Latest Publications

@article{lincova_multiple_2009,

title = {Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs.},

author = {Eva Lincová and Ales Hampl and Zuzana Pernicová and Andrea Starsíchová and Pavel Krcmár and Miroslav Machala and Alois Kozubík and Karel Soucek},

doi = {10.1016/j.bcp.2009.05.001},

issn = {1873-2968 0006-2952},

year  = {2009},

date = {2009-09-01},

journal = {Biochemical pharmacology},

volume = {78},

number = {6},

pages = {561–572},

abstract = {Antitumorigenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well established in several types of cancer disease. However, the mechanisms driving these processes are not understood in all details. In our study, we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent antiproliferative effects of NSAIDs. The prostate cancer cell line LNCaP, lacking both critical enzymes in the negative control of PKB/Akt activation, PTEN and SHIP2, was the most sensitive to these effects, as assessed by analysing the cell cycle profile and expression of cell cycle regulating proteins. We found that p53 protein and its signalling pathway is not involved in early antiproliferative action of the selected NSAID-indomethacin. RNAi provided evidence for the involvement of p21(Cip1/Waf1), but not GDF-15, in antiproliferative effects of indomethacin in LNCaP cells. Interestingly, we also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21(Cip1/Waf1) level and its intracellular localisation might be influenced by Akt2. Knock-down of SHIP2 by RNAi in PTEN negative prostate and colon cancer cell lines resulted in higher sensitivity to antiproliferative effects of indomethacin. Our data suggest novel mechanisms of NSAIDs antiproliferative action in cancer epithelial cells, which depends on the status of negative regulation of the PKB/Akt pathway and the isoform-specific action of Akt2. Thus, unexpectedly, multiple defects in negative regulation of the PKB/Akt pathway may contribute to increased sensitivity to chemopreventive effects of these widely used drugs.},

note = {Place: England},

keywords = {Anti-Inflammatory Agents, Antineoplastic Agents/pharmacology, Cell Cycle Proteins/metabolism, Cell Cycle/*drug effects/physiology, Cell Line, Cyclin-Dependent Kinase Inhibitor p21/*biosynthesis, Enzyme Induction, Epithelial Cells/*drug effects/pathology, Extracellular Signal-Regulated MAP Kinases/metabolism, Gene Expression/drug effects, Growth Differentiation Factor 15/biosynthesis, Humans, Indomethacin/pharmacology, Male, Non-Steroidal/*pharmacology, Phosphatidylinositol 3-Kinases, Prostatic Neoplasms/*pathology, Proto-Oncogene Proteins c-akt/*metabolism, RNA Interference, Signal Transduction/drug effects/physiology, Tumor, Tumor Suppressor Protein p53/genetics/*metabolism},

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{andrysik_aryl_2007,

title = {The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells.},

author = {Zdenek Andrysík and Jan Vondrácek and Miroslav Machala and Pavel Krcmár and Lenka Svihálková-Sindlerová and Anne Kranz and Carsten Weiss and Dagmar Faust and Alois Kozubík and Cornelia Dietrich},

doi = {10.1016/j.mrfmmm.2006.10.004},

issn = {0027-5107},

year  = {2007},

date = {2007-02-01},

journal = {Mutation research},

volume = {615},

number = {1-2},

pages = {87–97},

abstract = {Disruption of cell proliferation control by polycyclic aromatic hydrocarbons (PAHs) may contribute to their carcinogenicity. We investigated role of the aryl hydrocarbon receptor (AhR) in disruption of contact inhibition in rat liver epithelial WB-F344 'stem-like' cells, induced by the weakly mutagenic benz[a]anthracene (BaA), benzo[b]fluoranthene (BbF) and by the strongly mutagenic benzo[a]pyrene (BaP). There were significant differences between the effects of BaA and BbF, and those of the strongly genotoxic BaP. Both BaA and BbF increased percentage of cells entering S-phase and cell numbers, associated with an increased expression of Cyclin A and Cyclin A/cdk2 complex activity. Their effects were significantly reduced in cells expressing a dominant-negative AhR mutant (dnAhR). Roscovitine, a chemical inhibitor of cdk2, abolished the induction of cell proliferation by BbF. However, neither BaA nor BbF modulated expression of the principal cdk inhibitor involved in maintenance of contact inhibition, p27(Kip1), or pRb phosphorylation. The strongly mutagenic BaP induced apoptosis, a decrease in total cell numbers and significantly higher percentage of cells entering S-phase than either BaA or BbF. Given that BaP induced high levels of Cyclin A/cdk2 activity, downregulation of p27(Kip1) and hyperphosphorylation of pRb, the accumulation of cells in S-phase was probably due to cell proliferation, although S-phase arrest due to blocked replication forks can not be excluded. Both types of effects of BaP were significantly attenuated in dnAhR cells. Transfection of WB-F344 cells with siRNA targeted against AhR decreased induction of Cyclin A induced by BbF or BaP, further supporting the role of AhR in proliferative effects of PAHs. This suggest that activation of AhR plays a significant role both in disruption of contact inhibition by weakly mutagenic PAHs and in genotoxic effects of BaP possibly leading to enhanced cell proliferation. Thus, PAHs may increase proliferative rate and the likelihood of fixation of mutations.},

note = {Place: Netherlands},

keywords = {Animals, Apoptosis/drug effects, Aryl Hydrocarbon/antagonists & inhibitors/genetics/*metabolism, Base Sequence, Benz(a)Anthracenes/toxicity, Benzo(a)pyrene/toxicity, Cell Cycle Proteins/metabolism, Cell Cycle/*drug effects/*physiology, Cell Line, Cell Proliferation/drug effects, Cyclin A/metabolism, Cyclin-Dependent Kinase 2/metabolism, Cytochrome P-450 CYP1A1/genetics, Epithelial Cells/cytology/drug effects/metabolism, Fluorenes/toxicity, Gene Expression/drug effects, Hepatocytes/cytology/*drug effects/*metabolism, Messenger/genetics/metabolism, Multiprotein Complexes, Mutagens/toxicity, Mutation, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats, Receptors, RNA, Small Interfering/genetics},

pubstate = {published},

tppubtype = {article}

}