle arrest. Western blotting detected myogenic markers and other relevant proteins. Myotube formation was examined by immunofluorescence, and autophagy was measured using an LC3 antibody‑based kit via flow cytometry. The present study showed that treatment of C2C12 cells with GA significantly inhibited their viability and colony formation capacity but did not trigger apoptosis, as indicated by Annexin V/7‑AAD staining. However, Ki67 staining indicates that GA exerted dose‑dependent antiproliferative effects. Further analysis revealed that GA partially inhibited the growth of C2C12 cells via cell cycle arrest in S phase, highlighting its role in the disruption of cell proliferation. Furthermore, treatment with GA impaired myoblast differentiation, as evidenced by a reduction in the expression of the myogenesis markers, the myosin‑heavy chain, myoblast determination protein 1 and myogenin, and suppressed myotube formation. Notably, during C2C12 cell differentiation, GA promoted apoptosis without affecting cell cycle progression or Ki67 expression. Mechanistically, GA could suppress nuclear extracellular signal‑regulated kinase phosphorylation, suggesting that it modulates cell proliferation pathways. Moreover, GA triggered autophagy in differentiated C2C12 cells, as confirmed by elevated LC3 II levels. These findings highlight the multifaceted effects of GA on C2C12 cells.

Endometrial cancer (EC) is a common gynecological cancer worldwide, often associated with a poor prognosis after recurrence or metastasis. Ovatodiolide (OVA) is a macrocyclic diterpenoid derived from Anisomeles indica that shows anticancer effects in various malignancies. This study aimed to evaluate the cytotoxic effects of OVA on EC cell proliferation and cancer stem cell (CSC) activity and explore its underlying molecular mechanisms. OVA treatment dose-dependently reduced the viability and colony formation of three EC cell lines (AN3CA, HEC-1A, and EMC6). It induced G2/M phase cell cycle arrest, associated with decreased cell division cycle 25C (CDC25C) expression and reduced activation of cyclin-dependent kinases 1 (CDK1) and 2 (CDK2). OVA also increased reactive oxygen species (ROS) production and DNA damage, activating the DNA damage-sensitive cell cycle checkpoint kinases 1 (CHK1) and 2 (CHK2) and upregulating the DNA damage marker γ-H2A.X variant histone (H2AX). It also suppressed the activation of mechanistic target of rapamycin kinase (mTOR) and nuclear factor kappa B (NF-κB) and downregulated glutathione peroxidase 1 (GPX1), an antioxidant enzyme counteracting oxidative stress. Moreover, OVA reduced the self-renewal capacity of CSCs, reducing the expression of key stemness proteins Nanog homeobox (NANOG) and octamer-binding transcription factor 4 (OCT4). The ROS inhibitor N-acetylcysteine attenuated the anti-proliferative and anti-CSC effects of OVA. Our findings suggest that OVA acts via ROS generation, leading to oxidative stress and DNA damage, culminating in cell cycle arrest and the suppression of CSC activity in EC. Therefore, OVA is a promising therapeutic agent for EC, either as a standalone treatment or an adjunct to existing therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC., Competing Interests: Declaration of Competing Interest I would like to declare that all authors have given their permission to submit this manuscript. Furthermore, there are no conflicts of interest exist in the submission of this manuscript, including financial and personal relationships that may affect our work. The manuscript is approved by all authors for publication. The research described in the manuscript is original and has not been published elsewhere, in whole or in part. All the authors listed have approved the manuscript is enclosed., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The Nile Tilapia (Oreochromis niloticus) evolved in warm, freshwater rivers, but possesses a broad physiological tolerance to a range of environmental conditions. Due to this hardiness and resilience, this species has been successfully introduced to regions widely outside of its native range. Here, we examine the impact of temperature and salinity variation on this species at the sub-lethal level. Specifically, Nile Tilapia were exposed to two temperatures (21 °C or 14 °C) and three salinities (0, 16, 34 ppt) for 1-h. Given their native habitat, the 21 °C / 0 ppt exposure was considered the control condition. Both cell cycle arrest and apoptosis represent sub-lethal but deleterious responses to environmental stress. Flow cytometry was used to assess the percentage of cells in a given stage of the cell cycle as a metric of cell cycle arrest in spleen and liver. Percentage of apoptotic cells were also quantified. Spleen was more sensitive to cold stress, demonstrating an increase in cells in the G2/M phase after experimental treatment. Liver, however, was more sensitive to salinity stress, with a significant increase in cells stalled in G2/M phase at higher salinities, which is in keeping with the freshwater evolutionary history of the species. A modest apoptotic signal was observed in liver but not in spleen. Together, these findings demonstrate that even short, acute exposures to cold temperatures and elevated salinity can cause sub-lethal damage in a species that is otherwise tolerant of environmental stress at the whole organism level., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The author is an Associate Editor for Comparative Biochemistry and Physiology but was not involved in the decision to publish this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb, PM) is a medicinal plant that was an element of traditional Chinese medicine (TCM) for centuries as a treatment for a wide range of conditions. Recent studies reported that PM suppressed prostate cancer growth in an AR-dependent manner. However, its role and mechanism in the treatment of advanced prostate cancer remain to be explored. This study aims to explore the anti-tumor role and potential mechanism of PM on prostate cancer., Methods: Cell viability, colony formation, fluorescence-activated cell sorting (FACS), and wound-healing assays were conducted to evaluate the tumor suppression effect of PM on lethal prostate cancer models in vitro. A xenograft mice model was established to detect the impact of PM on tumor growth and evaluate its biosafety in vivo. Integrative network pharmacology, RNA-seq, and bioinformatics were applied to determine the mechanisms of PM in prostate cancer. Molecular docking, cellular thermal shift assay (CETSA), CRISPR-Cas13, RT-qPCR, and WB were collaboratively employed to identify the potential anti-tumor ingredient derived from PM and its corresponding targets., Results: PM significantly suppressed the growth of prostate cancer and sensitized prostate cancer to AR antagonists. Mechanistically, PM induced G2/M-phase cell-cycle arrest by modulating the phosphorylation of CDK1. Additionally, polygalacic acid derived from PM and its structural analog suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDK1 phosphorylation., Conclusion: PM and its ingredient polygalacic acid suppress lethal prostate cancer growth by regulating the CDC25B-CDK1 axis to induce cell cycle arrest., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer., Methods: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo., Results: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G 0 /G 1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05)., Conclusion: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer., (© 2024. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: β,β-Dimethylacrylalkannin (DMAKN), a natural naphthoquinone found in Zicao, a traditional Chinese medicine (TCM), serves as the designated quantitative marker in the Chinese Pharmacopoeia. Despite its established role in assessing Zicao quality, DMAKN's biological potential remains underexplored in research., Methods: We investigated DMAKN's involvement in Zicao's anti-hepatocellular carcinoma (HCC) properties using a combination of HPLC content analysis and comprehensive bioinformatics. Subsequently, both in vitro and in vivo experiments were conducted to evaluate DMAKN's efficacy against HCC. Mechanistic investigations focused on elucidating DMAKN's impact on cell cycle regulation and induction of cell death., Results: Integrated HPLC analysis and bioinformatics identified DMAKN as the primary active compound responsible for Zicao's anti-HCC activity. In vitro and in vivo studies confirmed DMAKN's potent efficacy against HCC. Notably, DMAKN demonstrated dual effects on HCC cells: inhibiting proliferation at lower doses and inducing rapid cell death at higher doses. Mechanistic insights revealed that low-dose DMAKN induced G2/M phase cell cycle arrest through modulation of CDK1 and Cdc25C phosphorylation, while high-dose DMAKN triggered necrosis. Importantly, high-dose DMAKN caused a sharp increase in intracellular ROS levels in a short time, while low-dose DMAKN gradually increased ROS levels over a long period. Additionally, low-dose DMAKN-induced ROS activated the JNK pathway, crucial for cell cycle arrest, whereas high-dose DMAKN-induced necrosis was ROS-dependent but JNK-independent., Conclusion: This study underscores DMAKN's pivotal role as the principal anti-HCC compound in Zicao, delineating its differential effects and underlying mechanisms. These results demonstrate the potential of DMAKN as a therapeutic agent for the treatment of HCC, providing important information for further study and advancement in cancer therapy., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Triphenylphosphine substitution reactions of [RuCl(PPh 3 ) 2 (tpm)]Cl, 1, featuring tris(pyrazolyl)methane (tpm) as ligand, with the chlorambucil-decorated pyridine ligand Py CA , 3-aminopyridine (Py NH2 ) and 4-pyridinemethanol (Py OH ) afforded the corresponding pyridine complexes 2-4 in high yields. Py CA was preliminarily obtained via esterification of 4-pyridinemethanol with chlorambucil. The new compounds Py CA and 2-3 were characterized by IR and multinuclear NMR spectroscopy. Additionally, the structure of 3 was ascertained by single crystal X-ray diffraction. The in vitro anti-proliferative activity of 2-4 and Py CA was determined against a panel of cancer cell lines, outlining 2 as the most performing compound. Targeted studies were subsequently undertaken using 2 to elucidate mechanistic aspects, including the assessment of ruthenium cellular uptake, cell cycle arrest, production of reactive oxygen species (ROS), western blotting and DNA damage (comet test). Overall, data highlight that the anticancer activity provided by 2 primarily affects the mitochondria pathway with a potential additional contribution from DNA damage., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Prostate cancer remains a major public health burden worldwide. Polo like kinase 4 (PLK4) has emerged as a promising therapeutic target in prostate cancer due to its key roles in cell cycle regulation and tumour progression. This study aims to develop and characterize the novel curcumin analogue NL13 as a potential therapeutic agent and PLK4 inhibitor against prostate cancer., Experimental Approach: NL13 was synthesized and its effects were evaluated in prostate cancer cells and mouse xenograft models. Kinome screening and molecular modelling identified PLK4 as the primary target. Antiproliferative and proapoptotic mechanisms were explored via cell cycle, apoptosis, gene and protein analyses., Key Results: Compared with curcumin, NL13 exhibited much greater potency in inhibiting PC3 (IC 50 , 3.51 μM vs. 35.45 μM) and DU145 (IC 50 , 2.53 μM vs. 29.35 μM) prostate cancer cells viability and PLK4 kinase activity (2.32 μM vs. 246.88 μM). NL13 induced G2/M cell cycle arrest through CCNB1/CDK1 down-regulation and triggered apoptosis via caspase-9/caspase-3 cleavage. These effects were mediated by PLK4 inhibition, which led to the inactivation of the AKT signalling pathway. In mice, NL13 significantly inhibited tumour growth and modulated molecular markers consistent with in vitro findings, including decreased p-AKT and increased cleaved caspase-9/3., Conclusion and Implications: NL13, a novel PLK4-targeted curcumin analogue, exerts promising anticancer properties against prostate cancer by disrupting the PLK4-AKT-CCNB1/CDK1 and apoptosis pathways. NL13 represents a promising new agent for prostate cancer therapy., (© 2024 British Pharmacological Society.)

Several clinical trials have been conducted to evaluate the use of flavopiridol (FP) to treat a variety of cancers, and almost all cancer drugs were found to be associated with toxicity and side effects. It is not clear whether the use of FP will affect the female reproductive system. Granulosa cells, as the important cells that constitute the follicle, play a crucial role in determining the reproductive ability of females. In this study, we investigated whether different concentrations of FP have a toxic effect on the growth of immortalized human ovarian granulosa cells. The results showed that FP had an inhibitory effect on cell proliferation at a level of nanomole concentration. FP reduced cell proliferation and induced apoptosis by inducing mitochondrial dysfunction and oxidative stress, as well as increasing BAX/BCL2 and pCDK1 levels. These results suggest that toxicity to the reproductive system should be considered when FP is used in clinical applications., (© 2024. The Author(s).)

Prorocentrin-5 ( 1 ) was isolated from the benthic marine dinoflagellate Prorocentrum lima . A combination of NMR spectroscopy, quantum chemical calculations, and chemical reactions was then employed to elucidate its molecular structure, including the configurations of all stereogenic centers. In cytotoxicity assays, prorocentin-5 exhibited potent activity against the HCT-116 and Neuro2a cell lines, with IC 50 values of 4.4 and 2.8 μM, respectively. Furthermore, 1 increased the apoptotic cell population and induced cell cycle arrest, leading to the accumulation of cells in the S or G2/M phase and an accompanying decrease in the G0/G1 phase in HCT-116, Neuro2a, and HepG2 cells.

As one of the most common malignancies, colorectal cancer (CRC) usually starts with a benign lesion and accumulates DNA damage as it progresses to full-fledged cancer. Glycyrrhizin (GL) has been found to alleviate tumor growth and inflammation, while the role of GL influences DNA damage response (DDR) in colorectal cancer remains unclear. GL exposure significantly reduced cell colony formation and viability with a concomitant increase in DNA fragmentation in CRC, meanwhile GL induced apoptosis by activating caspase-3. Moreover, GL induced cell cycle arrest in CRC cells at S phase, which was associated with decreased cyclin D1 in vitro. GL treatment significantly ameliorated tumor growth and promoted DDR in vivo. Mechanism analysis revealed that GL significantly downregulated the NHEJ pathway via inhibiting HMGB1. Finally, the expression of HMGB1 was abnormal regulated in CRC tissue than in adjacent normal tissues and associated with TNM stage and overall survival. Our findings indicate that HMGB1 may be a novel therapeutic target in CRC, a result that GL may serve as a promising drug for CRC treatment., (© 2024. The Author(s).)

Breast cancer is the most prevalent form of cancer in women worldwide. Triple-negative breast cancer is the most unfavorable for patients, but it is also the most sensitive to chemotherapy. Triterpene glycosides from sea cucumbers possess a high therapeutic potential as anticancer agents. This study aimed to identify the pathways triggered and regulated in MDA-MB-231 cells (triple-negative breast cancer cell line) by the glycosides cucumarioside A 0 -1 (Cuc A 0 -1) and djakonovioside A (Dj A), isolated from the sea cucumber Cucumaria djakonovi . Using flow cytometry, fluorescence microscopy, immunoblotting, and ELISA, the effects of micromolar concentrations of the compounds on cell cycle arrest, induction of apoptosis, the level of reactive oxygen species (ROS), mitochondrial membrane potential (Δψm), and expression of anti- and pro-apoptotic proteins were investigated. The glycosides caused cell cycle arrest, stimulated an increase in ROS production, and decreased Δψm in MDA-MB-231 cells. The depolarization of the mitochondrial membrane caused by cucumarioside A 0 -1 and djakonovioside A led to an increase in the levels of APAF-1 and cytochrome C. This, in turn, resulted in the activation of caspase-9 and caspase-3 and an increase in the level of their cleaved forms. Glycosides also affected the expression of Bax and Bcl-2 proteins, which are associated with mitochondria-mediated apoptosis in MDA-MB-231 cells. These results indicate that cucumarioside A 0 -1 and djakonovioside A activate the intrinsic apoptotic pathway in triple-negative breast cancer cells. Additionally, it was found that treatment with Cuc A 0 -1 resulted in in vivo inhibition of tumor growth and metastasis of murine solid Ehrlich adenocarcinoma.

Background: Cancer-associated fibroblasts (CAFs), mainly responsible for the desmoplastic reaction hallmark of intrahepatic Cholangiocarcinoma (iCCA), likely have a role in tumor aggressiveness and resistance to therapy, although the molecular mechanisms involved are unknown. Aim of the study is to investigate how targeting hCAF/iCCA cross-talk with a Notch1 inhibitor, namely Crenigacestat, may affect cancer progression., Methods: We used different in vitro models in 2D and established new 3D hetero-spheroids with iCCA cells and human (h)CAFs. The results were confirmed in a xenograft model, and explanted tumoral tissues underwent transcriptomic and bioinformatic analysis., Results: hCAFs/iCCA cross-talk sustains increased migration of both KKU-M213 and KKU-M156 cells, while Crenigacestat significantly inhibits only the cross-talk stimulated migration. Hetero-spheroids grew larger than homo-spheroids, formed by only iCCA cells. Crenigacestat significantly reduced the invasion and growth of hetero- but not of homo-spheroids. In xenograft models, hCAFs/KKU-M213 tumors grew significantly larger than KKU-M213 tumors, but were significantly reduced in volume by Crenigacestat treatment, which also significantly decreased the fibrotic reaction. Ingenuity pathway analysis revealed that genes of hCAFs/KKU-M213 but not of KKU-M213 tumors increased tumor lesions, and that Crenigacestat treatment inhibited the modulated canonical pathways. Cell cycle checkpoints were the most notably modulated pathway and Crenigacestat reduced CCNE2 gene expression, consequently inducing cell cycle arrest. In hetero-spheroids, the number of cells increased in the G2/M cell cycle phase, while Crenigacestat significantly decreased cell numbers in the G2/M phase in hetero but not in homo-spheroids., Conclusions: The hCAFs/iCCA cross-talk is a new target for reducing cancer progression with drugs such as Crenigacestat., (© 2024. The Author(s).)

Replication stress describes endogenous and exogenous challenges to DNA replication in the S-phase. Stress during this critical process causes helicase-polymerase decoupling at replication forks, triggering the S-phase checkpoint, which orchestrates global replication fork stalling and delayed entry into G2. The replication stressor most often used to induce the checkpoint response in yeast is hydroxyurea (HU), a clinically used chemotherapeutic. The primary mechanism of S-phase checkpoint activation by HU has thus far been considered to be a reduction of deoxynucleotide triphosphate synthesis by inhibition of ribonucleotide reductase (RNR), leading to helicase-polymerase decoupling and subsequent activation of the checkpoint, facilitated by the replisome-associated mediator Mrc1. In contrast, we observe that HU causes cell cycle arrest in budding yeast independent of both the Mrc1-mediated replication checkpoint response and the Psk1-Mrc1 oxidative signaling pathway. We demonstrate a direct relationship between HU incubation and reactive oxygen species (ROS) production in yeast and human cells and show that antioxidants restore growth of yeast in HU. We further observe that ROS strongly inhibits the in vitro polymerase activity of replicative polymerases (Pols), Pol α, Pol δ, and Pol ε, causing polymerase complex dissociation and subsequent loss of DNA substrate binding, likely through oxidation of their integral iron-sulfur (Fe-S) clusters. Finally, we present "RNR-deg," a genetically engineered alternative to HU in yeast with greatly increased specificity of RNR inhibition, allowing researchers to achieve fast, nontoxic, and more readily reversible checkpoint activation compared to HU, avoiding harmful ROS generation and associated downstream cellular effects that may confound interpretation of results., Competing Interests: Competing interests statement:The authors declare no competing interest.

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells. CDK12/13 degradation rapidly triggers gene-length-dependent transcriptional elongation defects, leading to DNA damage and cell-cycle arrest. In vivo, YJ9069 significantly suppresses prostate tumor growth. Modifications of YJ9069 yielded an orally bioavailable CDK12/13 degrader, YJ1206, which exhibits comparable efficacy with significantly less toxicity. To identify pathways synthetically lethal upon CDK12/13 degradation, phosphorylation pathway arrays were performed using cell lines treated with YJ1206. Interestingly, degradation or genetic knockdown of CDK12/13 led to activation of the AKT pathway. Targeting CDK12/13 for degradation, in conjunction with inhibiting the AKT pathway, resulted in a synthetic lethal effect in preclinical prostate cancer models., Competing Interests: Declaration of interests A.M.C. is a co-founder and serves on the scientific advisory board of the following: Lynx Dx, Flamingo Therapeutics, Medsyn Pharma, Oncopia Therapeutics, and Esanik Therapeutics. A.M.C. serves as an advisor to Aurigene Oncology Limited, Proteovant, Tempus, RAPPTA, and Ascentage. K.D. serves as a scientific advisor of Kinoteck Therapeutics Co. Ltd, Shanghai, and has received financial support from Livzon Pharmaceutical Group, Zhuhai, China. The University of Michigan and the Shanghai Institute of Organic Chemistry have filed patents on the CDK12/13 degraders and inhibitors mentioned in this manuscript. A.M.C., K.D., X.W., J.Y., Y. Chang, and J.C.-Y.T. have been named as co-inventors on these patents., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

CRM1 (chromosomal region maintenance 1, also referred to as exportin 1 or XPO1) plays a crucial role in maintaining the appropriate nuclear levels of tumor suppressor proteins (TSPs), growth regulatory proteins (GRPs), and antiapoptotic proteins, thereby contributing significantly to their anticancer effects. Dysregulation of CRM1-mediated nuclear transport, observed in a range of cancers such as colon cancer as well as autoimmune diseases, highlights its significance in various disease processes. In this paper, we employed a customized structure-based virtual screening campaign to search for novel covalent CRM1 inhibitors and purchased 50 potentially active compounds for in vitro bioassays. Among these candidates, AN-988 displayed a notably higher binding affinity ( K D = 615 nM) toward CRM1, as determined by the biolayer interferometry (BLI) assay. Furthermore, AN-988 exhibited a strong suppression of colorectal cancer cell proliferation and remarkable anti-inflammatory effects. Notably, AN-988 induced cell apoptosis and cell cycle arrest in a time- and dose-dependent manner by effectively inhibiting the translocation of FOXO3a from the nucleus to the cytosol, thereby preserving the activity of FOXO3a. Collectively, our study identified AN-988 as a promising CRM1 inhibitor, underscoring its potential as a preclinical colon cancer therapy candidate.

Papillary thyroid cancer (PTC) is the 8th most common cancer among women overall. Licorice contains over 300 active compounds, many of them with anti-cancer properties. Glycyrrhetinic acid (GA) is a major component of licorice. The aim of this study was to investigate the potential anti-proliferative effects of licorice and GA on PTC cell cultures. Licorice extract (LE) was produced from the root and tested on BCPAP and K1 cell lines, as well as GA and aldosterone. We used the MTT test to investigate the anti-proliferative activity, the wound healing test for the migratory activity, and finally, we analyzed cell cycle distribution, apoptosis, and oxidative stress after LE, GA, or aldosterone incubation. Both LE and GA reduced cell viability at 48 h and cell migration at 24 h in both PTC cultures. Aldosterone reduced cell migration only in K1 cells. LE and GA induced cell cycle arrest in the G0/G1 phase in the BCPAP cell line, while LE and aldosterone induced it in the K1 culture. GA but not LE increased the apoptosis rate in both cell lines, whereas LE but not GA increased oxidative stress in both cultures. This study presents the first evidence of the in vitro anti-proliferative and anti-migratory activity of LE and GA on PTC.

Breast cancer is the predominant form of cancer among women and ranks as the second most prevalent cancer globally, affecting both developed and less developed countries. Presently, accessible cancer treatment methods either employ recently created, secure, and efficient chemotherapeutic medications or directly target innovative pathways that cause apoptosis. One of the indirect strategies for treating this fatal illness has mostly depended on its essential role in cell cycle arrest and apoptosis induction, as well as the antagonistic interaction between the Bcl-2 and Mcl-1 proteins, in order to avert major health repercussions. We reported that newly synthesized fused chromenopyrimidines ( 3a and 4a ) showed potential cell cycle arrest and dual Bcl-2 and Mcl-1 inhibitory characteristics. Bcl-2 and Mcl-1 were the targets of a molecular docking procedure. The previous docking results are in line with the biological data and suggest that 3a may have promising anti-cancer activity.

Retinoblastoma is one of the most common primary intraocular malignancies in young children. Traditional treatment methods such as chemotherapy often come with significant adverse effects, such as hearing loss, cognitive impairment, and vision loss. Therefore, there is an urgent need to explore a novel therapeutic drug that is both effective and safe. S-adenosylmethionine (SAM) is a natural compound known to exhibit anti-proliferative effects in various cancer cell lines. However, to date, no studies investigated the effects of SAM on retinoblastoma cells and its potential mechanisms of action. Therefore, this study aims to investigate the impact of SAM on retinoblastoma cells and explore its possible mechanisms of action, with the hope of providing new insights into the treatment of this disease. The optimal concentration of SAM was determined using the Cell Counting Kit-8 assay. The effect of SAM on retinoblastoma proliferation was assessed using the 5-ethynyl-2'-deoxyuridine cell proliferation assay. Y79 cells were subjected to hematoxylin and eosin stain and electron microscopy to observe any morphological changes induced by SAM. The stages of SAM's action on the retinoblastoma cell cycle and its apoptotic effects were measured using flow cytometry. The apoptotic effect of SAM on retinoblastoma was further confirmed using the TUNEL assay. Differential expression of related genes was detected through RT-PCR. In vivo subcutaneous tumor formation in nude mice and immunohistochemistry were employed to validate the effect of SAM on retinoblastoma-related phenotypes. Western blotting was conducted to investigate whether SAM modulated retinoblastoma-related phenotypes via the Wnt2/β-catenin pathway. SAM arrested the cell cycle of retinoblastoma at the G1 phase, induced apoptosis of retinoblastoma cells through the Wnt2/β-catenin pathway, and affected their morphology and even ultrastructure. In addition, in vitro and in vivo experiments demonstrated that SAM had an oncogenic effect on retinoblastoma. In this study, we verify in vitro and in vivo whether SAM inhibits the proliferation of retinoblastoma cell Y7, induces apoptosis and cell cycle arrest of Y79 cells by inhibiting the Wnt2/β-catenin pathway, and affects the morphology and structure of retinoblastoma cell Y79., (© 2024 Mushi Liu et al., published by Sciendo.)

Objective: This study aimed to design and evaluate the efficacy of pyrrolidone derivatives as potential therapeutic agents against diffuse large B-cell lymphoma (DLBCL), a common and heterogeneous malignancy of the adult lymphohematopoietic system. Given the limitations of current therapies, there is a pressing need to develop new and effective drugs for DLBCL treatment., Methods: A series of pyrrolidone derivatives were synthesized, and their antitumor activities were assessed, particularly against DLBCL cell lines. Structure-activity relationship (SAR) analysis was conducted to identify key structural components essential for activity. The most promising compound, referred to as compound 7, was selected for further mechanistic studies. The expression levels of relevant mRNA and protein were detected by RT-qPCR and Western blotting, and the expression of mitochondrial membrane potential and ROS was detected using flow cytometry for further assessment of cell cycle arrest and apoptosis., Results: The compound 7 exhibited good antitumor activity among the synthesized derivatives, specifically in DLBCL cell lines. SAR analysis highlighted the critical role of α, β-unsaturated ketones in the antitumor efficacy of these compounds. Mechanistically, compound 7 was found to induce significant DNA damage, trigger an inflammatory response, cause mitochondrial dysfunction, and disrupt cell cycle progression, ultimately leading to apoptosis of DLBCL cells., Conclusion: The compound 7 has good antitumor activity and can induce multiple cellular mechanisms leading to cancer cell death. These findings warrant further investigation of the compound 7 as a potential therapeutic agent for DLBCL., (© 2024. Huazhong University of Science and Technology.)

Core binding factor acute myeloid leukemia (CBF-AML) stands out as the most common type of adult AML, characterized by specific chromosomal rearrangements involving CBF genes, particularly t(8;21). Shikonin (SHK), a naphthoquinone phytochemical widely employed as a food colorant and traditional Chinese herbal medicine, exhibits antioxidant, anti-inflammatory, and anti-cancer activities. In this study, we aim to investigate the antileukemic effects of SHK and its underlying mechanisms in human CBF-AML cells and zebrafish xenograft models. Our study revealed that SHK reduced the viability of CBF-AML cells. SHK induced cell cycle arrest, promoted cell apoptosis, and induced differentiation in Kasumi-1 cells. Additionally, SHK downregulated the gene expression of AML1-ETO and c-KIT in Kasumi-1 cells. In animal studies, SHK showed no toxic effects in zebrafish and markedly inhibited the growth of leukemia cells in zebrafish xenografts. Transcriptomic analysis showed that differentially expressed genes (DEGs) altered by SHK are linked to key biological processes like DNA repair, replication, cell cycle regulation, apoptosis, and division. Furthermore, KEGG pathways associated with cell growth, such as the cell cycle and p53 signaling pathway, were significantly enriched by DEGs. Analysis of AML-associated genes in response to SHK treatment using DisGeNET and the STRING database indicated that SHK downregulates the expression of cell division regulators regarding AML progression. Finally, we found that SHK combined with cytarabine synergistically reduced the viability of Kasumi-1 cells. In conclusion, our findings provide novel insights into the mechanisms of SHK in suppressing leukemia cell growth, suggesting its potential as a chemotherapeutic agent for human CBF-AML., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Triple Negative Breast cancer is an aggressive breast cancer subtype. It has a more aggressive clinical course, an earlier age of onset, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments however remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60-88 % of TNBC, translating p53 into the clinical situation is particularly important in TNBC. In this study, we screened and evaluated the therapeutic potential of cryptolepine (CRP) in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic targeting TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported before., Methods: MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate the cryptolepine's effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis mechanism. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay., Results: In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism by which cryptolepine induces intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability, hence activating its tumor suppressing potential significantly., Conclusion: Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability., Competing Interests: Declaration of Competing Interest We all the authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Pharmacological properties of flavonoids have been reported, with an anticancer role amongst them, however, its mechanisms are not fully elucidated. In this study, the activity of quercetin and chrysin towards MCF-7 and MDA-MB-231 breast cancer cells was investigated. Cellular viability was determined after treatment with the compounds in different concentrations for 24 h. Secondly, cells were treated with fixed concentration of chrysin and different concentrations of quercetin with preincubation for 1 h. Both compounds inhibited cellular proliferation in dose-dependent manner. The association showed improvement in their cytotoxicity, more expressively with preincubation of quercetin. Quercetin and chrysin association induced cell cycle arrest in sub-G0/G1 phase in MDA-MB-231 cells, modified the expression of caspases-3 and -8,-8, inducing late apoptosis cell death. Taken together, our results demonstrate that both flavonoids inhibited cells growth in a dose-dependent manner and the association of quercetin improved chrysin's toxic effect over the cell lines., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

One unreported flavonol namely morin-7- O -methyl ether ( 1 ) along with seven known compounds were isolated from the aerial parts of Trifolium vesiculosum Savi which were elucidated by using extensive spectroscopic methods such as 1D and 2D NMR and HR-MS. According to the cell viability assay (MTS) on the purified compounds ( 1 - 8 ), quercetin-3- O -(6''- trans - p -coumaroyl)- β -galactoside ( 4 ) revealed remarkable antiproliferative activity most particularly against breast cancer cells (IC 50  = 2.90 ± 0.25 µM in HCC1937 and 7.98 ± 0.57 µM in MCF7) while moderate inhibitory activity (IC 50  = 17.96 ± 0.51-51.70 ± 2.69 µM) on prostate, colorectal and liver cancer cell viability was observed. Further mechanistic examinations (Annexin V/PI staining, DNA content and detection of reactive oxygen species analyses) showed that compound 4 significantly induced apoptosis, enhanced mitochondrial reactive oxygen species (ROS) accumulation, and caused cell cycle arrest in cancer cells by increasing accumulation of cells at G 0 /G 1 and/or G 2 /M phases of the cell cycle.

Background: Recent 23 Na-MRI reports show higher salt deposition in malignant breast tissue than in surrounding normal tissue. The effect of high salt on cancer progression remains controversial. Here, we investigated the direct effect of high salt on breast cancer progression in vitro., Methods: Here, the impact of high salt on apoptosis, proliferation, cell cycle, adhesion, and migration of MDA-MB-231 and MCF-7 cells was studied using MTT, scratch, and clonogenic assays, as well as RT-PCR and flow cytometry. Gene expression was analyzed using Real-Time PCR and western blotting. The effect of high salt on global transcriptomics changes in MDA MB-231 cells was studied using RNA-sequencing analysis., Results: Flow cytometry with Annexin V and CFSE revealed that high salt-induced dose-dependent apoptosis and inhibited proliferation. High salt-induced cell cycle arrest at the G1/S phase of the cell cycle. p-MDM2 is known to suppress p53, which plays a crucial role in regulating apoptosis and cell cycle arrest under cellular stress conditions. High salt treatment led to decreased p-MDM2 and increased p53 expression, suggesting that high salt induces apoptosis through p53 stabilization. decreased p-MDM2 and increased p53 expression. High salt also reduced migration and adhesion of cells in a dose-dependent manner suggesting its inhibitory effect on metastatic properties as evident from wound healing assay. RNA sequencing analysis revealed overexpression of tumor suppressor genes and genes associated with anti-tumor activity (PCDHGA11, EIF3CL, RAVER1, TNFSF15, RANBP3L) and under-expression of genes involved in cancer-promoting activity (MT1X, CLDN14, CSF-2)., Conclusion: Our results unequivocally demonstrate the anti-tumor efficacy of high salt against breast cancer cells, suggesting its potential as a therapeutic strategy in cancer treatment., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Tumor cells invade normal surrounding tissues through continuous division. In this study, we hypothesized that cell cycle regulation changes the immune efficacy of ovarian cancer. To investigate this hypothesis, a Förster resonance energy transfer (FRET) sensor was constructed to characterize the cell activity in real time. Cell shrinkage caused by apoptosis induces the aggregation of proteins on the cell membrane, leading to variations in the fluorescence lifetime of FRET sensors. Moreover, we tracked cell activity across various cycles following co-culture with an immune checkpoint inhibitor. Consequently, we assessed how cell cycle regulation influences immunotherapy in a tumor mouse model. This approach, which involves inhibiting typical cell cycle processes, markedly enhances the effectiveness of immunotherapy. Our findings suggest that modulating the cycle progression of cancer cells may represent a promising approach to enhance the immune response of ovarian cancer cells and the efficacy of immunotherapy based on immune checkpoint inhibitors.

Background: Mini-chromosome maintenance protein 2 (MCM2) is a potential target for the development of cancer therapeutics. However, small molecule inhibitors targeting MCM2 need further investigation., Methods: Molecular dynamics simulation was performed to identify active pockets in the MCM2 protein structure (6EYC). The active pocket was used as a docking model to discover MCM2 inhibitors by using structure-based virtual screening and surface plasmon resonance (SPR) assay. Furthermore, the efficacy of pixantrone targeting MCM2 in ovarian cancer was evaluated in vitro and in vivo., Results: Pixantrone was identified as a novel inhibitor of MCM2 by virtual screening. SPR binding affinity analysis confirmed the direct binding of pixantrone to MCM2 protein. Pixantrone significantly reduced the viability of ovarian cancer cells A2780 and SKOV3 in a dose- and time-dependent manner. In addition, pixantrone inhibited DNA replication, and induced cell cycle arrest and apoptosis in ovarian cancer cells via targeting MCM2. Knockdown of MCM2 could attenuate the inhibitory activity of pixantrone in ovarian cancer cells. Furthermore, pixantrone significantly suppressed ovarian cancer growth in the A2780 cell xenograft mouse model and showed favorable safety., Conclusion: These findings suggest that pixantrone may be a promising drug for ovarian cancer patients by targeting MCM2 in the clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Da-Chai-Hu-Tang (DCHT), a Chinese traditional herbal compound, has been utilized for the treatment of Hepatic diseases in China for over 1800 years. The DCHT formula contains eight herbals: Bupleurum chinense DC. (chaihu), Scutellaria baicalensis Georgi (huangqin), Paeonia lactiflora Pall. (baishao), Pinellia ternata (Thunb.) Makino (banxia), Rheum officinale Baill. (dahuang), Citrus × aurantium L. (zhishi), Zingiber officinale Roscoe (shengjiang), Ziziphus jujuba Mill. (dazao). Clinical studies have demonstrated the effectiveness of DCHT in hepatocellular carcinoma (HCC) and its ability to enhance the immunity of patients with hepatocellular carcinoma. A total of 20 Chinese articles have been published on the use of DCHT in treating HCC., Aim of the Study: The study aimed to validate the effect of DCHT in HCC cells and to identify related targets (TP53, AKT1, BCL2, STAT3) in treating HCC by DCHT in vitro experiments., Materials and Methods: Cell proliferation and migration were investigated in vitro. Flow cytometry analysis was used to evaluate the cell cycle and apoptosis. Apoptotic bodies in HepG2 cells were observed using a confocal microscope. Biochemical detection was employed to analyze LDH release, MDA levels, and SOD levels. Bioinformatics analysis was used to predict core targets between DCHT and HCC, as well as potential signaling pathways. The protein levels of metastasis-associated, apoptosis, and PI3K, AKT, p-AKT, and STAT3 were further determined through Western blotting., Results: Following treatment with DCHT, the inhibition of viability, migration, and G2/M arrest was observed in HepG2 cells. Flow cytometry analysis and Morphological apoptosis studies provided evidence that DCHT could induce apoptosis in HepG2 cells. Biochemical detection revealed that DCHT could increase LDH release and the level of MDA, and inhibit the viability of the SOD. Bioinformatics analysis identified key targets such as TP53, AKT1, BCL2, STAT3. The PI3K/AKT/STAT3 signaling pathway emerged as a critical pathway in the KEGG enrichment analysis. Western blotting results indicated that DCHT could enhance the expression of E-cadherin, p53, and Bax, while reducing the content of N-cadherin, Bcl-2, PI3K, p-AKT, AKT1, and STAT3., Conclusions: The results proved that DCHT could inhibit the progression and metastasis of HCC by regulating the expression of E-cadherin, N-cadherin, p53, Bax, Bcl-2, PI3K, p-AKT, AKT, and STAT3 through the PI3K/AKT/STAT3 signaling pathway., Competing Interests: Declaration of competing interest The authors declared that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tumor heterogeneity results in aggressive cancer phenotypes with acquired resistance. However, combining chemical treatment with adjuvant therapies that cause cellular structure and function perturbations may diminish the ability of cancer cells to resist at chemical treatment and lead to a less aggressive cancer phenotype. Applied treatments on prostate hyperplasia primary cell cultures exerted their antitumor activities through mechanisms including cell cycle blockage, oxidative stress, and cell death induction by flow cytometry methods. A 5.37 mM Chloramphenicol dose acts on prostate hyperplasia cells by increasing the pro-oxidant status, inducing apoptosis, autophagy, and DNA damage, but without ROS changes. Adding 6.30 mM vitamin C or 622 µM vitamin E as a supplement to 859.33 µM Chloramphenicol dose in prostate hyperplasia cells determines a significant increase of ROS level for a part of cells. However, other cells remain refractory to initial ROS, with significant changes in apoptosis, autophagy, and cell cycle arrest in G0/G1 or G2/M. When the dose of Chloramphenicol was increased to 5.37 mM for 6.30 mM of vitamin C, prostate hyperplasia cells reacted by ROS level drastically decreased, cell cycle arrest in G2/M, active apoptosis, and autophagy. The pro-oxidant action of 1.51 mM Erythromycin dose in prostate hyperplasia cell cultures induces changes in the apoptosis mechanisms and cell cycle arrest in G0/G1. Addition of 6.30 mM vitamin C to 1.51 mM Erythromycin dose in hyperplasia cell cultures, the pro-oxidant status determines diminished caspase 3/7 mechanism activation, but ROS level presents similar changes as Chloramphenicol dose and cell cycle arrest in G2/M. Flow cytometric analysis of cell death, oxidative stress, and cell cycle are recommended as laboratory techniques in therapeutic and diagnostic fields., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Lung carcinoma is a frequently encountered cancerous growth that affects the respiratory tract and has a high occurrence rate globally. In light of the ongoing worldwide health emergency, the significance of efficient therapeutic agents and strategies is of utmost importance. A meticulous control of the cell cycle is crucial for comprehending the pathophysiology and molecular causes of lung cancer, as well as for the formulation of efficacious therapeutic medicines. The mechanism by which cells synchronize cell cycle with cell survival and death is still not fully understood. In this study, we demonstrate that the halting of the cell cycle has a strong inhibitory impact on ferroptosis, a specific type of controlled cell death triggered by excessive lipid peroxidation at the membranes of cells. Ferroptosis is halted through the mechanism of cell cycle arrest, which involves the deposition of intracellular lipids mediated by diacylglycerol acyltransferase (DGAT). Excessive amounts of polyunsaturated fatty acids (PUFAs) are stored as triacylglycerols (TAGs) within inactive cells. As a result, inhibiting DGAT causes a rearrangement of PUFAs from TAGs to phospholipids and makes arrested cells more susceptible to ferroptosis. We demonstrate that certain lung cancer cells that are resistant to antimitotic drugs and have a slow-cycling behavior exhibit an increase in lipid droplets. Furthermore, we find that the growth of tumors resistant to 5-fluorouracil, lorlatinib, and docetaxel can be effectively suppressed by a combination treatment involving the use of ferroptosis inducers and DGAT inhibitors, which induces ferroptosis. Collectively, these findings demonstrate the involvement of cell cycle arrest in conferring resistance to ferroptosis and propose a potential therapeutic approach for addressing the challenge of slow-cycling malignancies that exhibit resistance to ferroptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Melanoma is a malignant skin cancer associated with high mortality rates and drug resistance, posing a significant threat to human health. The combination of chemotherapy and photodynamic therapy (PDT) represents a promising strategy to enhance antitumor efficacy through synergistic anti-cancer effects. Topical delivery of chemotherapeutic drugs and photosensitizers (PS) offers a non-invasive and safe way to treat melanoma. However, the effectiveness of these treatments is often hindered by challenges such as limited skin permeability and instability of the PS. In this study, transfersomes (TFS) were designed to facilitate transdermal delivery of the chemotherapeutic drug 5-Fluorouracil (5-FU) and the PS Imperatorin (IMP) for combined chemo-photodynamic therapy for melanoma. The cytotoxic and phototoxic effects of TFS-mediated PDT (TFS-UVA) were investigated in A375 cells and nude mice. The study also demonstrated that TFS-UVA generated intracellular ROS, induced G2/ M phase cell cycle arrest, and promoted cell apoptosis. In conclusion, this study indicated that 5-FU/ IMP-TFS serves as an effective transdermal therapeutic strategy for chemo-PDT in treating melanoma.

Background: Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14-16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects., Methods: To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI., Results: The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p < 0.001), as determined by cell-based assays. ESL treatment led to significant enhancement of apoptosis (p < 0.01), as determined by flow cytometry, and upregulation of genes involved in cell apoptosis, such as the Bax/Bcl2 ratio at RNA (p < 0.05) and protein levels (5.37-fold). Flow cytometric analysis of ESL-treated cells revealed G2/M phase cell cycle arrest. ESL-treated cells demonstrated 2.49-fold upregulation of p21 alongside, 0.22-fold downregulation of cyclin B1, and 0.34-fold downregulation of cyclin-dependent kinase-1 at the protein level. Administration of ESL (30 mg/kg) to male rats bearing C6 intracranial tumors also suppressed the tumor volume and weight (p < 0.01)., Conclusions: Based on these novel findings, ESL has the potential for further experimental and clinical studies in glioblastoma., (© 2024. The Author(s).)

Sangre de drago, the sap of Croton lechleri Müll. Arg. tree, has been used for centuries in traditional medicine owing to its diverse biological activities. Extracts derived from different parts of the species contain a multitude of phytochemicals with varied applications. Twigs, however, are among the least studied parts of the plant. This study unveils new biological activities of Croton lechleri twig extracts recovered by applying Soxhlet and advanced green techniques. For all extracts, total phenolic content and antioxidant activity were determined. Subsequently, four were selected, and their cytotoxic effects were assessed on both normal (HaCat) and malignant melanoma (A375) skin cell lines using the MTT assay and trypan blue exclusion assay. All showed dose-dependent cytotoxicity, with the Soxhlet ethanol extract demonstrating the highest selectivity towards A375 cells over HaCat cells. The extracts induced apoptosis and necrosis, as confirmed by Annexin V/PI dual-labeling and flow cytometry, highlighting their ability to trigger programmed cell death in cancer cells. The selective inhibition of cell cycle progression in A375 compared to HaCat observed both for Soxhlet ethanol and pressurized ethanol extracts induces cell cycle arrest at multiple points, primarily in the G1 and G2/M phases, and significantly reduces DNA synthesis as evidenced by the decrease in the S-phase population, confirmed by the EdU assay. Consequently, the Soxhlet extract composition was analyzed using LC-MS, which revealed their richness in polyphenolic compounds, particularly flavonoids from the flavonol subclass., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Purpose: Therapeutic management of colorectal cancer (CRC) does not yet yield promising long-term results. Therefore, there is a need for further investigation of possible therapeutic options. Various experiments have studied the effects of apigenin on CRC and have shown conflicting results. This systematic review and meta-analysis investigates the currently existing evidence on the effect of apigenin on CRC., Methods: Medline, Embase, Scopus, and Web of Science databases were searched for articles related to apigenin and its effect on CRC in the preclinical setting. Cell viability, growth inhibition, apoptosis, and cell cycle arrest for in-vitro, and body weight, tumor size, and mortality in in-vivo studies were extracted as outcomes., Results: Thirty-nine articles investigating colorectal adenocarcinoma were included in this meta-analysis. Thirty-seven of these studies had data for in vitro experiments, with eight studies having data for in vivo experiments. Six articles had both in vitro and in vivo assessments. Our analysis showed apigenin reduces cell viability and induces growth inhibition, apoptosis, and cell cycle arrest in in vitro studies. The few in vivo studies indicate that apigenin decreases tumor size while showing no effects on the body weight of animal colorectal adenocarcinoma models., Conclusion: Our results demonstrated that apigenin, through reducing cell viability, inducing growth inhibition, apoptosis, and cell cycle arrest, and also by decreasing the tumor size, can be considered as a possible adjuvant agent in the management of colorectal adenocarcinoma. However, further in vivo studies are needed before any efforts to translate the current evidence into clinical studies., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Cratoxylum formosum ssp. pruniflorum (CF), a traditional medicinal plant in Southern China, is widely recognized as a popular medicinal and tea plant traditionally utilized by diverse linguistic groups in the region for the treatment of gastrointestinal ailments. The objective of this study was to explore the active components and mechanisms of CF against gastric cancer (GC). The chemical ingredients of CF were obtained by using UPLC-MS/MS-based metabolomics. MGC-803 and HGC-27 cells were employed to investigate the direct anti-GC effect. The potential targets and signaling pathway of CF were identified through network pharmacology and proteomics, followed by subsequent experimental validation. Through UPLC-MS/MS metabolomics analysis, a total of 197 chemical ingredients were identified in CF leaves. Network pharmacology and proteomics techniques revealed 25 potential targets for GC, with a protein-protein interaction (PPI) network highlighting 12 cores targets, including CTNNB1, CDK2, et al. Furthermore, seven key CF ingredients - vismione B, feruloylcholine, α-amyrin, vanillic acid, galangin, cinnamic acid, and caffeic acid - were found to mediate anti-GC effects through pathways such as reactive oxygen species (ROS) and cell cycle signaling pathway. In vitro experiments demonstrated that CF significantly inhibited the proliferation and migration of GC cells, increased intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels, arrested the cell cycle at the S-phase, induced apoptosis and pyroptosis, and upregulated expression of apoptosis proteins (Bax, Bax/Bcl-2, cleaved-Caspase-3/Caspase-3), and pyroptosis proteins (GSDMD-N/GSDMD and GSDME-N/GSDME), while downregulating expression of cell cycle proteins (CDK2 and cyclin A1) as well as necroptosis proteins (RIP1 and MLKL). Collectively, these findings reveal CF's therapeutic potential against GC by the augmentation of ROS production, cell cycle arrest, promotion of apoptosis, and pyroptosis, offering valuable evidence for the development and utilization of CF in clinical settings., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this study, seven isoniazid-hydrazone derivatives (3a-g) were synthesized and their structures elucidated by chromatographic techniques, and then the antiproliferative effects of these compounds on various cancer cells were tested. The advanced anticancer mechanism of the most potent compound was then investigated. Antiproliferative activities of the synthesized compounds were evaluated on human breast cancer MCF-7, lung cancer A-549, colon cancer HT-29, and non-cancerous mouse fibroblast 3T3-L1 cell lines by XTT assay. Flow cytometry analysis were carried out to determine cell cycle distribution, apoptosis, mitochondrial membrane potential, multi-caspase activity, and expression of PI3K/AKT signaling pathway. The XTT results showed that all the title molecules displayed cytotoxic activity at varying strengths in different dose ranges, and among them, the strongest cytotoxic effect and high selectivity were exerted by 3d against MCF-7 cells with the IC 50 value of 11.35 µM and selectivity index of 8.65. Flow cytometry results revealed that compound 3d induced apoptosis through mitochondrial membrane disruption and multi-caspase activation in MCF-7 cells. It also inhibited the cell proliferation via inhibition of expression of PI3K/AKT and arrested the cell cycle at G0/G1 phase. In conclusion, all these data disclosed that among the synthesized compounds, 3d is notable for in vivo anticancer studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Currently, a diagnosis with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) means a death warrant, so finding efficient therapeutic options is a pressing issue. Here, we presented that pharmacologic ascorbate, chloroquine and resveratrol co-treatment exerted a synergistic cytotoxic effect on PDAC cell lines. The observed synergistic cytotoxicity was a general feature in all investigated cancer cell lines independent of the KRAS mutational status and seems to be independent of the autophagy inhibitory effect of chloroquine. Furthermore, it seems that apoptosis and necroptosis are also not likely to play any role in the cytotoxicity of chloroquine. Both pharmacologic ascorbate and resveratrol caused double-strand DNA breaks accompanied by cell cycle arrest. It seems resveratrol-induced cytotoxicity is independent of reactive oxygen species (ROS) generation and accompanied by a significant elevation of caspase-3/7 activity, while pharmacologic ascorbate-induced cytotoxicity shows strong ROS dependence but proved to be caspase-independent. Our results are particularly important since ascorbate and resveratrol are natural compounds without significant harmful effects on normal cells, and chloroquine is a known antimalarial drug that can easily be repurposed., (© 2024 The Authors. BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Modifications at different positions on the aloperine molecule were performed to improve its anticancer activity and develop anticancer drugs. The in vitro anticancer activities of 44 synthesized compounds were evaluated. The effect of modification positions on anticancer activity was discussed and a structure-activity relationship analysis was established. A novel series of compounds with modifications at the N 12 position showed much higher cytotoxicity than aloperine. Among them, compound 22 displayed promising in vitro anticancer activity against PC9 cells with a median inhibitory concentration (IC 50 ) of 1.43 μM. The mechanism studies indicated that compound 22 induced cell apoptosis and cell cycle arrest in PC9 cells. These results demonstrate the potential of aloperine thiourea derivatives in anticancer activity.

Titanium dioxide nanoparticles (TiO 2 NPs) can result in the reduction of sperm numbers, but the mechanisms have not been well elucidated. The purpose of this study was to investigate the effects of TiO 2 NPs on cell cycle and apoptosis in spermatogonia and to explore the role of PI3K/AKT/mTOR signaling pathway in this process. The mouse spermatogonia cell line (GC-1) was treated with TiO 2 NPs at different concentrations (0, 25, 50, 75 and 100 μg/mL) for 24 h to detect cell viability, cell cycle, apoptosis, and key proteins related to cell cycle and PI3K/AKT/mTOR signaling pathway. The agonist (IGF-1) and inhibitor (LY294002) of PI3K were used to verify the role of PI3K/AKT/mTOR signaling pathway in cell cycle and apoptosis. TiO 2 NPs significantly inhibited cell proliferation, induced cell cycle arrest at G0/G1 phase and resulted in apoptosis. TiO 2 NPs downregulated the levels of cyclin-dependent kinases (CDKs) and cyclins, including CDK4, CDK2, Cyclin D1 and Cyclin E1, while upregulated the levels of p21 and p53 proteins. Furthermore, TiO 2 NPs inhibited the PI3K/AKT/mTOR signaling pathway by decreasing the levels of p-PI3K, p-AKT and p-mTOR. IGF-1 reversed the G0/G1 phase arrest and apoptosis caused by TiO 2 NPs. However, LY294002 aggravated the G0/G1 phase arrest and apoptosis resulting from TiO 2 NPs. Collectively, TiO 2 NPs induced cell cycle arrest at G0/G1 phase and apoptosis through inhibiting the activation of PI3K/AKT/mTOR pathway, which could be the main reason for the reduction in sperm numbers caused by TiO 2 NPs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cancer is one of the leading causes of mortality worldwide. Despite the advancement of cancer treatment by various means including surgery, chemotherapy etc, cancer is still a challenging disease to manage. This study was undertaken to investigate extraction, purification, structural elucidation, and the potential anti-cancer effects of Pleurotus ostreatus polysaccharide (POP). The anti-cancer activities were performed on the Ehrlich Ascites Carcinoma Cell Line. The results demonstrated that the MW of POP was154649.8 Da with homopolysaccharide composed of D-glucose units, featuring (1→6)-α-D-Glcp backbone with O-6 branches and T-α-D-Glcp terminations. and the yield was 6.27 %. The antitumor activity assessment demonstrated significant cytotoxicity of POP against Ehrlich Ascites Carcinoma (EAC) cells, with an IC 50 of 121.801 μg mL, supported by LDH release analysis. POP inhibited cell migration, invasion, and colony formation, indicating its potential as an anti-cancer agent. POP elicited the apoptotic activity with the upregulation of Caspase-9 and Bax, and downregulation of Bcl-2. The DNA fragmentation assay further confirmed apoptosis-mediated DNA degradations. Additionally, POP-induced cell cycle arrest at the G0/G1 phase, by altering the expression of p53, Cyclin D, and Cdk4 proteins. So, Pleurotus ostreatus polysaccharide (POP) showed significant cytotoxicity on Ehrlich Ascites Carcinoma cells, indicating potential as an anti-cancer agent., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential., Purpose: The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA., Methods: Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities., Conclusion: BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound., Competing Interests: Declaration of competing interest Given their role as Editor/Associate Editor/Editorial board members, Anupam Bishayee had no involvement in the peer-review of this article and has no access to information regarding its peer-review., (Copyright © 2024 Elsevier GmbH. All rights reserved.)