2017
Herůdková, Jarmila; Paruch, Kamil; Khirsariya, Prashant; Souček, Karel; Krkoška, Martin; Blanářová, Olga Vondálová; Sova, Petr; Kozubík, Alois; Vaculová, Alena Hyršlová
Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells. Journal Article
In: Neoplasia (New York, N.Y.), vol. 19, no. 10, pp. 830–841, 2017, ISSN: 1476-5586 1522-8002, (Place: United States).
Abstract | Links | BibTeX | Tags: Antineoplastic Agents/*pharmacology, Apoptosis/drug effects, Cell Cycle/drug effects/genetics, Cell Line, Cell Survival/drug effects, Cellular Senescence/drug effects, Checkpoint Kinase 1/*antagonists & inhibitors/genetics/*metabolism, Cisplatin/pharmacology, Colonic Neoplasms/drug therapy/genetics/*metabolism/pathology, Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism, DNA Damage/drug effects, Gene Knockout Techniques, Humans, Platinum Compounds/*pharmacology, Pyrazoles/*pharmacology, Pyrimidines/*pharmacology, Tumor, Tumor Suppressor Protein p53/genetics/metabolism
@article{herudkova_chk1_2017,
title = {Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells.},
author = {Jarmila Herůdková and Kamil Paruch and Prashant Khirsariya and Karel Souček and Martin Krkoška and Olga Vondálová Blanářová and Petr Sova and Alois Kozubík and Alena Hyršlová Vaculová},
doi = {10.1016/j.neo.2017.08.002},
issn = {1476-5586 1522-8002},
year = {2017},
date = {2017-10-01},
journal = {Neoplasia (New York, N.Y.)},
volume = {19},
number = {10},
pages = {830–841},
abstract = {Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase-related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells.},
note = {Place: United States},
keywords = {Antineoplastic Agents/*pharmacology, Apoptosis/drug effects, Cell Cycle/drug effects/genetics, Cell Line, Cell Survival/drug effects, Cellular Senescence/drug effects, Checkpoint Kinase 1/*antagonists & inhibitors/genetics/*metabolism, Cisplatin/pharmacology, Colonic Neoplasms/drug therapy/genetics/*metabolism/pathology, Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism, DNA Damage/drug effects, Gene Knockout Techniques, Humans, Platinum Compounds/*pharmacology, Pyrazoles/*pharmacology, Pyrimidines/*pharmacology, Tumor, Tumor Suppressor Protein p53/genetics/metabolism},
pubstate = {published},
tppubtype = {article}
}
Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate the ability of one of the most specific Chk1 inhibitors, SCH900776 (MK-8776), to enhance human colon cancer cell sensitivity to the cytotoxic effects of platinum(II) cisplatin and platinum(IV)- LA-12 complexes. The combined treatment with SCH900776 and cisplatin or LA-12 results in apparent increase in G1/S phase-related apoptosis, stimulation of mitotic slippage, and senescence of HCT116 cells. We further show that the cancer cell response to the drug combinations is significantly affected by the p21, p53, and PTEN status. In contrast to their wt counterparts, the p53- or p21-deficient cells treated with SCH900776 and cisplatin or LA-12 enter mitosis and become polyploid, and the senescence phenotype is strongly suppressed. While the cell death induced by SCH900776 and cisplatin or LA-12 is significantly delayed in the absence of p53, the anticancer action of the drug combinations is significantly accelerated in p21-deficient cells, which is associated with stimulation of apoptosis beyond G2/M cell cycle phase. We also show that cooperative killing action of the drug combinations in HCT116 cells is facilitated in the absence of PTEN. Our results indicate that SCH900776 may act as an important modulator of cytotoxic response triggered by platinum-based drugs in colon cancer cells.
2010
Svihálková-Sindlerová, Lenka; Foltinová, Vendula; Vaculová, Alena; Horváth, Viktor; Soucek, Karel; Sova, Petr; Hofmanová, Jirina; Kozubík, Alois
LA-12 overcomes confluence-dependent resistance of HT-29 colon cancer cells to Pt (II) compounds. Journal Article
In: Anticancer research, vol. 30, no. 4, pp. 1183–1188, 2010, ISSN: 1791-7530 0250-7005, (Place: Greece).
Abstract | BibTeX | Tags: Adenocarcinoma/*drug therapy, Amantadine/*analogs & derivatives/pharmacology, Antineoplastic Agents/*pharmacology, Apoptosis/drug effects, Cell Adhesion/drug effects, Cisplatin/pharmacology, Colonic Neoplasms/*drug therapy/pathology, Dose-Response Relationship, Drug, Drug resistance, HT29 Cells, Humans, Neoplasm, Organoplatinum Compounds/*pharmacology, Oxaliplatin
@article{svihalkova-sindlerova_-12_2010,
title = {LA-12 overcomes confluence-dependent resistance of HT-29 colon cancer cells to Pt (II) compounds.},
author = {Lenka Svihálková-Sindlerová and Vendula Foltinová and Alena Vaculová and Viktor Horváth and Karel Soucek and Petr Sova and Jirina Hofmanová and Alois Kozubík},
issn = {1791-7530 0250-7005},
year = {2010},
date = {2010-04-01},
journal = {Anticancer research},
volume = {30},
number = {4},
pages = {1183–1188},
abstract = {BACKGROUND: LA-12 is a new platinum (IV) drug with promising cytotoxic effects in a wide range of cancer cell lines. Its confluence-dependent effects were compared with cisplatin (CDDP) and oxaliplatin (L-OHP) in HT-29 cells. MATERIALS AND METHODS: Cytotoxicity was determined by MTT test, eosin exclusion assay, and cell number quantification. The cell cycle was analysed using propidium iodide DNA staining (flow cytometry), apoptosis by phosphatidylserine externalisation (annexin-V assay), mitochondrial membrane potential by flow cytometry, nuclear morphology by means of fluorescence microscopy, and PARP cleavage by Western blotting. RESULTS: While L-OHP and CDDP were practically inactive in the subconfluent cell population, LA-12 showed a similar toxicity in both subconfluent and growing populations. All compounds induced apoptosis, although with different potentials. CONCLUSION: LA-12 was able to overcome confluence-dependent resistance of HT-29 cells observed for other platinum compounds, which may have potential therapeutic use in slowly growing tumours.},
note = {Place: Greece},
keywords = {Adenocarcinoma/*drug therapy, Amantadine/*analogs & derivatives/pharmacology, Antineoplastic Agents/*pharmacology, Apoptosis/drug effects, Cell Adhesion/drug effects, Cisplatin/pharmacology, Colonic Neoplasms/*drug therapy/pathology, Dose-Response Relationship, Drug, Drug resistance, HT29 Cells, Humans, Neoplasm, Organoplatinum Compounds/*pharmacology, Oxaliplatin},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: LA-12 is a new platinum (IV) drug with promising cytotoxic effects in a wide range of cancer cell lines. Its confluence-dependent effects were compared with cisplatin (CDDP) and oxaliplatin (L-OHP) in HT-29 cells. MATERIALS AND METHODS: Cytotoxicity was determined by MTT test, eosin exclusion assay, and cell number quantification. The cell cycle was analysed using propidium iodide DNA staining (flow cytometry), apoptosis by phosphatidylserine externalisation (annexin-V assay), mitochondrial membrane potential by flow cytometry, nuclear morphology by means of fluorescence microscopy, and PARP cleavage by Western blotting. RESULTS: While L-OHP and CDDP were practically inactive in the subconfluent cell population, LA-12 showed a similar toxicity in both subconfluent and growing populations. All compounds induced apoptosis, although with different potentials. CONCLUSION: LA-12 was able to overcome confluence-dependent resistance of HT-29 cells observed for other platinum compounds, which may have potential therapeutic use in slowly growing tumours.