Latest Publications

@article{hyzdalova_aryl_2018,

title = {Aryl Hydrocarbon Receptor-Dependent Metabolism Plays a Significant Role in Estrogen-Like Effects of Polycyclic Aromatic Hydrocarbons on Cell Proliferation.},

author = {Martina Hýžd'alová and Jakub Pivnicka and Ondrej Zapletal and Gerardo Vázquez-Gómez and Jason Matthews and Jirí Neca and Katerina Pencíková and Miroslav Machala and Jan Vondrácek},

doi = {10.1093/toxsci/kfy153},

issn = {1096-0929 1096-6080},

year  = {2018},

date = {2018-10-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {165},

number = {2},

pages = {447–461},

abstract = {Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants that interact in a complex manner with both the aryl hydrocarbon receptor (AhR) and estrogen receptors (ER). Their potential endocrine-disrupting activities may depend on both inhibitory AhR-ER cross-talk and on AhR-dependent metabolic production of estrogenic PAH metabolites. Here, we analyzed the impact of AhR on estrogen-like effects of PAHs, such as benzo[a]pyrene (BaP), in particular, on control of cell cycle progression/cell proliferation. Using AhR knockout variant of estrogen-sensitive human breast cancer MCF-7 cells (MCF-7 AhRKO cells), we observed that the AhR-dependent control of cytochrome P450 family 1 (CYP1) expression played a major role in formation of estrogenic BaP metabolites, most notably 3-OH-BaP, which contributed to the ER-dependent induction of cell cycle progression/cell proliferation. Both BaP metabolism and the BaP-induced S-phase transition/cell proliferation were inhibited in MCF-7 AhRKO cells, whereas these cells remained sensitive towards both endogenous estrogen 17β-estradiol or hydroxylated BaP metabolites. BaP was found to increase the activity of ER-dependent luciferase reporter gene in wild-type MCF-7 cells; however, unlike its hydroxylated metabolite, BaP failed to stimulate luciferase activity in MCF-7 AhRKO cells. Similarly, estrogen-like effects of other known estrogenic PAHs, such as benz[a]anthracene or 3-methylcholanthrene, were diminished in MCF-7 AhRKO cells. Ectopic expression of human CYP1A1 and CYP1B1 enzymes partly restored both BaP metabolism and its effects on cell proliferation. Taken together, our data suggest that the AhR-dependent metabolism of PAHs contributes significantly to the impact of PAHs on cell proliferation in estrogen-sensitive cells.},

note = {Place: United States},

keywords = {Aryl Hydrocarbon/genetics/*metabolism, Cell Culture Techniques, Cell Cycle/drug effects/genetics, Cell Proliferation/*drug effects/genetics, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1/genetics/metabolism, Endocrine Disruptors/metabolism/*toxicity, Estrogen/genetics/metabolism, Gene Expression/drug effects, Gene Knockdown Techniques, Genes, Genetic Vectors, Humans, MCF-7 Cells, Plasmids, Polycyclic Aromatic Hydrocarbons/metabolism/*toxicity, Receptors, Reporter, Transfection},

pubstate = {published},

tppubtype = {article}

}

@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{vondracek_modulation_2002,

title = {Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells.},

author = {Jan Vondrácek and Alois Kozubík and Miroslav Machala},

doi = {10.1093/toxsci/70.2.193},

issn = {1096-6080 1096-0929},

year  = {2002},

date = {2002-12-01},

journal = {Toxicological sciences : an official journal of the Society of Toxicology},

volume = {70},

number = {2},

pages = {193–201},

abstract = {It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.},

note = {Place: United States},

keywords = {Breast Neoplasms/*metabolism, Cell Cycle/*drug effects/genetics, Cell Cycle/drug effects/genetics, Cultured, Estrogen Receptor alpha, Estrogen Receptor Modulators/pharmacology, Estrogen/genetics/*metabolism, G1 Phase/drug effects/genetics, Genes, Genetic/drug effects, Humans, Phosphorylation/drug effects, Polycyclic Aromatic Hydrocarbons/metabolism/*toxicity, Receptors, Reporter/*genetics, Resting Phase, S Phase/drug effects/genetics, Transcription, Tumor Cells},

pubstate = {published},

tppubtype = {article}

}