Latest Publications

@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}

}

@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}

}

@article{ondrouskova_alternative_2008,

title = {Alternative pathways of programmed cell death are activated in cells with defective caspase-dependent apoptosis.},

author = {Eva Ondrousková and Karel Soucek and Viktor Horváth and Jan Smarda},

doi = {10.1016/j.leukres.2007.05.012},

issn = {0145-2126},

year  = {2008},

date = {2008-04-01},

journal = {Leukemia research},

volume = {32},

number = {4},

pages = {599–609},

abstract = {Loss of programmed cell death pathways is one of the features of malignancy that complicate the response of cancer cells to a therapy. Activation of alternative cell death pathways offers a promising approach to enhance efficiency of cancer chemotherapy. We analysed programmed cell death pathways of v-myb-transformed BM2 monoblasts induced by arsenic trioxide, cycloheximide and camptothecin with U937 promonocytes as a reference cell line. We show that induced death of BM2 cells is not executed by caspases but rather by alternative cell death pathways. Camptothecin induces the lysosome-dependent cell death, arsenic trioxide induces autophagy, and most of cycloheximide-treated BM2 cells die by necrosis. The fact that alternative cell death pathways can be switched in cells with defects in activation and/or function of caspases suggests that understanding and targeting of these pathways could improve therapy of cancer cells suffering from defective apoptosis.},

note = {Place: England},

keywords = {Animals, Antineoplastic Agents/*pharmacology, Apoptosis/*drug effects, Arsenic Trioxide, Arsenicals/pharmacology, Autophagy/*drug effects, Blotting, Camptothecin/pharmacology, Caspases/*metabolism, Cell Line, Cell Transformation, Chickens, Cycloheximide/pharmacology, Fluorescence, Genes, Humans, Microscopy, myb/physiology, Necrosis, Neoplastic/*pathology, Oxides/pharmacology, Signal Transduction/*drug effects, Transformed, U937 Cells/drug effects, Western},

pubstate = {published},

tppubtype = {article}

}

@article{horvath_different_2007,

title = {Different cell cycle modulation following treatment of human ovarian carcinoma cells with a new platinum(IV) complex vs cisplatin.},

author = {Viktor Horváth and Karel Soucek and Lenka Svihálková-Sindlerová and Jan Vondrácek and Olga Blanárová and Jirina Hofmanová and Petr Sova and Alois Kozubík},

doi = {10.1007/s10637-007-9062-7},

issn = {0167-6997},

year  = {2007},

date = {2007-10-01},

journal = {Investigational new drugs},

volume = {25},

number = {5},

pages = {435–443},

abstract = {Platinum (IV) derivative with adamantylamine-LA-12-represents a new generation of highly efficient anti-cancer drug derived from cisplatin and is currently in the final stage of phase I clinical trials. Understanding the specific mechanisms of its effects on cell cycle is necessary for defining the mode of action of LA-12. In this study, we characterized the ability of LA-12 to induce cell cycle perturbations in ovarian cancer cell line A2780 as compared to equitoxic cisplatin treatment. LA-12 induced a permanent accumulation of A2780 cells in S phase while cisplatin caused G2/M arrest at 24-h time point, where we also detected an increased expression of Gadd45alpha protein. Although both derivatives induced a rapid increase of p53 expression, this was not associated with a down-regulation of Mdm2 protein. Increased expression of p21(Cip1/WAF1) protein and its association with cyclins A and B1 suggested that this cyclin-dependent kinase inhibitor might contribute significantly to the observed perturbations of cell cycle. The results of this study provide insight into the mechanism of action of platinum-based derivative with adamantylamine on cell cycle in ovarian cancer cells. The differences between effects of LA-12 and cisplatin suggest that more attention should be paid to elucidation of modes of action of novel platinum(IV) complexes at cellular level.},

note = {Place: United States},

keywords = {Amantadine/*analogs & derivatives/pharmacology, Antineoplastic Agents/*pharmacology, bcl-2-Associated X Protein/metabolism, Carcinoma/drug therapy/metabolism, Cell Cycle Proteins/metabolism, Cell Cycle/*drug effects, Cell Line, Cell Proliferation/drug effects, Cisplatin/*pharmacology, Female, Humans, Organoplatinum Compounds/*pharmacology, Ovarian Neoplasms/drug therapy/metabolism, Proto-Oncogene Proteins c-mdm2/metabolism, Tumor, Tumor Suppressor Protein p53/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{kozubik_high_2005,

title = {High effectiveness of platinum(IV) complex with adamantylamine in overcoming resistance to cisplatin and suppressing proliferation of ovarian cancer cells in vitro.},

author = {Alois Kozubík and Viktor Horváth and Lenka Svihálková-Sindlerová and Karel Soucek and Jirina Hofmanová and Petr Sova and Ales Kroutil and Frantisek Zák and Adolf Mistr and Jaroslav Turánek},

doi = {10.1016/j.bcp.2004.09.005},

issn = {0006-2952},

year  = {2005},

date = {2005-02-01},

journal = {Biochemical pharmacology},

volume = {69},

number = {3},

pages = {373–383},

abstract = {[(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], coded as LA-12, is an octahedral platinum(IV) complex containing a bulky hydrophobic ligand - adamantylamine. The use of bulky hydrophobic amines as non-leaving ligands, may increase uptake of the compound by the cancer cells. Therefore, the effects of LA-12 on sensitive (A2780) and cisplatin resistant (A2780cis) ovarian cancer cell lines were investigated and compared to those of cisplatin. IC(50) and IC(90) concentrations of LA-12 were 6- (A2780) or 18-fold (A2780cis) lower than those for cisplatin (MTT assay). Equitoxic concentrations (IC(50) or IC(90)) of both compounds caused a significant and similar time- and dose-dependent inhibition of cell proliferation and an increase in the number of floating cells which corresponded to the decrease of total cell viability. A different type and dynamics of cell cycle perturbation after cisplatin and LA-12 treatment were detected. Exposure to LA-12 resulted in transient accumulation of A2780 and A2780cis cells in S phase, while cisplatin caused G(2)/M arrest in sensitive and S phase arrest in resistant cells. A relatively low rate of apoptosis after exposure to IC(50) or IC(90) of both complexes was observed, markedly higher in resistant A2780cis cells. Western blot analysis indicated a concentration-dependent p53 level increase in both lines (higher after cisplatin treatment). PARP cleavage was observed only in A2780cis cells. In conclusion, LA-12 was found to be significantly more efficient than cisplatin, and it was able to overcome the acquired cisplatin resistance (showing resistance factor 2.84-fold lower than those for cisplatin). In spite of the low rate of apoptosis, LA-12 caused increase of p53 level and cell cycle perturbations in the ovarian cancer cell lines studied.},

note = {Place: England},

keywords = {Amantadine/*analogs & derivatives/*pharmacology, Antineoplastic Agents/*pharmacology, Cell Cycle/drug effects, Cell Line, Cell Proliferation/drug effects, Cisplatin/*pharmacology, DNA Fragmentation/drug effects, Drug resistance, Female, Humans, Neoplasm, Organoplatinum Compounds/*pharmacology, Ovarian Neoplasms/*drug therapy/pathology, Poly(ADP-ribose) Polymerases/analysis, Tumor, Tumor Suppressor Protein p53/analysis},

pubstate = {published},

tppubtype = {article}

}