80 results on '"Medical University of Bialystok"'
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2. Recent Development of Fluoroquinolone Derivatives as Anticancer Agents.
- Author
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Nowakowska J, Radomska D, Czarnomysy R, and Marciniec K
- Subjects
- Humans, Structure-Activity Relationship, Neoplasms drug therapy, Animals, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Drug Repositioning, Cell Proliferation drug effects, Fluoroquinolones chemistry, Fluoroquinolones pharmacology, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis
- Abstract
Cancer is the second leading cause of death in the world following cardiovascular disease. Its treatment, including radiation therapy and surgical removal of the tumour, is based on pharmacotherapy, which prompts a constant search for new and more effective drugs. There are high costs associated with designing, synthesising, and marketing new substances. Drug repositioning is an attractive solution. Fluoroquinolones make up a group of synthetic antibiotics with a broad spectrum of activity in bacterial diseases. Moreover, those compounds are of particular interest to researchers as a result of reports of their antiproliferative effects on the cells of the most lethal cancers. This article presents the current progress in the development of new fluoroquinolone derivatives with potential anticancer and cytotoxic activity, as well as structure-activity relationships, along with possible directions for further development.
- Published
- 2024
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3. Di- and Triselenoesters-Promising Drug Candidates for the Future Therapy of Triple-Negative Breast Cancer.
- Author
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Radomska D, Czarnomysy R, Szymanowska A, Radomski D, Chalecka M, Surazynski A, Domínguez-Álvarez E, Bielawska A, and Bielawski K
- Subjects
- Humans, Female, Cell Line, Tumor, Membrane Potential, Mitochondrial drug effects, Organoselenium Compounds pharmacology, Organoselenium Compounds therapeutic use, Organoselenium Compounds chemistry, Cell Survival drug effects, Esters chemistry, Esters pharmacology, MCF-7 Cells, Apoptosis drug effects, Cell Proliferation drug effects, Autophagy drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology
- Abstract
Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨ
m ), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41-0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨm and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.- Published
- 2024
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4. Modifications of Nanobubble Therapy for Cancer Treatment.
- Author
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Terlikowska KM, Dobrzycka B, and Terlikowski SJ
- Subjects
- Humans, Animals, Drug Delivery Systems methods, Nanoparticles, Neoplasms drug therapy, Antineoplastic Agents therapeutic use
- Abstract
Cancer development is related to genetic mutations in primary cells, where 5-10% of all cancers are derived from acquired genetic defects, most of which are a consequence of the environment and lifestyle. As it turns out, over half of cancer deaths are due to the generation of drug resistance. The local delivery of chemotherapeutic drugs may reduce their toxicity by increasing their therapeutic dose at targeted sites and by decreasing the plasma levels of circulating drugs. Nanobubbles have attracted much attention as an effective drug distribution system due to their non-invasiveness and targetability. This review aims to present the characteristics of nanobubble systems and their efficacy within the biomedical field with special emphasis on cancer treatment. In vivo and in vitro studies on cancer confirm nanobubbles' ability and good blood capillary perfusion; however, there is a need to define their safety and side effects in clinical trials.
- Published
- 2024
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5. Evaluation of anticancer activity of novel platinum(II) bis(thiosemicarbazone) complex against breast cancer.
- Author
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Radomska D, Szewczyk-Roszczenko OK, Marciniec K, Książek M, Kusz J, Roszczenko P, Szymanowska A, Radomski D, Bielawski K, and Czarnomysy R
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Female, Dose-Response Relationship, Drug, Cell Line, Tumor, Organoplatinum Compounds pharmacology, Organoplatinum Compounds chemistry, Organoplatinum Compounds chemical synthesis, Coordination Complexes pharmacology, Coordination Complexes chemistry, Coordination Complexes chemical synthesis, Platinum chemistry, Platinum pharmacology, Autophagy drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Thiosemicarbazones pharmacology, Thiosemicarbazones chemistry, Thiosemicarbazones chemical synthesis, Drug Screening Assays, Antitumor, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Apoptosis drug effects, Cell Proliferation drug effects
- Abstract
The study aims to synthesize a novel bis(thiosemicarbazone) derivative based on platinum (thioPt) and evaluate its anticancer properties against MFC-7 and MDA-MB-231 breast cancer cells. A new platinum complex was synthesised by reacting K
2 PtCl4 with 2,2'-(1,2-diphenylethane-1,2-diylidene)bis(hydrazine-1-carbothioamide) in ethanol in the presence of K2 CO3 . In the obtained complex, the platinum atom is coordinated by a conjugated system = N-NC-S-The structures of the new compound were characterised using NMR spectroscopy, HR MS, IR, and X-ray structural analysis. The obtained results of the cytotoxicity assay indicate that compound thioPt had potent anticancer activity (MCF-7: 61.03 ± 3.57 µM, MDA-MB-231: 60.05 ± 5.40 µM) with less toxicity against normal MCF-10A breast epithelial cells, even compared to the reference compound (cisplatin). In addition, subsequent experiments found that thioPt induces apoptosis through both an extrinsic (↑caspase 8 activity) and intrinsic (↓ΔΨm ) pathway, which ultimately leads to an increase in active caspase 3/7 levels. The induction of autophagy and levels of proteins involved in this process (LC3A/B and Beclin-1) were examined in MCF-7 and MDA-MB-231 breast cancer cells exposed to tested compounds (thio, thioPt, cisPt) at a concentration of 50 µM for 24 h. Based on these results, it can be concluded that thio and thioPt do not significantly affect the autophagy process. This demonstrates their superiority over cisplatin, which can stimulate cancer cell survival through its effect on stimulation of autophagy., 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 Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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6. The activity of pyrazolo[4,3- e ][1,2,4]triazine and pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulphonamide derivatives in monolayer and spheroid breast cancer cell cultures.
- Author
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Szymanowska A, Radomska D, Czarnomysy R, Mojzych M, Kotwica-Mojzych K, Bielawski K, and Bielawska A
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Tumor Cells, Cultured, Pyrazoles pharmacology, Pyrazoles chemistry, Pyrazoles chemical synthesis, Female, Cell Line, Tumor, Spheroids, Cellular drug effects, Triazines pharmacology, Triazines chemistry, Triazines chemical synthesis, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms metabolism, Drug Screening Assays, Antitumor, Sulfonamides pharmacology, Sulfonamides chemistry, Sulfonamides chemical synthesis, Cell Proliferation drug effects, Apoptosis drug effects, Dose-Response Relationship, Drug
- Abstract
In the last decade, an increasing interest in compounds containing pyrazolo[4,3- e ][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3- e ][1,2,4]triazines ( 2a , 2b ) and pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulphonamide derivatives ( 3a , 3b ) to assess their anticancer activity. The MTT assay showed that 2a , 2b , 3a , 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b -induced anti-cancer activity against breast cancer cell lines.
- Published
- 2024
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7. Tumor-Homing Peptides as Crucial Component of Magnetic-Based Delivery Systems: Recent Developments and Pharmacoeconomical Perspective.
- Author
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Milewska S, Sadowska A, Stefaniuk N, Misztalewska-Turkowicz I, Wilczewska AZ, Car H, and Niemirowicz-Laskowska K
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- Humans, Animals, Drug Delivery Systems methods, Magnetite Nanoparticles chemistry, Magnetite Nanoparticles therapeutic use, Economics, Pharmaceutical, Drug Carriers chemistry, Neoplasms drug therapy, Peptides chemistry, Antineoplastic Agents therapeutic use, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry
- Abstract
According to data from the World Health Organization (WHO), cancer is considered to be one of the leading causes of death worldwide, and new therapeutic approaches, especially improved novel cancer treatment regimens, are in high demand. Considering that many chemotherapeutic drugs tend to have poor pharmacokinetic profiles, including rapid clearance and limited on-site accumulation, a combined approach with tumor-homing peptide (THP)-functionalized magnetic nanoparticles could lead to remarkable improvements. This is confirmed by an increasing number of papers in this field, showing that the on-target peptide functionalization of magnetic nanoparticles improves their penetration properties and ensures tumor-specific binding, which results in an increased clinical response. This review aims to highlight the potential applications of THPs in combination with magnetic carriers across various fields, including a pharmacoeconomic perspective.
- Published
- 2024
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8. Synthesis, Pharmacokinetic Profile, Anticancer Activity and Toxicity of the New Amides of Betulonic Acid-In Silico and In Vitro Study.
- Author
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Bębenek E, Rzepka Z, Hermanowicz JM, Chrobak E, Surażyński A, Beberok A, and Wrześniok D
- Subjects
- Humans, Animals, Cell Line, Tumor, Computer Simulation, MCF-7 Cells, Cell Survival drug effects, Amides chemistry, Amides pharmacology, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacokinetics, Zebrafish, Oleanolic Acid analogs & derivatives, Oleanolic Acid pharmacology, Oleanolic Acid chemistry, Oleanolic Acid chemical synthesis, Oleanolic Acid pharmacokinetics, Betulinic Acid
- Abstract
Betulonic acid (B(O)A) is a pentacyclic lupane-type triterpenoid that widely exists in plants. There are scientific reports indicating anticancer activity of B(O)A, as well as the amides and esters of this triterpenoid. In the first step of the study, the synthesis of novel amide derivatives of B(O)A containing an acetylenic moiety was developed. Subsequently, the medium-soluble compounds (EB171 and EB173) and the parent compound, i.e., B(O)A, were investigated for potential cytotoxic activity against breast cancer (MCF-7 and MDA-MB-231) and melanoma (C32, COLO 829 and A375) cell lines, as well as normal human fibroblasts. Screening analysis using the WST-1 test was applied. Moreover, the lipophilicity and ADME parameters of the obtained derivatives were determined using experimental and in silico methods. The toxicity assay using zebrafish embryos and larvae was also performed. The study showed that the compound EB171 exhibited a significant cytotoxic effect on cancer cell lines: MCF-7, A-375 and COLO 829, while it did not affect the survival of normal cells. Moreover, studies on embryos and larvae showed no toxicity of EB171 in an animal model. Compared to EB171, the compound EB173 had a weaker effect on all tested cancer cell lines and produced less desirable effects against normal cells. The results of the WST-1 assay obtained for B(O)A revealed its strong cytotoxic activity on the examined cancer cell lines, but also on normal cells. In conclusion, this article describes new derivatives of betulonic acid-from synthesis to biological properties. The results allowed to indicate a promising direction for the functionalization of B(O)A to obtain derivatives with selective anticancer activity and low toxicity.
- Published
- 2024
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9. Tubulin inhibitors. Selected scaffolds and main trends in the design of novel anticancer and antiparasitic agents.
- Author
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Podolak M, Holota S, Deyak Y, Dziduch K, Dudchak R, Wujec M, Bielawski K, Lesyk R, and Bielawska A
- Subjects
- Tubulin metabolism, Antiparasitic Agents pharmacology, Prospective Studies, Structure-Activity Relationship, Tubulin Modulators pharmacology, Antineoplastic Agents pharmacology
- Abstract
Design of tubulin inhibitors as anticancer drugs dynamically developed over the past 20 years. The modern arsenal of potential tubulin-targeting anticancer agents is represented by small molecules, monoclonal antibodies, and antibody-drug conjugates. Moreover, targeting tubulin has been a successful strategy in the development of antiparasitic drugs. In the present review, an overall picture of the research and development of potential tubulin-targeting agents using small molecules between 2018 and 2023 is provided. The data about some most often used and prospective chemotypes of small molecules (privileged heterocycles, moieties of natural molecules) and synthetic methodologies (analogue-based, fragment-based drug design, molecular hybridization) applied for the design of novel agents with an impact on the tubulin system are summarized. The design and prospects of multi-target agents with an impact on the tubulin system were also highlighted. Reported in the review data contribute to the "structure-activity" profile of tubulin-targeting small molecules as anticancer and antiparasitic agents and will be useful for the application by medicinal chemists in further exploration, design, improvement, and optimization of this class of molecules., 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 © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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10. The Role of p53 in Nanoparticle-Based Therapy for Cancer.
- Author
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Szewczyk-Roszczenko O and Barlev NA
- Subjects
- Humans, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Genetic Therapy, Neoplasms pathology, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Nanoparticles
- Abstract
p53 is arguably one of the most important tumor suppressor genes in humans. Due to the paramount importance of p53 in the onset of cell cycle arrest and apoptosis, the p53 gene is found either silenced or mutated in the vast majority of cancers. Furthermore, activated wild-type p53 exhibits a strong bystander effect, thereby activating apoptosis in surrounding cells without being physically present there. For these reasons, p53-targeted therapy that is designed to restore the function of wild-type p53 in cancer cells seems to be a very appealing therapeutic approach. Systemic delivery of p53-coding DNA or RNA using nanoparticles proved to be feasible both in vitro and in vivo. In fact, one p53-based therapeutic (gendicine) is currently approved for commercial use in China. However, the broad use of p53-based therapy in p53-inactivated cancers is severely restricted by its inadequate efficacy. This review highlights the current state-of-the-art in this area of biomedical research and also discusses novel approaches that may help overcome the shortcomings of p53-targeting nanomedicine.
- Published
- 2023
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11. Synthesis, Biological Activity, ADME and Molecular Docking Studies of Novel Ursolic Acid Derivatives as Potent Anticancer Agents.
- Author
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Michalak O, Cybulski M, Szymanowski W, Gornowicz A, Kubiszewski M, Ostrowska K, Krzeczyński P, Bielawski K, Trzaskowski B, and Bielawska A
- Subjects
- Cell Line, Tumor, Structure-Activity Relationship, Molecular Docking Simulation, Cell Proliferation, Drug Screening Assays, Antitumor, Molecular Structure, Ursolic Acid, Antineoplastic Agents chemistry
- Abstract
A series of new ursolic acid (UA) derivatives substituted with various amino acids (AAs) or dipeptides (DP) at the C-3 position of the steroid skeleton was designed and synthesized. The compounds were obtained by the esterification of UA with the corresponding AAs. The cytotoxic activity of the synthesized conjugates was determined using the hormone-dependent breast cancer cell line MCF-7 and the triple-negative breast cancer cell line MDA. Three derivatives ( l -seryloxy-, l -prolyloxy- and l -alanyl- l -isoleucyloxy-) showed micromolar IC
50 values and reduced the concentrations of matrix metalloproteinases 2 and 9. Further studies revealed that for two compounds ( l -seryloxy- and l -alanyl- l -isoleucyloxy-), a possible mechanism of their antiproliferative action is the activation of caspase-7 and the proapoptotic Bax protein in the apoptotic pathway. The third compound ( l -prolyloxy- derivative) showed a different mechanism of action as it induced autophagy as measured by an increase in the concentrations of three autophagy markers: LC3A, LC3B, and beclin-1. This derivative also showed statistically significant inhibition of the proinflammatory cytokines TNF-α and IL-6. Finally, for all synthesized compounds, we computationally predicted their ADME properties as well as performed molecular docking to the estrogen receptor to assess their potential for further development as anticancer agents.- Published
- 2023
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12. Molecular design, synthesis and anticancer activity of new thiopyrano[2,3-d]thiazoles based on 5-hydroxy-1,4-naphthoquinone (juglone).
- Author
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Ivasechko I, Lozynskyi A, Senkiv J, Roszczenko P, Kozak Y, Finiuk N, Klyuchivska O, Kashchak N, Manko N, Maslyak Z, Lesyk D, Karkhut A, Polovkovych S, Czarnomysy R, Szewczyk O, Kozytskiy A, Karpenko O, Khyluk D, Gzella A, Bielawski K, Bielawska A, Dzubak P, Gurska S, Hajduch M, Stoika R, and Lesyk R
- Subjects
- Humans, Animals, Mice, Thiazoles chemistry, Doxorubicin pharmacology, Drug Screening Assays, Antitumor, Molecular Structure, Molecular Docking Simulation, Structure-Activity Relationship, Cell Proliferation, Cell Line, Tumor, Antineoplastic Agents chemistry, Naphthoquinones pharmacology
- Abstract
A series of 11-substituted 9-hydroxy-3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]thiazole-2,5,10-triones 3.1-3.13 were synthesized via hetero-Diels-Alder reaction of 5-ene-4-thioxo-2-thiazolidinones and 5-hydroxy-1,4-naphthoquinone (juglone). The structure of newly synthesized compounds was established by means of spectral data and a single-crystal X-ray diffraction analysis. The synthesized compounds were tested on a panel of cell lines representing different types of cancer as well as normal and pseudonormal cells and peripheral human blood lymphocytes. Compound 3.10 was found to be the most active derivative, exhibiting a cytotoxic effect similar to doxorubicin's one (IC
50 ranged from 0.6 to 5.98 μM), but less toxic to normal and pseudonormal cells. All synthesized compounds were able to interact with DNA, although their anticancer activity did not correlate with the potency of interaction with DNA. The status of p53 in colorectal cancer cells correlated with the activity of the synthesized derivatives 3.1, 3.7, and 3.10. Compound 3.10 did not have an acute toxic effect on the body of С57BL/6 mice, unlike the well-known anticancer drug doxorubicin, which was used as a positive control. The injection of 3.10 (20 mg/kg) to mice had no effect on the counts of leukocytes, erythrocytes, platelets and hemoglobin level in their blood, in contrast to doxorubicin, which caused anemia and leukopenia, indicating bio-tolerance of 3.10in vivo., 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2023
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13. Thiosemicarbazide Derivatives Targeting Human TopoIIα and IDO-1 as Small-Molecule Drug Candidates for Breast Cancer Treatment.
- Author
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Kaproń B, Czarnomysy R, Radomska D, Bielawski K, and Plech T
- Subjects
- Female, Humans, Apoptosis, ATP Binding Cassette Transporter, Subfamily G, Member 2, Cell Line, Tumor, Cell Proliferation, MCF-7 Cells, Neoplasm Proteins metabolism, Semicarbazides pharmacology, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents chemistry, Breast Neoplasms drug therapy, Breast Neoplasms metabolism
- Abstract
In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identified as dual inhibitors targeting topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1), on two distinct types of breast cancer cells (MCF-7 and MDA-MB-231). The investigated compounds ( 1 - 3 ) selectively suppressed the growth of breast cancer cells and promoted apoptosis via caspase-8- and caspase-9-related pathways. Moreover, these compounds caused S-phase cell cycle arrest and dose-dependently inhibited the activity of ATP-binding cassette transporters (MDR1, MRP1/2 and BCRP) in MCF-7 and MDA-MB-231 cells. Additionally, following incubation with compound 1, an increased number of autophagic cells within both types of the investigated breast cancer cells was observed. During preliminary testing of ADME-Tox properties, the possible hemolytic activities of compounds 1 - 3 and their effects on specific cytochrome P450 enzymes were evaluated.
- Published
- 2023
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14. Metal-promoted synthesis of steroidal ethynyl selenides having anticancer activity.
- Author
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Grzes PA, Sawicka A, Niemirowicz-Laskowska K, Wielgat P, Sawicka D, Car H, and Jastrzebska I
- Subjects
- Humans, Female, Molecular Structure, Structure-Activity Relationship, Cell Proliferation, Drug Screening Assays, Antitumor, MCF-7 Cells, Steroids pharmacology, Steroids therapeutic use, Metals, Estrogens pharmacology, Apoptosis, Cell Line, Tumor, Antineoplastic Agents, Breast Neoplasms metabolism
- Abstract
In this study, we have described simple and efficient methodology for the metal-promoted (Cu
2 I2 ) preparation of steroidal ethynyl selenides. The compounds were characterized using1 H,13 C and77 Se NMR, FT IR spectroscopy, and MS analysis. A proposed mechanism of the metal-promoted reaction involves the formation of a σ-bound copper acetylide. Due to the fact that organoselenium-based compounds possess a pleiotropic properties and associated with their promising biological activities, in the next step of the study biocompatibility and anticancer activity of the synthesized compounds was evaluated. Steroidal selenides were tested in vitro against estrogen-depend breast cancer cells MCF-7 using spectrophotometric, fluorometric and luminometric methods. Designed selenides showed high hemocompatibility, lack of toxicity against cardiomyocytes cell and great anti-cancer activity in vitro against estrogen-depend breast cancer cells upon 24 h of treatment. We revealed that selenides decrease the viability and proliferation ability of MCF-7 cells by induction of cell apoptosis. It has been noted that the overproduction of reactive oxygen species (ROS) and associated with its activation of Caspase 3/7 are a major mechanism that is responsible of selenides-caused cell death. These data indicate that organoselenium based compounds have great antineoplastic potential and might be developed as novel class of agents dedicated to the breast-cancer therapies., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2023
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15. Substrate viscosity impairs temozolomide-mediated inhibition of glioblastoma cells' growth.
- Author
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Cieśluk M, Piktel E, Wnorowska U, Skłodowski K, Kochanowicz J, Kułakowska A, Bucki R, and Pogoda K
- Subjects
- Cell Proliferation, Humans, Hydrogels pharmacology, Hydrogels therapeutic use, Polymers, Temozolomide pharmacology, Temozolomide therapeutic use, Viscosity, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Brain Neoplasms genetics, Glioblastoma metabolism, Glioma pathology
- Abstract
Background: The mechanical state of the extracellular environment of the brain cells considerably affects their phenotype during the development of central nervous system (CNS) pathologies, and when the cells respond to drugs. The reports on the evaluation of the viscoelastic properties of different brain tumors have shown that both tissue stiffness and viscosity can be altered during cancer development. Although a compelling number of reports established the role of substrate stiffness on the proliferation, motility, and drug sensitivity of brain cancer cells, there is a lack of parallel data in terms of alterations in substrate viscosity., Methods: Based on viscoelasticity measurements of rat brain samples using strain rheometry, polyacrylamide (PAA) hydrogels mimicking elastic and viscous parameters of the tissues were prepared. Optical microscopy and flow cytometry were employed to assess the differences in glioblastoma cells morphology, proliferation, and cytotoxicity of anticancer drug temozolomide (TMZ) due to increased substrate viscosity., Results: Our results indicate that changes in substrate viscosity affect the proliferation of untreated glioma cells to a lesser extent, but have a significant impact on the apoptosis-associated depolarization of mitochondria and level of DNA fragmentation. This suggests that viscosity sensing and stiffness sensing machinery can activate different signaling pathways in glioma cells., Conclusion: Collected data indicate that viscosity should be considered an important parameter in in vitro polymer-based cell culture systems used for drug screening., 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 © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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16. 4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design.
- Author
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Roszczenko P, Holota S, Szewczyk OK, Dudchak R, Bielawski K, Bielawska A, and Lesyk R
- Subjects
- Thiazolidines pharmacology, Thiazolidines chemistry, Chemistry, Pharmaceutical, Drug Design, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Antineoplastic Agents chemistry
- Abstract
Oncological diseases have currently reached an epidemic scale, especially in industrialized countries. Such a situation has prompted complex studies in medicinal chemistry focused on the research and development of novel effective anticancer drugs. In this review, the data concerning new 4-thiazolidinone-bearing hybrid molecules with potential anticancer activity reported during the period from the years 2017-2022 are summarized. The main emphasis is on the application of molecular hybridization methodologies and strategies in the design of small molecules as anticancer agents. Based on the analyzed data, it was observed that the main directions in this field are the hybridization of scaffolds, the hybrid-pharmacophore approach, and the analogue-based drug design of 4-thiazolidinone cores with early approved drugs, natural compounds, and privileged heterocyclic scaffolds. The mentioned design approaches are effective tools/sources for the generation of hit/lead compounds with anticancer activity and will be relevant to future studies.
- Published
- 2022
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17. Synthesis and Anticancer Activity of 1,3,4-Thiadiazoles with 3-Methoxyphenyl Substituent.
- Author
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Janowska S, Khylyuk D, Gornowicz A, Bielawska A, Janowski M, Czarnomysy R, Bielawski K, and Wujec M
- Subjects
- Humans, Female, Drug Screening Assays, Antitumor, Caspase 8, Structure-Activity Relationship, Molecular Structure, Cell Proliferation, Estrogens pharmacology, DNA therapeutic use, Cell Line, Tumor, Dose-Response Relationship, Drug, Thiadiazoles, Antineoplastic Agents, Breast Neoplasms drug therapy
- Abstract
Based on the results of previous work, we designed and synthesized 1,3,4-thiadiazole derivatives. The cytotoxic activity of the obtained compounds was then determined in biological studies using MCF-7 and MDA-MB-231 breast cancer cells and a normal cell line (fibroblasts). The results showed that all compounds displayed weak anticancer activity towards two breast cancer lines: an estrogen-dependent cell line (MCF-7) and an estrogen-independent cell line (MDA-MB-231). The compound most active towards MCF-7 breast cancer cells was SCT-4, which decreased DNA biosynthesis to 70% ± 3 at 100 µM. The mechanism of the anticancer action of 1,3,4-thiadiazole was also investigated. We choose a set of the most investigated proteins, which are attractive anticancer targets. In silico studies demonstrated a possible multitarget mode of action for the synthesized compounds but the most likely mechanism of action for the new compounds is connected with the activity of caspase 8.
- Published
- 2022
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18. Development of Novel Pyridine-Thiazole Hybrid Molecules as Potential Anticancer Agents.
- Author
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Ivasechko I, Yushyn I, Roszczenko P, Senkiv J, Finiuk N, Lesyk D, Holota S, Czarnomysy R, Klyuchivska O, Khyluk D, Kashchak N, Gzella A, Bielawski K, Bielawska A, Stoika R, and Lesyk R
- Subjects
- Benzoic Acid pharmacology, Cell Line, Tumor, Cell Proliferation, DNA pharmacology, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Esters pharmacology, Humans, Molecular Structure, Pyridines pharmacology, Structure-Activity Relationship, Thiazoles chemistry, Thiazoles pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Leukemia, Neoplasms
- Abstract
Novel pyridine-thiazole hybrid molecules were synthesized and subjected to physico-chemical characterization and screening of their cytotoxic action towards a panel of cell lines derived from different types of tumors (carcinomas of colon, breast, and lung, glioblastoma and leukemia), and normal human keratinocytes, for comparison. High antiproliferative activity of the 3-(2-fluorophenyl)-1-[4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl]-propenone 3 and 4-(2-{1-(2-fluorophenyl)-3-[4-methyl-2-(pyridin-2-ylamino)-thiazol-5-yl]-3-oxopropylsulfanyl}-acetylamino)-benzoic acid ethyl ester 4 was revealed. The IC50 of the compound 3 in HL-60 cells of the acute human promyelocytic leukemia was 0.57 µM, while in the pseudo-normal human cell lines, the IC50 of this compound was >50 µM, which suggests that the compounds 3 and 4 might be perspective anticancer agents. The detected selectivity of the derivatives 3 and 4 for cancer cell lines inspired us to study the mechanisms of their cytotoxic action. It was shown that preincubation of tumor cells with Fluzaparib (inhibitor of PARP1) reduced the cytotoxic activity of the derivatives 3 and 4 by more than twice. The ability of these compounds to affect DNA nativity and cause changes in nucleus morphology allows for the suggestion that the mechanism of action of the novel pyridine-thiazole derivatives might be related to inducing the genetic instability in tumor cells.
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- 2022
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19. The promoting effect of neutrophil-derived BAFF molecule on the proliferation and life span of CAL-27 oral squamous carcinoma cells.
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Jablonska E, Iwaniuk A, Ratajczak-Wrona W, Grubczak K, Dziemianczyk-Pakiela D, Moniuszko M, Nowak K, Borys J, and Garley M
- Subjects
- Apoptosis, Apoptosis Regulatory Proteins, B-Cell Activating Factor pharmacology, B-Cell Activating Factor therapeutic use, Cell Line, Tumor, Cell Proliferation, Flavonoids pharmacology, Flavonoids therapeutic use, Humans, Longevity, Neutrophils metabolism, Transforming Growth Factor beta pharmacology, Tumor Microenvironment, Antineoplastic Agents therapeutic use, Carcinoma, Squamous Cell pathology, Mouth Neoplasms drug therapy, Mouth Neoplasms pathology
- Abstract
Tumor-associated neutrophils (TANs) are the major cellular component of the tumor microenvironment and have been shown to release of different bioactive molecules such as B-cell activating factor (BAFF). The data on the interactions between OSCC cells and neutrophils are limited and do not explain the actual role of the BAFF in the development of the OSCC. In the present study we examined the direct effect of neutrophils-derived BAFF on the OSCC cell line CAL-27 proliferation and apoptosis. PMNs of OSCC patients and healthy control were isolated from whole blood and separated by magnetic selection with monoclonal anti-human CD16 antibodies. CD-16 - positive neutrophils were incubated in the presence of TGF-β and/or LPS as well as flavonoids (luteolin and quercetin). CAL-27 cells were co-incubated with supernatants of neutrophils. BAFF expression in neutrophils, BAFF-R expression on CAL-27 cells and apoptosis of CAL-27 cells were assessed by flow cytometry. To determine the CAL-27 cells proliferation, the MTT test was used. Expression of select mitochondrial proteins in CAL-27 cells were measured by Western blot. Neutrophils from OSCC patients showed significantly higher expression of BAFF than those from the healthy controls. The results obtained revealed upregulation of the proliferation and downregulation of the apoptosis of the CAL-27 cells in the presence of the supernatants of TGF-β-treated neutrophils. Flavonoids reduced BAFF expression in neutrophils of patients with OSCC and control group. Lower intensity of apoptosis in CAL-27 cells was associated with the increased expression of anti-apoptotic Bcl-2, Mcl-1 and activated form of PI3K kinase (pPI3K) and simultaneously reduced expression of pro-apoptotic Bax protein in the presence of rhBAFF, as well as of supernatants of neutrophils derived from OSCC patients. In conclusion, the data presented confirm the previously suggested role of neutrophil-derived BAFF in OSCC development. The favorable effects of examined flavonoids on tumor-promoting BAFF expression in neutrophils suggest that they might be promising candidates as chemo-preventive agents in the therapy of patients with OSCC., 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 © 2022 Elsevier GmbH. All rights reserved.)
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- 2022
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20. Establishment of In Vitro and In Vivo Anticolorectal Cancer Efficacy of Lithocholic Acid-Based Imidazolium Salts.
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Sawicka D, Hryniewicka A, Gohal S, Sadowska A, Pryczynicz A, Guzińska-Ustymowicz K, Sokołowska E, Morzycki JW, and Car H
- Subjects
- Animals, Apoptosis, Cell Line, Tumor, Fluorouracil pharmacology, Fluorouracil therapeutic use, Humans, Lithocholic Acid pharmacology, Mice, Salts pharmacology, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy
- Abstract
Imidazolium salts (IMSs) are the subject of many studies showing their anticancer activities. In this research, a series of novel imidazolium salts substituted with lithocholic acid (LCA) and alkyl chains of various lengths ( S1 - S10 ) were evaluated against colon cancer cells. A significant reduction in the viability and metabolic activity was obtained in vitro for DLD-1 and HT-29 cell lines when treated with tested salts. The results showed that the activities of tested agents are directly related to the alkyl chain length, where S6 - S8 compounds were the most cytotoxic against the DLD-1 line and S4 - S10 against HT-29. The research performed on the xenograft model of mice demonstrated a lower tendency of tumor growth in the group receiving compound S6 , compared with the group receiving 5-fluorouracil (5-FU). Obtained results indicate the activity of S6 in the induction of apoptosis and necrosis in induced colorectal cancer. LCA-based imidazolium salts may be candidates for chemotherapeutic agents against colorectal cancer.
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- 2022
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21. The Outcomes of Ponatinib Therapy in Patients With Chronic Myeloid Leukemia Resistant or Intolerant to Previous Tyrosine Kinase Inhibitors, Treated in Poland Within the Donation Program.
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Sacha T, Szczepanek E, Dumnicka P, Góra-Tybor J, Niesiobędzka-Krężel J, Prejzner W, Wasilewska E, Kłoczko J, Ciepłuch H, Makowska W, Patkowska E, Wasilewska J, Bober G, Kopera M, Wichary R, Kroll-Balcerzak R, Gromek T, Wach M, Rudkowska-Kazanowska A, Świniarska M, Paczkowska E, Biernat M, Joks M, Oller M, Kasza R, Kostyra A, Gil J, and Grzybowska-Izydorczyk O
- Subjects
- Adult, Drug Resistance, Neoplasm, Humans, Imidazoles, Poland, Protein Kinase Inhibitors adverse effects, Pyridazines, Retrospective Studies, Antineoplastic Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics
- Abstract
Introduction: Tyrosine kinase inhibitors (TKIs) have greatly improved the treatment outcome for most patients with chronic myeloid leukemia (CML). Ponatinib is a new pan-inhibitor of TK active in resistant CML. This study aimed to evaluate the efficacy and safety of ponatinib in patients suffering from CML., Patients and Methods: This multicenter, non-randomized, observational, retrospective study evaluated the efficacy and safety of ponatinib administered in adult CML patients in any disease phase, including those with a detected ABL T315I mutation, which were resistant or intolerant to previous-generation TKIs. The study comprised 43 patients benefiting from the ponatinib donation program who were treated in 16 Polish centers., Results: For patients who started treatment with ponatinib in chronic phase (CP) (n = 23) and in accelerated phase (AP) (n = 3) the median time on ponatinib was 19.5 months (range: 1.0-35.4), and 31.7 months (range: 31.0-34.1), respectively. All these patients were in CP after 1 month of treatment and at the end of observation - none of them progressed to AP or blastic phase (BP) during the study, meaning that progression-free survival was 100% at the end of observation (35.4 months). The estimated 2-year survival in this group of patients was 84%. For all 43 patients, median survival was not reached (lower quartile 6.3 months), and estimated 2-year survival was 60%., Conclusion: Our analysis confirmed ponatinib efficacy in a significant proportion of patients heavily pre-treated with TKIs achieving durable responses in both CP and AP/BP CML groups., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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22. 2-{5-[( Z ,2 Z )-2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}-3-methylbutanoic Acid as a Potential Anti-Breast Cancer Molecule.
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Buzun K, Gornowicz A, Lesyk R, Kryshchyshyn-Dylevych A, Gzella A, Czarnomysy R, Latacz G, Olejarz-Maciej A, Handzlik J, Bielawski K, and Bielawska A
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- Apoptosis, Beclin-1 metabolism, Caspase 8 metabolism, Caspase 9 metabolism, Cell Line, Tumor, Cell Proliferation, DNA Topoisomerases, Type II metabolism, Female, Humans, Nitrophenols, Antineoplastic Agents chemistry, Breast Neoplasms drug therapy, Breast Neoplasms metabolism
- Abstract
It was established that the synthesis of hybrid molecules containing a thiazolidinone and a (2 Z )-2-chloro-3-(4-nitrophenyl)prop-2-ene structural fragments is an effective approach for the design of potential anticancer agents. Given the results of the previous SAR-analysis, the aim of the study was to synthesize a novel 4-thiazolidinone derivative Les-3331 and investigate its molecular mechanism of action in MCF-7 and MDA-MB-231 breast cancer cells. The cytotoxic properties and antiproliferative potential of Les-3331 were determined. The effect of the tested compound on apoptosis induction and mitochondrial membrane potential was checked by flow cytometry. ELISA was used to determine caspase-8 and caspase-9, LC3A, LC3B, Beclin-1, and topoisomerase II concentration. Additionally, PAMPA, in silico or in vitro prediction of metabolism, CYP3A4/2D6 inhibition, and an Ames test were performed. Les-3331 possesses high cytotoxic and antiproliferative activity in MCF-7 and MDA-MB-231 breast cancer cells. Its molecular mechanism of action is associated with apoptosis induction, decreased mitochondrial membrane potential, and increased caspase-9 and caspase-8 concentrations. Les-3331 decreased LC3A, LC3B, and Beclin-1 concentration in tested cell lines. Topoisomerase II concentration was also lowered. The most probable metabolic pathways and no DDIs risk of Les-3331 were confirmed in in vitro assays. Our studies confirmed that a novel 4-thiazolidinone derivative represents promising anti-breast cancer activity.
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- 2022
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23. Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis.
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Kazberuk A, Chalecka M, Palka J, and Surazynski A
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- Apoptosis, Breast Neoplasms drug therapy, Cell Proliferation drug effects, Cell Survival drug effects, Collagen biosynthesis, Collagen drug effects, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, MCF-7 Cells, Oxidative Phosphorylation drug effects, PPAR gamma agonists, Proline metabolism, Reactive Oxygen Species metabolism, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents pharmacology, Breast Neoplasms metabolism, PPAR gamma metabolism, Proline Oxidase metabolism
- Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be therapeutics in cancer prevention because of their inhibitory effect on cyclooxygenases (COX), which are frequently overexpressed in many types of cancer. However, it was also demonstrated that NSAIDs provoked a proapoptotic effect in COX knocked-out cancer cells. Here, we suggest that this group of drugs may provoke antineoplastic activity through the activation of PPARγ, which induces proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that catalyzes proline degradation, during which ATP or reactive oxygen species (ROS) are generated. We have found that NSAIDs induced PRODH/POX and PPARγ expressions (as demonstrated by Western Blot or immunofluorescence analysis) and cytotoxicity (as demonstrated by MTT, cytometric assay, and DNA biosynthesis assay) in breast cancer MCF7 cells. Simultaneously, the NSAIDs inhibited collagen biosynthesis, supporting proline for PRODH/POX-induced ROS-dependent apoptosis (as demonstrated by an increase in the expression of apoptosis markers). The data suggest that targeting proline metabolism and the PRODH/POX-PPARγ axis can be considered a novel approach for breast cancer treatment.
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- 2022
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24. Exploration of novel heterofused 1,2,4-triazine derivative in colorectal cancer.
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Hermanowicz JM, Szymanowska A, Sieklucka B, Czarnomysy R, Pawlak K, Bielawska A, Bielawski K, Kalafut J, Przybyszewska A, Surazynski A, Rivero-Muller A, Mojzych M, and Pawlak D
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Structure-Activity Relationship, Triazines chemical synthesis, Triazines chemistry, Tumor Cells, Cultured, Zebrafish, Antineoplastic Agents pharmacology, Colorectal Neoplasms drug therapy, Triazines pharmacology
- Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in men and in women. The impact of the new pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulphonamide ( MM-129 ) was evaluated against human colon cancer in vitro and in zebrafish xenografts. Our results show that this new synthesised compound effectively inhibits cell survival in BTK-dependent mechanism. Its effectiveness is much higher at a relatively low concentration as compared with the standard chemotherapy used for CRC, i.e. 5-fluorouracil (5-FU). Flow cytometry analysis after annexin V-FITC and propidium iodide staining revealed that apoptosis was the main response of CRC cells to MM-129 treatment. We also found that MM-129 effectively inhibits tumour development in zebrafish embryo xenograft model, where it showed a markedly synergistic anticancer effect when used in combination with 5-FU. The above results suggest that this novel heterofused 1,2,4-triazine derivative may be a promising candidate for further evaluation as chemotherapeutic agent against CRC.
- Published
- 2021
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25. Thioredoxin-dependent system. Application of inhibitors.
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Jastrząb A and Skrzydlewska E
- Subjects
- Antineoplastic Agents chemical synthesis, Benzene Derivatives chemistry, Benzene Derivatives pharmacology, Enzyme Inhibitors chemical synthesis, Gene Expression Regulation, Neoplastic, Homeostasis drug effects, Homeostasis genetics, Humans, Imidazoles chemistry, Imidazoles pharmacology, Isoindoles chemistry, Isoindoles pharmacology, MAP Kinase Kinase Kinase 5 genetics, MAP Kinase Kinase Kinase 5 metabolism, NF-kappa B genetics, NF-kappa B metabolism, Neoplasms enzymology, Neoplasms genetics, Neoplasms pathology, Neovascularization, Pathologic enzymology, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Nitrosourea Compounds chemistry, Nitrosourea Compounds pharmacology, Organoselenium Compounds chemistry, Organoselenium Compounds pharmacology, Oxidation-Reduction, Signal Transduction, Structure-Activity Relationship, Thioredoxin-Disulfide Reductase antagonists & inhibitors, Thioredoxin-Disulfide Reductase metabolism, Thioredoxins antagonists & inhibitors, Thioredoxins metabolism, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Neoplasms drug therapy, Neovascularization, Pathologic drug therapy, Thioredoxin-Disulfide Reductase genetics, Thioredoxins genetics
- Abstract
One of the systems responsible for maintaining cellular redox homeostasis is the thioredoxin-dependent system. An equally important function of this system is the regulation of the expression of many proteins by the transcription factor NF-κB or the apoptosis regulating kinase (ASK-1). Since it has been shown that the Trx-dependent system can contribute to both the enhancement of tumour angiogenesis and growth as well as apoptosis of neoplastic cells, the search for compounds that inhibit the level/activity of Trx and/or TrxR and thus modulate the course of the neoplastic process is ongoing. It has been shown that many naturally occurring polyphenolic compounds inactivate elements of the thioredoxin system. In addition, the effectiveness of Trx is inhibited by imidazole derivatives, while the activity of TrxR is reduced by transition metal ions complexes, dinitrohalobenzene derivatives, Michael acceptors, nitrosourea and ebselen. In addition, research is ongoing to identify new selective Trx/TrxR inhibitors.
- Published
- 2021
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26. Treasures from the forest: Evaluation of mushroom extracts as anti-cancer agents.
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Nowakowski P, Markiewicz-Żukowska R, Bielecka J, Mielcarek K, Grabia M, and Socha K
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- Animals, Antineoplastic Agents isolation & purification, Apoptosis drug effects, Apoptosis Regulatory Proteins metabolism, Cell Cycle Proteins metabolism, Cell Proliferation drug effects, Humans, Neoplasms metabolism, Neoplasms pathology, Signal Transduction, Agaricales chemistry, Agaricales classification, Antineoplastic Agents pharmacology, Neoplasms drug therapy
- Abstract
Mushrooms provide a reliable source of bioactive compounds and have numerous nutritional values, which is one of the reasons why they are widely used for culinary purposes. They may also be a remedy for several medical conditions, including cancer diseases. Given the constantly increasing number of cancer incidents, the great anticancer potential of mushrooms has unsurprisingly become an object of interest to researchers. Therefore, this review aimed to collect and summarize all the available scientific data on the anti-cancer activity of mushroom extracts. Our research showed that mushroom extracts from 92 species, prepared using 12 different solvents, could reduce the viability of 38 various cancers. Additionally, we evaluated different experimental models: in vitro (cell model), in vivo (mice and rat model, case studies and randomized controlled trials), and in silico. Breast cancer proved to be sensitive to the highest number of mushroom extracts. The curative mechanisms of the studied mushrooms consisted in: inhibition of cancer cell proliferation, unregulated proportion of cells in cell cycle phases, induction of autophagy and phagocytosis, improved response of the immune system, and induction of apoptotic death of cells via upregulation of pro-apoptotic factors and downregulation of anti-apoptotic genes. The processes mainly involved the expression of caspases -3, -8, -9, AKT, p27, p53, BAX, and BCL2. The quoted results could lead to the classification of mushrooms as nutraceuticals used to prevent a variety of disorders or to support treatment of cancer diseases., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2021
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27. Thromboelastometric Analysis of Anticancer Cerrena unicolor Subfractions Reveal Their Potential as Fibrin Glue Drug Carrier Enhancers.
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Stefaniuk D, Misztal T, Pięt M, Zając A, Kopycińska M, Matuszewska A, Ruminowicz-Stefaniuk M, Matuszewski Ł, Marcińczyk N, Belcarz A, Żuchowski J, Skrabalak I, Grąz M, Ciołek B, Paduch R, and Jaszek M
- Subjects
- Apoptosis drug effects, Blood Coagulation drug effects, Cell Line, Cell Proliferation drug effects, Cell Survival drug effects, Elasticity, Fibrin metabolism, Fungi drug effects, Gelatin metabolism, Humans, Kinetics, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Thrombin pharmacology, Viscosity, Antineoplastic Agents pharmacology, Drug Carriers chemistry, Fibrin Tissue Adhesive pharmacology, Polyporales chemistry, Thrombelastography
- Abstract
In this study, the influence of two subfractions (with previously proven anti-cancer properties) isolated from wood rot fungus Cerrena unicolor on the formation of a fibrin clot was investigated in the context of potential use as fibrin glue and sealant enhancers and potential wound healing agents. With the use of ROTEM thromboelastometry, we demonstrated that, in the presence of fibrinogen and thrombin, the S6 fraction accelerated the formation of a fibrin clot, had a positive effect on its elasticity modulus, and enhanced the degree of fibrin cross-linking. The S5 fraction alone showed no influence on the fibrin coagulation process; however, in the presence of fibrin, it exhibited a decrease in anti-proliferative properties against the HT-29 line, while it increased the proliferation of cells in general at a concentration of 100 µg/mL. Both fractions retained their proapoptotic properties to a lesser degree. In combination with the S6 fraction in the ratio of 1:1 and 1:3, the fractions contributed to increased inhibition of the activity of matrix metalloproteinases (MMPs). This may suggest anti-metastatic activity of the combined fractions. In conclusion, the potential of the fractions isolated from the C. unicolor secretome to be used as a means of improving the wound healing process was presented. The potential for delivering agents with cytostatic properties introduced far from the site of action or exerting a pro-proliferative effect at the wound site with the aid of a fibrin sealant was demonstrated.
- Published
- 2021
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28. Platinum and Palladium Complexes as Promising Sources for Antitumor Treatments.
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Czarnomysy R, Radomska D, Szewczyk OK, Roszczenko P, and Bielawski K
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- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Clinical Trials as Topic, Drug Synergism, Humans, Organoplatinum Compounds pharmacology, Organoplatinum Compounds therapeutic use, Antineoplastic Agents chemistry, Neoplasms drug therapy, Organoplatinum Compounds chemistry, Palladium chemistry
- Abstract
There is a need for new, safer, and more effective agents to treat cancer. Cytostatics that have transition metals at their core have attracted renewed interest from scientists. Researchers are attempting to use chemotherapeutics, such as cisplatin, in combination therapy (i.e., in order to enhance their effectiveness). Moreover, studies are being carried out to modify molecules, by developing them into multinuclear structures, linking different compounds to commonly used drugs, or encapsulating them in nanoparticles to improve pharmacokinetic parameters, and increase the selectivity of these drugs. Therefore, we attempted to organize recent drug findings that contain palladium and platinum atoms in their structures.
- Published
- 2021
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29. Sialic Acid-Modified Nanoparticles-New Approaches in the Glioma Management-Perspective Review.
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Wielgat P, Niemirowicz-Laskowska K, Wilczewska AZ, and Car H
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Glioma pathology, Glycosylation, Humans, Nanoparticles chemistry, Antineoplastic Agents pharmacology, Blood-Brain Barrier drug effects, Brain Neoplasms drug therapy, Glioma drug therapy, Nanoparticles administration & dosage, Polysaccharides chemistry
- Abstract
The cell surface is covered by a dense and complex network of glycans attached to the membrane proteins and lipids. In gliomas, the aberrant sialylation, as the final stage of glycosylation, is an important regulatory mechanism of malignant cell behavior and correlates with worse prognosis. Better understanding of the role of sialylation in cellular and molecular processes opens a new way in the development of therapeutic tools for human brain tumors. According to the recent clinical observation, the cellular heterogeneity, activity of brain cancer stem cells (BCSCs), immune evasion, and function of the blood-brain barrier (BBB) are attractive targets for new therapeutic strategies. In this review, we summarize the importance of sialic acid-modified nanoparticles in brain tumor progression.
- Published
- 2021
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30. Autophagy Modulators in Cancer Therapy.
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Buzun K, Gornowicz A, Lesyk R, Bielawski K, and Bielawska A
- Subjects
- Animals, Apoptosis Regulatory Proteins metabolism, Beclin-1 metabolism, Humans, Neoplasms metabolism, Neoplasms pathology, Proto-Oncogene Proteins c-bcl-2 metabolism, Tumor Suppressor Protein p53 metabolism, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Autophagy drug effects, Neoplasms drug therapy
- Abstract
Autophagy is a process of self-degradation that plays an important role in removing damaged proteins, organelles or cellular fragments from the cell. Under stressful conditions such as hypoxia, nutrient deficiency or chemotherapy, this process can also become the strategy for cell survival. Autophagy can be nonselective or selective in removing specific organelles, ribosomes, and protein aggregates, although the complete mechanisms that regulate aspects of selective autophagy are not fully understood. This review summarizes the most recent research into understanding the different types and mechanisms of autophagy. The relationship between apoptosis and autophagy on the level of molecular regulation of the expression of selected proteins such as p53, Bcl-2/Beclin 1, p62, Atg proteins, and caspases was discussed. Intensive studies have revealed a whole range of novel compounds with an anticancer activity that inhibit or activate regulatory pathways involved in autophagy. We focused on the presentation of compounds strongly affecting the autophagy process, with particular emphasis on those that are undergoing clinical and preclinical cancer research. Moreover, the target points, adverse effects and therapeutic schemes of autophagy inhibitors and activators are presented.
- Published
- 2021
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31. Mechanism of Anticancer Action of Novel Imidazole Platinum(II) Complex Conjugated with G2 PAMAM-OH Dendrimer in Breast Cancer Cells.
- Author
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Czarnomysy R, Muszyńska A, Rok J, Rzepka Z, and Bielawski K
- Subjects
- Apoptosis drug effects, Autophagy drug effects, Female, Humans, MAP Kinase Signaling System drug effects, MCF-7 Cells, Neoplasm Proteins metabolism, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Coordination Complexes chemical synthesis, Coordination Complexes chemistry, Coordination Complexes pharmacokinetics, Coordination Complexes pharmacology, Dendrimers chemistry, Dendrimers pharmacokinetics, Dendrimers pharmacology, Imidazoles chemistry, Imidazoles pharmacokinetics, Imidazoles pharmacology, Platinum chemistry, Platinum pharmacokinetics, Platinum pharmacology
- Abstract
Transition metal coordination compounds play an important role in the treatment of neoplastic diseases. However, due to their low selectivity and bioavailability, as well as the frequently occurring phenomenon of drug resistance, new chemical compounds that could overcome these phenomena are still being sought. The solution seems to be the synthesis of new metal complexes conjugated with drug carriers, e.g., dendrimers. Numerous literature data have shown that dendrimers improve the bioavailability of the obtained metal complexes, solving the problem of their poor solubility and stability in an aqueous environment and also breaking down inborn and acquired drug resistance. Therefore, the aim of this study was to synthesize a novel imidazole platinum(II) complex conjugated with and without the second-generation PAMAM dendrimer (PtMet2-PAMAM and PtMet2, respectively) and to evaluate its antitumor activity. Cell viability studies indicated that PtMet2-PAMAM exhibited higher cytotoxic activity than PtMet2 in MCF-7 and MDA-MB-231 breast cancer cells at relatively low concentrations. Moreover, our results indicated that PtMet2-PAMAM exerted antiproliferative effects in a zebrafish embryo model. Treatment with PtMet2-PAMAM substantially increased apoptosis in a dose-dependent manner via caspase-9 (intrinsic pathway) and caspase-8 (extrinsic pathway) activation along with pro-apoptotic protein expression modulation. Additionally, we showed that apoptosis can be induced by activating POX, which induces ROS production. Furthermore, our results also clearly showed that the tested compounds trigger autophagy through p38 pathway activation and increase Beclin-1, LC3, AMPK, and mTOR inhibition. The high pro-apoptotic activity and the ability to activate autophagy by the imidazole platinum(II) complex conjugated with a dendrimer may be due to its demonstrated ability to reverse multidrug resistance (MDR) and thereby increase cellular accumulation in breast cancer cells.
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- 2021
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32. Synthesis and Anticancer Activity Evaluation of 5-[2-Chloro-3-(4-nitrophenyl)-2-propenylidene]-4-thiazolidinones.
- Author
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Buzun K, Kryshchyshyn-Dylevych A, Senkiv J, Roman O, Gzella A, Bielawski K, Bielawska A, and Lesyk R
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Spectrum Analysis methods, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Thiazolidines chemistry, Thiazolidines pharmacology
- Abstract
A series of novel 5-[( Z ,2 Z )-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-thiazolidinones (Ciminalum-thiazolidinone hybrid molecules) have been synthesized. Anticancer activity screening toward the NCI60 cell lines panel, gastric cancer (AGS), human colon cancer (DLD-1), and breast cancer (MCF-7 and MDA-MB-231) cell lines allowed the identification of 3-{5-[( Z ,2 Z )-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}propanoic acid ( 2h ) with the highest level of antimitotic activity with mean GI
50 /TGI values of 1.57/13.3 μM and a certain sensitivity profile against leukemia (MOLT-4, SR), colon cancer (SW-620), CNS cancer (SF-539), melanoma (SK-MEL-5), gastric cancer (AGS), human colon cancer (DLD-1), and breast cancers (MCF-7 and MDA-MB-231) cell lines. The hit compounds 2f , 2i , 2j , and 2h have been found to have low toxicity toward normal human blood lymphocytes and a fairly wide therapeutic range. The significant role of the 2-chloro-3-(4-nitrophenyl)prop-2-enylidene ( Ciminalum ) substituent in the 5 position and the substituent's nature in the position 3 of core heterocycle in the anticancer cytotoxicity levels of 4-thiazolidinone derivatives have been established.- Published
- 2021
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33. IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen.
- Author
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Libura M, Bialopiotrowicz E, Giebel S, Wierzbowska A, Roboz GJ, Piatkowska-Jakubas B, Pawelczyk M, Gorniak P, Borg K, Wojtas M, Florek I, Matiakowska K, Jazwiec B, Solarska I, Noyszewska-Kania M, Piechna K, Zawada M, Czekalska S, Salamanczuk Z, Karabin K, Wasilewska K, Paluszewska M, Urbanowska E, Gajkowska-Kulik J, Semenczuk G, Rybka J, Wrobel T, Ejduk A, Kata D, Grosicki S, Robak T, Pluta A, Kominek A, Piwocka K, Pyziak K, Sroka-Porada A, Wrobel A, Przybylowicz A, Wojtaszewska M, Lewandowski K, Gil L, Piekarska A, Knopinska W, Bolkun L, Warzocha K, Kuliczkowski K, Sacha T, Basak G, Jedrzejczak WW, Holowiecki J, Juszczynski P, and Haus O
- Subjects
- Adolescent, Adult, Aged, Cladribine therapeutic use, Cytarabine therapeutic use, Daunorubicin therapeutic use, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Middle Aged, Pharmacogenomic Variants, Poland epidemiology, Randomized Controlled Trials as Topic, Retrospective Studies, Young Adult, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics
- Abstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2
+ ) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.- Published
- 2021
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34. The Anticancer Action of a Novel 1,2,4-Triazine Sulfonamide Derivative in Colon Cancer Cells.
- Author
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Gornowicz A, Szymanowska A, Mojzych M, Czarnomysy R, Bielawski K, and Bielawska A
- Subjects
- Antineoplastic Agents chemistry, Apoptosis drug effects, Beclin-1 metabolism, Caspases metabolism, Cell Cycle drug effects, Cell Line, Tumor, Cell Shape drug effects, Cell Survival drug effects, Humans, TOR Serine-Threonine Kinases metabolism, Triazines chemistry, Antineoplastic Agents pharmacology, Colonic Neoplasms pathology, Sulfonamides pharmacology, Triazines pharmacology
- Abstract
Cancer therapy is one of the most important challenges of modern medical and chemical sciences. Among the many methods of combating cancer, chemotherapy plays a special role. Imperfect modern chemotherapy justifies continuing the search for new, more effective, and safe drugs. Sulfonamides are the classic group of chemotherapeutic drugs with a broad spectrum of pharmacological activity. Recent literature reports show that sulfonamide derivatives have anti-tumor activity in vitro and in vivo. The aim of the study was to synthesize a novel 1,2,4-triazine sulfonamide derivative and check its anticancer potential in DLD-1 and HT-29 colon cancer cells. The biological studies included MTT assay, DNA biosynthesis, cell cycle analysis, Annexin V binding assay, ethidium bromide/acridine orange staining, and caspase-8, -9, and -3/7 activity. The concentrations of important molecules (sICAM-1, mTOR, Beclin-1, cathepsin B) involved in the pathogenesis and poor prognosis of colorectal cancer were also evaluated by ELISA. We demonstrated that the novel compound was able to induce apoptosis through intrinsic and extrinsic pathways and was capable of decreasing sICAM-1, mTOR, cathepsin B concentrations, whereas increased Beclin-1 concentration was detected in both colon cancer cell lines. The novel compound represents promising multi-targeted potential in colorectal cancer, but further in vivo examinations are needed to confirm the claim.
- Published
- 2021
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35. The Pro-Apoptotic Effect of Silica Nanoparticles Depends on Their Size and Dose, as Well as the Type of Glioblastoma Cells.
- Author
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Krętowski R, Kusaczuk M, Naumowicz M, and Cechowska-Pasko M
- Subjects
- Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Tumor, Cell Survival drug effects, Female, Glioblastoma metabolism, Glioblastoma pathology, Humans, Middle Aged, Nanoparticles administration & dosage, Necrosis, Oxidative Stress drug effects, Particle Size, Reactive Oxygen Species metabolism, Antineoplastic Agents pharmacology, Glioblastoma drug therapy, Nanoparticles chemistry, Silicon Dioxide pharmacology
- Abstract
Despite intensive investigations, nanoparticle-induced cellular damage is an important problem that has not been fully elucidated yet. Here, we report that silica nanoparticles (SiNPs) demonstrated anticancer influence on glioblastoma cells by the induction of apoptosis or necrosis. These effects are highly cell type-specific, as well as dependent on the size and dose of applied nanoparticles. Exposure of LN-18 and LBC3 cells to different sizes of SiNPs-7 nm, 5-15 nm, or 10-20 nm-at dosages, ranging from 12.5 to 1000 µg/mL, for 24 and 48 h reduced the viability of these cells. Treatment of LN-18 and LBC3 cells with 7 nm or 10-20 nm SiNPs at doses ≥50 µg/mL caused a strong induction of apoptosis, which is connected with an increase of intracellular reactive oxygen species (ROS) production. The 5-15 nm SiNPs exhibited distinct behavior comparing to silica nanoparticles of other studied sizes. In contrast to LBC3, in LN-18 cells exposed to 5-15 nm SiNPs we did not observe any effect on apoptosis. These nanoparticles exerted only strong necrosis, which was connected with a reduction in ROS generation. This suggests that SiNPs can trigger different cellular/molecular effects, depending on the exposure conditions, the size and dose of nanoparticles, and cell type of glioblastoma.
- Published
- 2021
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36. High immunoproteasome concentration in the plasma of patients with newly diagnosed multiple myeloma treated with bortezomib is predictive of longer OS.
- Author
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Breczko W, Lemancewicz D, Dzięcioł J, Kłoczko J, and Bołkun Ł
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Middle Aged, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Multiple Myeloma pathology, Prognosis, Survival Rate, Antineoplastic Agents therapeutic use, Biomarkers metabolism, Bortezomib therapeutic use, Multiple Myeloma mortality, Proteome metabolism
- Abstract
Purpose: Proteasome inhibitors (PI) bortezomib or carfilzomib among them, play a crucial role in the modern standard therapy for multiple myeloma (MM). In this study, we intended to evaluate whether immunoproteasome (IMP) concentration could act as an effective biomarker which determines the probability of response to treatment with bortezomib, in order to detect groups of patients who are more likely to respond to treatment with PI., Materials and Methods: In our study, we evaluated IMP concentration in the plasma of 40 patients with monoclonal gammopathy of undetermined significance (MGUS) and 116 patients with newly diagnosed MM during treatment with or without PI., Results: The values of all the studied parameters after the applied chemotherapy in the responders' group of patients declined considerably during the consecutive cycles of chemotherapy compared to their initial levels. On the contrary, in the group of non-responders, we observed no change in the measured IMP parameters during the consecutive cycles of therapy. We also showed that higher baseline IMP concentration might indicate longer overall survival (OS) in all patients., Conclusions: Our results indicate that assessing plasma IMP concentration can be applied as a strong biomarker for predicting clinical response to treatment and OS in patients with newly diagnosed MM., (Copyright © 2020 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
37. Selenium Compounds as Novel Potential Anticancer Agents.
- Author
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Radomska D, Czarnomysy R, Radomski D, and Bielawski K
- Subjects
- Animals, Antineoplastic Agents chemistry, Chemoprevention methods, Clinical Trials as Topic, Humans, Neoplasms metabolism, Neoplasms prevention & control, Selenium Compounds chemistry, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Selenium Compounds therapeutic use
- Abstract
The high number of new cancer incidences and the associated mortality continue to be alarming, leading to the search for new therapies that would be more effective and less burdensome for patients. As there is evidence that Se compounds can have chemopreventive activity, studies have begun to establish whether these compounds can also affect already existing cancers. This review aims to discuss the different classes of Se-containing compounds, both organic and inorganic, natural and synthetic, and the mechanisms and molecular targets of their anticancer activity. The chemical classes discussed in this paper include inorganic (selenite, selenate) and organic compounds, such as diselenides, selenides, selenoesters, methylseleninic acid, 1,2-benzisoselenazole-3[2H]-one and selenophene-based derivatives, as well as selenoamino acids and Selol.
- Published
- 2021
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38. Mushrooms as potential therapeutic agents in the treatment of cancer: Evaluation of anti-glioma effects of Coprinus comatus, Cantharellus cibarius, Lycoperdon perlatum and Lactarius deliciosus extracts.
- Author
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Nowakowski P, Markiewicz-Żukowska R, Gromkowska-Kępka K, Naliwajko SK, Moskwa J, Bielecka J, Grabia M, Borawska M, and Socha K
- Subjects
- Antineoplastic Agents isolation & purification, Basidiomycota chemistry, Brain Neoplasms enzymology, Brain Neoplasms pathology, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Coprinus chemistry, DNA Replication drug effects, Glioblastoma enzymology, Glioblastoma pathology, Humans, Matrix Metalloproteinases metabolism, Oxidative Stress drug effects, Agaricales chemistry, Antineoplastic Agents pharmacology, Brain Neoplasms drug therapy, Glioblastoma drug therapy
- Abstract
Cancer incidence rates are on the increase worldwide. The most common brain cancer in adults is glioblastoma. Currently available treatment modalities are limited and natural products such as mushrooms could enhance them. Apart from nutritional value, mushrooms are an excellent source of bioactive compounds and therefore could be used to treat various disorders. The aim of the study was to assess the anti-glioma potential of selected mushrooms on U87MG, LN-18 glioblastoma and SVGp12 normal human astroglial cell lines. The materials were Cantharellus cibarius, Coprinus comatus, Lycoperdon perlatum and Lactarius delicious. Aqueous, 70 % ethanol or 95 % ethanol extracts from mushrooms were used for analysis including assessment of antioxidant activity by DPPH assay, cell viability by MTT assay, DNA biosynthesis by thymidine incorporation assay, activity of metalloproteinase by gelatin zymography and cell cycle assay by flow cytometry. Mushroom extracts influenced the viability and DNA biosynthesis of cancer cells. Activity of ethanol mushroom extracts was stronger than that of aqueous extracts. Anti-glioma mechanism consisted in inhibition of cancer cell proliferation and induction of apoptosis associated with arrest of cells in subG1 or G2/M phase of cell cycle, and inhibition of metalloproteinases activity. Among investigated mushrooms, L. deliciosus and C. comatus showed the greatest anti-glioma potential., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2021
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39. DNA topoisomerases as molecular targets for anticancer drugs.
- Author
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Buzun K, Bielawska A, Bielawski K, and Gornowicz A
- Subjects
- Acridines chemistry, Acridines pharmacology, Animals, Antineoplastic Agents pharmacology, Dexrazoxane chemistry, Dexrazoxane pharmacology, Drug Screening Assays, Antitumor, Humans, Molecular Docking Simulation, Quinolones chemistry, Quinolones pharmacology, Structure-Activity Relationship, Thiobarbiturates chemistry, Thiobarbiturates pharmacology, Topoisomerase Inhibitors pharmacology, Antineoplastic Agents chemistry, DNA Topoisomerases metabolism, Topoisomerase Inhibitors chemistry
- Abstract
The significant role of topoisomerases in the control of DNA chain topology has been confirmed in numerous research conducted worldwide. The prevalence of these enzymes, as well as the key importance of topoisomerase in the proper functioning of cells, have made them the target of many scientific studies conducted all over the world. This article is a comprehensive review of knowledge about topoisomerases and their inhibitors collected over the years. Studies on the structure-activity relationship and molecular docking are one of the key elements driving drug development. In addition to information on molecular targets, this article contains details on the structure-activity relationship of described classes of compounds. Moreover, the work also includes details about the structure of the compounds that drive the mode of action of topoisomerase inhibitors. Finally, selected topoisomerases inhibitors at the stage of clinical trials and their potential application in the chemotherapy of various cancers are described.
- Published
- 2020
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40. The intensification of anticancer activity of LFM-A13 by erythropoietin as a possible option for inhibition of breast cancer.
- Author
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Rozkiewicz D, Hermanowicz JM, Tankiewicz-Kwedlo A, Sieklucka B, Pawlak K, Czarnomysy R, Bielawski K, Surazynski A, Kalafut J, Przybyszewska A, Koda M, Jakubowska K, Rivero-Muller A, and Pawlak D
- Subjects
- Adult, Aged, Aged, 80 and over, Amides chemistry, Antineoplastic Agents chemistry, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Erythropoietin metabolism, Female, Humans, Middle Aged, Molecular Structure, Nitriles chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Amides pharmacology, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Erythropoietin antagonists & inhibitors, Nitriles pharmacology
- Abstract
Recombinant human erythropoietin (Epo) is an effective and convenient treatment for cancer-related anaemia. In our study for the first time, we evaluated the effect of simultaneous use of Epo and Bruton's tyrosine kinase (BTK) inhibitor LFM-A13 on the viability and tumour development of breast cancer cells. The results demonstrated that Epo significantly intensifies the anticancer activity of LFM-A13 in MCF-7 and MDA-MB-231. The featured therapeutic scheme efficiently blocked the tumour development in zebrafish experimental cancer model. Epo and LFM-A13 administered together resulted in effective cell killing, accompanied by attenuation of the BTK signalling pathways, loss of mitochondrial membrane potential (MMP), accumulation of apoptotic breast cancer cells with externalised PS, a slight increase in phase G0/G1 and a reduction in cyclin D1 expression. Simultaneous use of Epo with LFM-A13 inhibited early stages of tumour progression. This therapeutic scheme may be rationale for further possible research.
- Published
- 2020
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41. Urine NGAL and KIM-1: tubular injury markers in acute lymphoblastic leukemia survivors.
- Author
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Latoch E, Konończuk K, Taranta-Janusz K, Muszyńska-Rosłan K, Szymczak E, Wasilewska A, and Krawczuk-Rybak M
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury epidemiology, Acute Kidney Injury urine, Adolescent, Biomarkers urine, Cancer Survivors statistics & numerical data, Case-Control Studies, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Renal Insufficiency, Chronic chemically induced, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic urine, Young Adult, Acute Kidney Injury diagnosis, Antineoplastic Agents administration & dosage, Hepatitis A Virus Cellular Receptor 1 analysis, Lipocalin-2 urine, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Renal Insufficiency, Chronic diagnosis
- Abstract
Introduction: Nephrotoxicity is a potential adverse effect of anticancer treatment in childhood. Cytostatics, abdominal radiotherapy, total body irradiation (TBI) and some agents used in supportive care may induce acute kidney injury (AKI) or lead to chronic kidney disease (CKD). The aim of this study was to test the hypothesis whether urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are increased in acute lymphoblastic leukemia (ALL) survivors., Method: The study cohort consisted of 86 patients (42 females) previously treated for ALL. The median time after cessation of treatment was 6.55 (IQR: 1.96-9.93) years and median age at the time of study: 12 (IQR: 6.76-16.00). The control group included 53 healthy peers. Immunoenzymatic ELISA commercial kits were used to measure urine KIM-1 and NGAL levels., Results: The median levels of urine uNGAL (p < 0.05), uNGAL/creatinine (cr.) ratio (p < 0.0001) and uKIM-1/creatinine ratio (p < 0.0001) were significantly higher in ALL survivors in comparison with healthy controls. Female patients had significantly higher levels of NGAL and NGAL/cr. than males (mean 8.42 ± 7.1 vs. 4.59 ± 4.5 ng/mL and 86.57 ± 77 vs. 37.7 ± 37 ng/mg, respectively; p < 0.01). Of all the study participants, 11 (13%) presented eGFR below 90 mL/min/1.73 m
2 . The NGAL/cr. ratio seemed to be the best predictor of decreased eGFR (AUC = 0.65). The cumulative dose of methotrexate and cyclophosphamide did not predict the values of the urine NGAL, NGAL/cr., KIM-1/cr. and eGFR. Five years after the end of treatment, the patients had higher levels of uKIM-1 (1.02 ± 0.8 vs. 0.62 ± 0.6 ng/mL, p < 0.01), uNGAL (7.9 ± 6.7 vs. 4.6 ± 5 ng/mL, p < 0.01) and lower eGFR (114 ± 29 vs. 134 ± 35 mL/min/1.73 m2 , p < 0.01) in comparison with ALL survivors with the observation period of less than 5 years., Conclusion: We demonstrated that ALL survivors have higher levels of urine NGAL, NGAL/cr. and uKIM-1/cr. ratio as compared to the control group. Further long-term follow-up studies are necessary to assess the significance of the NGAL and KIM-1 and their relationship to kidney damage after anticancer treatment in childhood.- Published
- 2020
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42. Evaluation of Cytotoxic Effect of Cholesterol End-Capped Poly( N -Isopropylacrylamide)s on Selected Normal and Neoplastic Cells.
- Author
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Misiak P, Niemirowicz-Laskowska K, Markiewicz KH, Misztalewska-Turkowicz I, Wielgat P, Kurowska I, Siemiaszko G, Destarac M, Car H, and Wilczewska AZ
- Subjects
- Adult, Animals, Antineoplastic Agents chemistry, Cell Line, Tumor, Drug Carriers adverse effects, Fibroblasts drug effects, Glioblastoma drug therapy, Glioblastoma pathology, Hemolysis drug effects, Humans, Hydrophobic and Hydrophilic Interactions, Mice, Micelles, Molecular Weight, Phase Transition, Polymerization, Polymers chemistry, Temperature, Water, Acrylic Resins chemistry, Antineoplastic Agents pharmacology, Cholesterol chemistry, Drug Carriers chemistry, Drug Carriers pharmacology
- Abstract
Purpose: Efficient intracellular delivery of a therapeutic compound is an important feature of smart drug delivery systems (SDDS). Modification of a carrier structure with a cell-penetrating ligand, ie, cholesterol moiety, is a strategy to improve cellular uptake. Cholesterol end-capped poly( N -isopropylacrylamide)s offer a promising foundation for the design of efficient thermoresponsive drug delivery systems., Methods: A series of cholesterol end-capped poly( N -isopropylacrylamide)s (PNIPAAm) with number-average molar masses ranging from 3200 to 11000 g·mol
-1 were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization from original xanthate-functionalized cholesterol and self-assembled into micelles. The physicochemical characteristics and cytotoxicity of cholesterol end-capped poly( N -isopropylacrylamide)s have been thoroughly investigated., Results: Phase transition temperature dependence on the molecular weight and hydrophilic/hydrophobic ratio in the polymers were observed in water. Biological test results showed that the obtained materials, both in disordered and micellar form, are non-hemolytic, highly compatible with fibroblasts, and toxic to glioblastoma cells. It was found that the polymer termini dictates the mode of action of the system., Conclusion: The cholesteryl moiety acts as a cell-penetrating agent, which enables disruption of the plasma membrane and in effect leads to the restriction of the tumor growth. Cholesterol end-capped PNIPAAm showing in vitro anticancer efficacy can be developed not only as drug carriers but also as components of combined/synergistic therapy., Competing Interests: All authors report no conflicts of interest in this work., (© 2020 Misiak et al.)- Published
- 2020
- Full Text
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43. Review of the Synthesis and Anticancer Properties of Pyrazolo[4,3- e ][1,2,4]triazine Derivatives.
- Author
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Bernat Z, Szymanowska A, Kciuk M, Kotwica-Mojzych K, and Mojzych M
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Sulfonamides chemical synthesis, Sulfonamides pharmacology, Triazines chemical synthesis, Triazines pharmacology
- Abstract
This review focuses on the cytotoxic effect of new synthetic pyrazolo[4,3- e ][1,2,4]triazine derivatives against different tumor cell lines. Some annulated pyrazolotriazines i.e., pyrazolo[4,3- e ][1,2,4]triazolo[4,3- b ][1,2,4]triazines and pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine demonstrated significant broad cytotoxic activity in micromolar range concentration, which could have excellent potential to be new candidate therapeutic agents in cancer chemotherapy., Competing Interests: The authors declare no conflict of interest.
- Published
- 2020
- Full Text
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44. Synthesis and cellular effects of novel 1,3,5-triazine derivatives in DLD and Ht-29 human colon cancer cell lines.
- Author
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Wróbel A, Kolesińska B, Frączyk J, Kamiński ZJ, Tankiewicz-Kwedlo A, Hermanowicz J, Czarnomysy R, Maliszewski D, and Drozdowska D
- Subjects
- Antineoplastic Agents chemical synthesis, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Colonic Neoplasms metabolism, Humans, Membrane Potential, Mitochondrial drug effects, Proto-Oncogene Proteins c-bcl-2 metabolism, Triazines chemical synthesis, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, Triazines pharmacology
- Abstract
This study provides new information on the cellular effects of 1,3,5-triazine nitrogen mustards with different peptide groups in DLD and Ht-29 human colon cancer cell lines. A novel series of 2,4,6-trisubstituted 1,3,5-triazine derivatives bearing 2-chloroethyl and oligopeptide moieties was designed and synthesized. The most cytotoxic derivative was triazine with an Ala-Ala-OMe substituent on the ring (compound 7b). This compound induced time- and dose-dependent cytotoxicity in the DLD-1 and HT-29 colon cancer cell lines. The triazine derivative furthermore induced apoptosis through intracellular signaling pathway attenuation. Compound 7b may be a candidate for further evaluation as a chemotherapeutic agent against colorectal cancer.
- Published
- 2020
- Full Text
- View/download PDF
45. The Effect of Novel 7-methyl-5-phenyl-pyrazolo[4,3- e ]tetrazolo[4,5- b ][1,2,4]triazine Sulfonamide Derivatives on Apoptosis and Autophagy in DLD-1 and HT-29 Colon Cancer Cells.
- Author
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Gornowicz A, Szymanowska A, Mojzych M, Bielawski K, and Bielawska A
- Subjects
- Caspase 8 metabolism, Drug Screening Assays, Antitumor, HT29 Cells, Humans, Mitochondrial Membranes metabolism, Mitochondrial Membranes pathology, Neoplasm Proteins metabolism, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Autophagy drug effects, Colonic Neoplasms drug therapy, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Triazines chemical synthesis, Triazines chemistry, Triazines pharmacology
- Abstract
The discovery of cytotoxic drugs is focused on designing a compound structure that directly affects cancer cells without an impact on normal cells. The mechanism of anticancer activity is mainly related with activation of apoptosis. However, recent scientific reports show that autophagy also plays a crucial role in cancer cell progression. Thus, the objective of this study was to synthesize 7-methyl-5-phenyl-pyrazolo[4,3- e ]tetrazolo[4,5- b ][1,2,4]triazine utilizing nucleophilic substitution reaction at the position N1. The biological activity of tested compounds was assessed in DLD-1 and HT-29 cell lines. The induction of apoptosis was confirmed by Annexin V binding assay and acridine orange/ethidium bromide staining. The loss of mitochondrial membrane potential and caspase-8 activity was estimated using cytometer flow analysis. The concentration of p53, LC3A, LC3B and beclin-1 was measured using the ELISA technique. Our study revealed that anticancer activity of 7-methyl-5-phenyl-pyrazolo[4,3- e ]tetrazolo[4,5- b ][1,2,4]triazine derivatives is related with initiation of apoptosis occur on the intrinsic pathway with mitochondrial membrane decrease and extrinsic with increase of activity of caspase-8. Moreover, a decrease in beclin-1, LC3A, and LC3B were observed in two cell lines after treatment with novel compounds. This study showed that novel 7-methyl-5-phenyl-pyrazolo[4,3- e ]tetrazolo[4,5- b ][1,2,4]triazine derivatives might be a potential strategy in colon cancer treatment.
- Published
- 2020
- Full Text
- View/download PDF
46. Combinatory Treatment with miR-7-5p and Drug-Loaded Cubosomes Effectively Impairs Cancer Cells.
- Author
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Gajda E, Godlewska M, Mariak Z, Nazaruk E, and Gawel D
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic drug effects, HeLa Cells, Humans, MicroRNAs genetics, MicroRNAs pharmacology, Neoplasms genetics, Antineoplastic Agents administration & dosage, Drug Carriers chemistry, MicroRNAs administration & dosage, Neoplasms therapy
- Abstract
Background: Multidrug resistance (MDR) is an emerging problem in the treatment of cancer. Therefore, there is a necessity for novel strategies that would sensitize tumor cells to the administered chemotherapeutics. One of the innovative approaches in fighting drug-resistant tumors is the treatment of cancer with microRNA (miRNA), or the use of cubosomes (lipid nanoparticles) loaded with drugs. Here, we present a study on a novel approach, which combines both tools., Methods: Cubosomes loaded with miR-7-5p and chemotherapeutics were developed. The effects of drug- and miRNA-loaded vehicles on glioma- (A172, T98G), papillary thyroid- (TPC-1) and cervical carcinoma-derived (HeLa) cells were analyzed using molecular biology techniques, including quantitative real-time PCR, MTS-based cell proliferation test, flow cytometry and spheroids formation assay., Results: The obtained data indicate that miR-7-5p increases the sensitivity of the tested cells to the drug, and that nanoparticles loaded with both miRNA and the drug produce a greater anti-tumor effect in comparison to the free drug treatment. It was found that an increased level of apoptosis in the drug/miRNA co-treated cells is accompanied by an alternation in the expression of the genes encoding for key MDR proteins of the ABC family., Conclusions: Overall, co-administration of miR-7-5p with a chemotherapeutic can be considered a promising strategy, leading to reduced MDR and the induction of apoptosis in cancer cells.
- Published
- 2020
- Full Text
- View/download PDF
47. Evaluation of the Anticancer Activities of Novel Transition Metal Complexes with Berenil and Nitroimidazole.
- Author
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Czarnomysy R, Radomska D, Muszyńska A, Hermanowicz JM, Prokop I, Bielawska A, and Bielawski K
- Subjects
- Animals, Apoptosis drug effects, Apoptosis genetics, Cell Line, Tumor, Cell Survival drug effects, Cisplatin pharmacology, Coordination Complexes chemical synthesis, Coordination Complexes chemistry, DNA drug effects, DNA metabolism, DNA Topoisomerases, Type II metabolism, Diminazene chemistry, Female, Gold pharmacology, Humans, Membrane Potential, Mitochondrial drug effects, Mitochondria drug effects, Mitochondria metabolism, Palladium pharmacology, Platinum pharmacology, Transition Elements chemistry, Xenograft Model Antitumor Assays, Zebrafish, Antineoplastic Agents pharmacology, Autophagosomes drug effects, Breast Neoplasms drug therapy, Coordination Complexes pharmacology, Diminazene analogs & derivatives, Nitroimidazoles chemistry, Organometallic Compounds pharmacology
- Abstract
Novel transition metal complexes (Au, Pd, Pt) with berenil and 2-(1-methyl-5-nitroimidazol-2-yl)ethanol were obtained through two-step synthesis. The cytotoxicity assay against MCF-7 and MDA-MB-231 breast cancer cells revealed that novel platinum and palladium complexes cause a reduction on the viability of MCF-7 and MDA-MB-231 breast cancer cells to a greater extent than cisplatin. The complexes showed lower cytotoxicity on normal MCF-10A human breast epithelial cells than on tumor cells. Furthermore, we observed that these complexes selectively concentrate in tumor cell mitochondria due to the characteristic for these cells increased membrane potential that may explain their increased proapoptotic activity. The activity of the synthesized compounds against topoisomerase type IIα and their increased impact on DNA defragmentation also were documented. The novel complexes also induced autophagosome changes and inhibited tumor growth in xenograft models (established using breast cancer cells).
- Published
- 2020
- Full Text
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48. 1,2,4-Triazine Sulfonamides: Synthesis by Sulfenamide Intermediates, In Vitro Anticancer Screening, Structural Characterization, and Molecular Docking Study.
- Author
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Branowska D, Karczmarzyk Z, Wolińska E, Wysocki W, Morawiak M, Urbańczyk-Lipkowska Z, Bielawska A, and Bielawski K
- Subjects
- Antineoplastic Agents pharmacology, Binding Sites, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Chlorambucil pharmacology, Drug Design, Drug Screening Assays, Antitumor, Estrogen Receptor alpha antagonists & inhibitors, Estrogen Receptor alpha metabolism, Humans, Inhibitory Concentration 50, MCF-7 Cells, Protein Binding, Protein Conformation, alpha-Helical, Protein Interaction Domains and Motifs, Structure-Activity Relationship, Sulfonamides pharmacology, Triazines pharmacology, Antineoplastic Agents chemical synthesis, Estrogen Receptor alpha chemistry, Molecular Docking Simulation, Sulfonamides chemical synthesis, Triazines chemical synthesis
- Abstract
In this study, we synthesized novel sulfonamides with a 1,2,4-triazine moiety according to pharmacophore requirements for biological activity. All the synthesized compounds were tested in vitro to verify whether they exhibited anticancer activity against the human breast cancer cell lines MCF-7 and MDA-MB-231. Among them, two most active ones, having IC
50 values of 50 and 42 µM, respectively, were found to show higher anticancer activity than chlorambucil used as the reference in the in vitro tests. In addition, two other compounds, which had IC50 values of 78 and 91 µM, respectively, exhibited a similar level of activity as chlorambucil. X-ray analysis carried out for two of the compounds confirmed their synthesis pathway as well as their assumed molecular structures. Furthermore, a conformational analysis was performed, and electronic parameters of molecules were characterized using theoretical calculations at AM1 and DFT level. Moreover, molecular docking revealed the mode of binding of the investigated 1,2,4-triazine sulfonamides with the human estrogen receptor alpha (ER α ).- Published
- 2020
- Full Text
- View/download PDF
49. The modulating effect of lipid bilayer/p-coumaric acid interactions on electrical properties of model lipid membranes and human glioblastoma cells.
- Author
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Naumowicz M, Kusaczuk M, Kruszewski MA, Gál M, Krętowski R, Cechowska-Pasko M, and Kotyńska J
- Subjects
- Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Line, Tumor, Cell Membrane Permeability drug effects, Cell Survival drug effects, Coumaric Acids, Dielectric Spectroscopy, Dose-Response Relationship, Drug, Electric Impedance, Electrophoresis, Glioblastoma metabolism, Glioblastoma pathology, Humans, Lipid Bilayers metabolism, Liposomes, Permeability, Phospholipids chemistry, Propionates administration & dosage, Propionates pharmacokinetics, Surface Properties, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Lipid Bilayers chemistry, Membranes, Artificial, Models, Biological, Propionates pharmacology
- Abstract
Biological membranes are one of the most important elements of living cells determining their permeability to the active compounds. Still, little is known about the drug-membrane interactions in terms of pharmacological properties of potential drugs. Chemoprevention based on natural compounds is becoming a strong trend in modern oncopharmacology, and p-coumaric acid (p-CoA) is one such compound with tentative anticancer activity. The microelectrophoretic mobility measurements and electrochemical impedance spectroscopy were applied to study the effects of p-CoA on electrical properties of liposomes, spherical bilayers, and human glioblastoma cell membranes. Our results demonstrated that after treatment with p-CoA, the surface charge of LBC3, LN-229 and LN-18 cell lines was significantly changed in alkaline pH solutions, but not in acidic pH solutions. In contrast, no changes in surface charge density values were registered for phosphatidylethanolamine liposomal membranes and A172 cell membranes after p-CoA treatment. The impedance data showed an increase in values of both the electrical capacitance and the electrical resistance, indicating that p-CoA can be partially inserted into the phosphatidylcholine bilayers. The MTT assay showed cell line-dependent cytotoxic effect of p-CoA. Further molecular analyses revealed the ATP depletion and gene transcription modulation, which might indicate organelle membrane-crossing potential of p-CoA. These results suggest, that changes in surface charge of membranes of living cells not only might be potential predictor of membrane permeability, but also indicate differential composition of cell membranes in various cell lines. Thus further multidirectional analyses are required to implement electrochemical methods as standard testing procedures during drug development process., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
50. The cellular effects of novel triazine nitrogen mustards in glioblastoma LBC3, LN-18 and LN-229 cell lines.
- Author
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Krętowski R, Drozdowska D, Kolesińska B, Kamiński Z, Frączyk J, and Cechowska-Pasko M
- Subjects
- Glioblastoma drug therapy, Humans, Necrosis, Triazines chemistry, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Proliferation drug effects, Glioblastoma pathology, Nitrogen Mustard Compounds pharmacology, Triazines pharmacology
- Abstract
1,3,5-triazine is an important heterocyclic skeleton for mono, two or three 2-chloroethylamine groups. The study presented here provides novel information on cellular effects of 1,3,5-triazine with mono, two or three 2-chloroethylamine groups in glioblastoma LBC3, LN-18 and LN-229 cell lines. In our study, the most cytotoxic effect was observed in 1,3,5-triazine with three 2-chloroethylamine groups (12f compound). It has been demonstrated that 12f induce time- and dose-dependent cytotoxicity in all investigated glioma cell lines. Apart from that in glioblastoma cells, treated with 12f compound, we noticed strong induction of apoptosis. In conclusion, this research provides novel information concerning cellular effects of apoptosis in LBC3, LN-18 and LN-229 cell lines. Moreover, we suggest that 12f compound may be a candidate for further evaluation as an effective chemotherapeutic agent for human glioblastoma cells.
- Published
- 2019
- Full Text
- View/download PDF
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