Latest Publications

@article{kauerova_ring-substituted_2020,

title = {Ring-Substituted 1-Hydroxynaphthalene-2-Carboxanilides Inhibit Proliferation and Trigger Mitochondria-Mediated Apoptosis.},

author = {Tereza Kauerová and Tomáš Goněc and Josef Jampílek and Susanne Hafner and Ann-Kathrin Gaiser and Tatiana Syrovets and Radek Fedr and Karel Souček and Peter Kollar},

doi = {10.3390/ijms21103416},

issn = {1422-0067},

year  = {2020},

date = {2020-05-01},

journal = {International journal of molecular sciences},

volume = {21},

number = {10},

abstract = {Ring-substituted 1-hydroxynaphthalene-2-carboxanilides were previously investigated for their antimycobacterial properties. In our study, we have shown their antiproliferative and cell death-inducing effects in cancer cell lines. Cell proliferation and viability were assessed by WST-1 assay and a dye exclusion test, respectively. Cell cycle distribution, phosphatidylserine externalization, levels of reactive oxygen or nitrogen species (RONS), mitochondrial membrane depolarization, and release of cytochrome c were estimated by flow cytometry. Levels of regulatory proteins were determined by Western blotting. Our data suggest that the ability to inhibit the proliferation of THP-1 or MCF-7 cells might be referred to meta- or para-substituted derivatives with electron-withdrawing groups -F, -Br, or -CF(3) at anilide moiety. This effect was accompanied by accumulation of cells in G1 phase. Compound 10 also induced apoptosis in THP-1 cells in association with a loss of mitochondrial membrane potential and production of mitochondrial superoxide. Our study provides a new insight into the action of salicylanilide derivatives, hydroxynaphthalene carboxamides, in cancer cells. Thus, their structure merits further investigation as a model moiety of new small-molecule compounds with potential anticancer properties.},

note = {Place: Switzerland},

keywords = {Anilides/chemistry/*pharmacology, Antineoplastic Agents/chemistry/pharmacology, antiproliferative effect, Apoptosis, Apoptosis/*drug effects, Cell Cycle, Cell Cycle/drug effects, Cell Proliferation/*drug effects, Cell Survival/drug effects, Humans, hydroxynaphthalene carboxamides, MCF-7 Cells, Membrane Potential, Mitochondria/*drug effects/metabolism, Mitochondrial/drug effects, Molecular Structure, Naphthols/*chemistry, Reactive Oxygen Species/metabolism, salicylanilides, Salicylanilides/chemistry/pharmacology, Structure-Activity Relationship, Superoxides/metabolism, THP-1 Cells},

pubstate = {published},

tppubtype = {article}

}

@article{kabatkova_interactive_2015,

title = {Interactive effects of inflammatory cytokine and abundant low-molecular-weight PAHs on inhibition of gap junctional intercellular communication, disruption of cell proliferation control, and the AhR-dependent transcription.},

author = {Markéta Kabátková and Jana Svobodová and Kateřina Pěnčíková and Dilshad Shaik Mohatad and Lenka Šmerdová and Alois Kozubík and Miroslav Machala and Jan Vondráček},

doi = {10.1016/j.toxlet.2014.09.023},

issn = {1879-3169 0378-4274},

year  = {2015},

date = {2015-01-01},

journal = {Toxicology letters},

volume = {232},

number = {1},

pages = {113–121},

abstract = {Polycyclic aromatic hydrocarbons (PAHs) with lower molecular weight exhibit lesser genotoxicity and carcinogenicity than highly carcinogenic PAHs with a higher number of benzene rings. Nevertheless, they elicit specific effects linked with tumor promotion, such as acute inhibition of gap junctional intercellular communication (GJIC). Although inflammatory reaction may alter bioactivation and toxicity of carcinogenic PAHs, little is known about the impact of pro-inflammatory cytokines on toxic effects of the low-molecular-weight PAHs. Here, we investigated the impact of a pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), on the effects associated with tumor promotion and with induction of the aryl hydrocarbon receptor (AhR)-dependent gene expression in rat liver epithelial cells. We found that a prolonged incubation with TNF-α induced a down-regulation of GJIC, associated with reduced expression of connexin 43 (Cx43), a major connexin isoform found in liver epithelial cells. The Cx43 down-regulation was partly mediated by the activity of the mitogen-activated protein (MAP) p38 kinase. Independently of GJIC modulation, or p38 activation, TNF-α potentiated the AhR-dependent proliferative effect of a model low-molecular-weight PAH, fluoranthene, on contact-inhibited cells. In contrast, this pro-inflammatory cytokine repressed the fluoranthene-induced expression of a majority of model AhR gene targets, such as Cyp1a1, Ahrr or Tiparp. The results of the present study indicate that inflammatory reaction may differentially modulate various toxic effects of low-molecular-weight PAHs; the exposure to pro-inflammatory cytokines may both strengthen (inhibition of GJIC, disruption of contact inhibition) and repress (expression of a majority of AhR-dependent genes) their impact on toxic endpoints associated with carcinogenesis.},

note = {Place: Netherlands},

keywords = {Animals, Aryl hydrocarbon receptor, Aryl Hydrocarbon/*agonists/genetics/metabolism, Basic Helix-Loop-Helix Transcription Factors/*agonists/genetics/metabolism, Cell Communication/*drug effects, Cell Line, Cell Proliferation, Cell Proliferation/*drug effects, Cell Transformation, Connexin 43/genetics/metabolism, Dose-Response Relationship, Drug, Enzyme Activation, Epithelial Cells/*drug effects/metabolism/pathology, Fluorenes/*toxicity, Gap junctions, Gap Junctions/*drug effects/metabolism/pathology, Gene Expression Regulation/drug effects, Genetic/*drug effects, Inflammation, Inflammation/chemically induced/genetics/metabolism/pathology, Liver Neoplasms/chemically induced/metabolism/pathology, Liver/*drug effects/metabolism/pathology, Molecular Weight, Neoplastic/chemically induced/metabolism/pathology, p38 Mitogen-Activated Protein Kinases/metabolism, PAHs, Rats, Receptors, Signal Transduction/drug effects, Time Factors, Transcription, Tumor Necrosis Factor-alpha/*toxicity},

pubstate = {published},

tppubtype = {article}

}

@article{vondracek_concentrations_2007,

title = {Concentrations of methylated naphthalenes, anthracenes, and phenanthrenes occurring in Czech river sediments and their effects on toxic events associated with carcinogenesis in rat liver cell lines.},

author = {Jan Vondrácek and Lenka Svihálková-Sindlerová and Katerina Pencíková and Sona Marvanová and Pavel Krcmár and Miroslav Ciganek and Jirí Neca and James E. Trosko and Brad Upham and Alois Kozubík and Miroslav Machala},

doi = {10.1897/07-161R.1},

issn = {0730-7268},

year  = {2007},

date = {2007-11-01},

journal = {Environmental toxicology and chemistry},

volume = {26},

number = {11},

pages = {2308–2316},

abstract = {Alkylated polycyclic aromatic hydrocarbons (PAHs) are important environmental pollutants. In the present study, we determined levels of monomethylated naphthalenes (MeNap), phenanthrenes (MePhe), and anthracenes (MeAnt) in Czech river sediments. The levels of MePhe generally were lower than the concentrations of phenanthrene. In contrast, both MeNap and MeAnt were found at levels higher than their respective parent compounds in the majority of sampling sites. We then investigated their aryl hydrocarbon receptor (AhR)-mediated activity, accumulation of phosphorylated p53 protein, induction of expression of cytochrome P450 1A1 (CYP1A1), inhibition of gap junctional intercellular communication (GJIC), and effects on cell proliferation in rat liver cell models to evaluate the relative importance of these toxicity mechanisms of low-molecular-weight methylated PAHs. Methylated phenanthrene and anthracene compounds were weak inducers of AhR-mediated activity as determined both in a reporter gene assay system and by detection of the endogenous gene (Cyp1a1) induction. 2-Methylphenanthrene was the most potent AhR ligand. Contribution of MeAnt and MePhe to overall AhR-inducing potencies should be taken into account in PAH-contaminated environments. Nevertheless, their effects on AhR were not sufficient to modulate cell proliferation in a normal rat liver progenitor cell model system. These PAHs only had a marginal effect on p53 phosphorylation at high doses of 1-, 3-, and 9-MePhe as well as 1 MeAnt. On the other hand, both 2- and 9-MeAnt as well as all the MePhe under study were efficient inhibitors of GJIC, suggesting that these compounds might act as tumor promoters. In summary, inhibition of GJIC and partial activation of AhR seem to be the most prominent toxic effects of the methylated PAHs in the present study.},

note = {Place: United States},

keywords = {Animals, Anthracenes/toxicity, Aryl Hydrocarbon/metabolism, Carcinogens/*toxicity, Cell Line, Cell Proliferation/*drug effects, Cytochrome P-450 CYP1A1/genetics/metabolism, Czech Republic, Dose-Response Relationship, Drug, Environmental Pollutants/*toxicity, Gap Junctions/*drug effects/metabolism, Gene Expression Regulation/*drug effects/physiology, Geologic Sediments/*chemistry, Liver/cytology/pathology, Methylation, Naphthalenes/toxicity, Phenanthrenes/toxicity, Rats, Receptors, Rivers/*chemistry, Tumor, Tumor Suppressor Protein p53/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{zatloukalova_beta-naphthoflavone_2007,

title = {beta-Naphthoflavone and 3'-methoxy-4'-nitroflavone exert ambiguous effects on Ah receptor-dependent cell proliferation and gene expression in rat liver 'stem-like' cells.},

author = {Jirina Zatloukalová and Lenka Svihálková-Sindlerová and Alois Kozubík and Pavel Krcmár and Miroslav Machala and Jan Vondrácek},

doi = {10.1016/j.bcp.2007.01.032},

issn = {0006-2952},

year  = {2007},

date = {2007-05-01},

journal = {Biochemical pharmacology},

volume = {73},

number = {10},

pages = {1622–1634},

abstract = {Both natural and synthetic flavonoids are known to interact with the aryl hydrocarbon receptor (AhR); however, their agonist/antagonist properties in vitro have been so far studied mostly in the context of cytochrome P450 1A1 gene (Cyp1a1) regulation. We investigated effects of two synthetic flavones known either as AhR agonist (beta-naphthoflavone; BNF) or antagonist (3'-methoxy-4'-nitroflavone; 3M4NF), using an in vitro model of liver 'stem-like' cells, on expression of various AhR target genes and AhR-dependent cell proliferation. We found that the presumed antagonist 3M4NF induces a partial nuclear translocation and activation of AhR. Although inhibiting the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced Cyp1a1 expression, 3M4NF alone induced a minor increase of CYP1A1 mRNA and protein. However, 3M4NF did not induce AhR binding to synthetic dioxin response elements (DRE). In contrast to Cyp1a1, 3M4NF induced a marked expression of other AhR-regulated genes, such as Cyp1b1 and Nqo1, as well as transcriptional repression of Cdh13 gene, confirming that its effects may be promoter-context specific. Like BNF, 3M4NF induced AhR-dependent cell proliferation of contact-inhibited rat liver 'stem-like' WB-F344 cells, associated with a marked upregulation of Cyclin A, as well as the downregulation of proteins involved in formation of cell-cell contacts. Based on these experimental findings, we conclude that partial agonists/antagonists of AhR can increase cell proliferation rate and AhR-dependent genes expression in both cell type- and gene-specific manner. The specificity of effects of flavones on diverse AhR targets should be taken into account, when studying AhR signaling using presumed AhR antagonists.},

note = {Place: England},

keywords = {Animals, Aryl Hydrocarbon/genetics/*metabolism, beta-Naphthoflavone/*pharmacology, Cadherins/genetics/metabolism, Cell Proliferation/*drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/genetics/metabolism, Flavonoids/*pharmacology, Gene Expression/*drug effects/physiology, Hepatocytes/*drug effects/physiology, Inbred F344, Liver/cytology, NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism, Rats, Receptors},

pubstate = {published},

tppubtype = {article}

}

@article{pliskova_deregulation_2005,

title = {Deregulation of cell proliferation by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells reflects both genotoxic and nongenotoxic events.},

author = {Martina Plísková and Jan Vondrácek and Borivoj Vojtesek and Alois Kozubík and Miroslav Machala},

doi = {10.1093/toxsci/kfi040},

issn = {1096-6080 1096-0929},

year  = {2005},

date = {2005-02-01},

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

volume = {83},

number = {2},

pages = {246–256},

abstract = {Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are carcinogens suggested to be involved in development of human cancer. Several recent studies have reported that PAHs can activate estrogen receptors (ER), either directly or indirectly by producing estrogenic metabolites. We hypothesized that the activation of ER by PAHs or their metabolites could induce cell proliferation in estrogen-sensitive cells. In the present study, we found that two PAHs, benz[a]anthracene (BaA) and BaP, can stimulate proliferation of human breast carcinoma MCF-7 cells at concentrations 100 nM and higher. This effect was ER-dependent, because it was blocked by the pure antiestrogen ICI 182,780. Although both PAHs partially inhibited S-phase entry and DNA synthesis induced by 17beta-estradiol, they stimulated S-phase entry when applied to MCF-7 cells synchronized by serum deprivation. This was in contrast with model antiestrogenic aryl hydrocarbon receptor ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, which fully suppressed S-phase entry. BaP, which is a strong mutagen, was found to induce p53 tumor suppressor expression, a partial S-phase arrest and at higher concentrations also cell death. Pifithrin-alpha, a synthetic inhibitor of p53 activity, abolished both S-phase arrest and apoptosis induced by genotoxic PAHs, and it potentiated the proliferative effect of BaP. Thus, both genotoxic and nongenotoxic events seem to interact in the effects of BaP on cell proliferation. Taken together, our data indicate that both BaA and BaP can stimulate cell proliferation through activation of ER. The proliferative effects of these carcinogenic compounds might contribute to tumor promotion in estrogen-sensitive tissues.},

note = {Place: United States},

keywords = {Benz(a)Anthracenes/*toxicity, Benzo(a)pyrene/*toxicity, Benzothiazoles, Breast Neoplasms/drug therapy/*genetics/metabolism, Bromodeoxyuridine/metabolism, Carcinogens/*toxicity, Carcinoma/drug therapy/*genetics/metabolism, Cell Cycle/drug effects, Cell Line, Cell Proliferation/*drug effects, Cell Survival/drug effects, DNA Replication/drug effects, Dose-Response Relationship, Drug, Drug Interactions, Epigenesis, Estradiol/*analogs & derivatives/pharmacology, Estrogen, Estrogen Antagonists/pharmacology, Female, Fulvestrant, Genetic, Humans, Receptors, Thiazoles/pharmacology, Toluene/*analogs & derivatives/pharmacology, Tumor, Tumor Suppressor Protein p53/antagonists & inhibitors/genetics/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{vondracek_aryl_2005,

title = {Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.},

author = {Jan Vondrácek and Miroslav Machala and Vítezslav Bryja and Katerina Chramostová and Pavel Krcmár and Cornelia Dietrich and Ales Hampl and Alois Kozubík},

doi = {10.1093/toxsci/kfi009},

issn = {1096-6080 1096-0929},

year  = {2005},

date = {2005-01-01},

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

volume = {83},

number = {1},

pages = {53–63},

abstract = {Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon/*metabolism, Cell Line, Cell Proliferation/*drug effects, Cyclin A/biosynthesis, Cyclin D2, Cyclin-Dependent Kinases/biosynthesis, Cyclins/biosynthesis, Dose-Response Relationship, Drug, Epithelial Cells/*drug effects/enzymology/metabolism, Hydroxylation, Liver/*cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology/metabolism, Up-Regulation},

pubstate = {published},

tppubtype = {article}

}