Latest Publications

@article{larsson_consensus_2015,

title = {Consensus toxicity factors for polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls combining in silico models and extensive in vitro screening of AhR-mediated effects in human and rodent cells.},

author = {Malin Larsson and Martin Berg and Petra Brenerová and Majorie B. M. Duursen and Karin I. Ede and Christiane Lohr and Sandra Luecke-Johansson and Miroslav Machala and Sylke Neser and Kateřina Pěnčíková and Lorenz Poellinger and Dieter Schrenk and Simona Strapáčová and Jan Vondráček and Patrik L. Andersson},

doi = {10.1021/tx500434j},

issn = {1520-5010 0893-228X},

year  = {2015},

date = {2015-04-01},

journal = {Chemical research in toxicology},

volume = {28},

number = {4},

pages = {641–650},

abstract = {Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.},

note = {Place: United States},

keywords = {Animals, Aryl Hydrocarbon/*physiology, Benzofurans/chemistry/*toxicity, Computer Simulation, Dibenzofurans, Humans, In Vitro Techniques, Polychlorinated, Polychlorinated Biphenyls/chemistry/*toxicity, Polychlorinated Dibenzodioxins/*analogs & derivatives/chemistry/toxicity, Quantitative Structure-Activity Relationship, Rats, Receptors, Rodentia},

pubstate = {published},

tppubtype = {article}

}

@article{fedr_automatic_2013,

title = {Automatic cell cloning assay for determining the clonogenic capacity of cancer and cancer stem-like cells.},

author = {Radek Fedr and Zuzana Pernicová and Eva Slabáková and Nicol Straková and Jan Bouchal and Michal Grepl and Alois Kozubík and Karel Souček},

doi = {10.1002/cyto.a.22273},

issn = {1552-4930 1552-4922},

year  = {2013},

date = {2013-05-01},

journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},

volume = {83},

number = {5},

pages = {472–482},

abstract = {The clonogenic assay is a well-established in vitro method for testing the survival and proliferative capability of cells. It can be used to determine the cytotoxic effects of various treatments including chemotherapeutics and ionizing radiation. However, this approach can also characterize cells with different phenotypes and biological properties, such as stem cells or cancer stem cells. In this study, we implemented a faster and more precise method for assessing the cloning efficiency of cancer stem-like cells that were characterized and separated using a high-speed cell sorter. Cell plating onto a microplate using an automatic cell deposition unit was performed in a single-cell or dilution rank mode by the fluorescence-activated cell sorting method. We tested the new automatic cell-cloning assay (ACCA) on selected cancer cell lines and compared it with the manual approach. The obtained results were also compared with the results of the limiting dilution assay for different cell lines. We applied the ACCA to analyze the cloning capacity of different subpopulations of prostate and colon cancer cells based on the expression of the characteristic markers of stem (CD44 and CD133) and cancer stem cells (TROP-2, CD49f, and CD44). Our results revealed that the novel ACCA is a straightforward approach for determining the clonogenic capacity of cancer stem-like cells identified in both cell lines and patient samples.},

note = {Place: United States},

keywords = {*Cell Proliferation, AC133 Antigen, Antigens, Biomarkers, CD/metabolism, Cell Adhesion Molecules/metabolism, Cell Line, Cell Survival, Colonic Neoplasms/metabolism/*pathology, Flow Cytometry/*methods, Glycoproteins/metabolism, Humans, Hyaluronan Receptors/metabolism, In Vitro Techniques, Integrin alpha6/metabolism, Male, Neoplasm/metabolism, Neoplastic Stem Cells/metabolism/*pathology, Peptides/metabolism, Prostatic Neoplasms/metabolism/*pathology, Tumor, Tumor Stem Cell Assay/*methods, Tumor/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{hamers_vitro_2011,

title = {In vitro toxicity profiling of ultrapure non-dioxin-like polychlorinated biphenyl congeners and their relative toxic contribution to PCB mixtures in humans.},

author = {Timo Hamers and Jorke H. Kamstra and Peter H. Cenijn and Katerina Pencikova and Lenka Palkova and Pavlina Simeckova and Jan Vondracek and Patrik L. Andersson and Mia Stenberg and Miroslav Machala},

doi = {10.1093/toxsci/kfr043},

issn = {1096-0929},

year  = {2011},

date = {2011-05-01},

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

volume = {121},

number = {1},

pages = {88–100},

abstract = {The toxic equivalency concept used for the risk assessment of polychlorinated biphenyls (PCBs) is based on the aryl hydrocarbon receptor (AhR)-mediated toxicity of coplanar dioxin-like (DL) PCBs. Most PCBs in the environment, however, are non-dioxin-like (NDL) PCBs that cannot adopt a coplanar structure required for AhR activation. For NDL-PCBs, no generally accepted risk concept is available because their toxicity is insufficiently characterized. Here, we systematically determined in vitro toxicity profiles for 24 PCBs regarding 10 different mechanisms of action. Prior to testing, NDL-PCB standards were purified to remove traces of DL compounds. All NDL-PCBs antagonized androgen receptor activation and inhibited gap junctional intercellular communication (GJIC). Lower chlorinated NDL-PCBs were weak estrogen receptor (ER) agonists, whereas higher chlorinated NDL-PCBs were weak ER antagonists. Several NDL-PCBs inhibited estradiol-sulfotransferase activity and bound to transthyretin (TTR) but with much weaker potencies than reported for hydroxylated PCB metabolites. AhR-mediated expression of uridine-glucuronyl transferase isozyme UGT1A6 was induced by DL-PCBs only. Hierarchical cluster analysis of the toxicity profiles yielded three separate clusters of NDL-PCBs and a fourth cluster of reference DL-PCBs. Due to small differences in relative potency among congeners, the highly abundant indicator PCBs 28, 52, 101, 118, 138, 153, and 180 also contributed most to the antiandrogenic, (anti)estrogenic, antithyroidal, tumor-promoting, and neurotoxic potencies calculated for PCB mixtures reported in human samples, whereas the most potent AhR-activating DL-PCB-126 contributed at maximum 0.2% to any of these calculated potencies. PCB-168 is recommended as an additional indicator congener, given its relatively high abundance and antiandrogenic, TTR-binding, and GJIC-inhibiting potencies.},

note = {Place: United States},

keywords = {Humans, In Vitro Techniques, Polychlorinated Biphenyls/administration & dosage/*toxicity},

pubstate = {published},

tppubtype = {article}

}

@article{forejtnikova_chemoprotective_2005,

title = {Chemoprotective and toxic potentials of synthetic and natural chalcones and dihydrochalcones in vitro.},

author = {Hana Forejtníková and Kamila Lunerová and Renata Kubínová and Dagmar Jankovská and Radek Marek and Radovan Kares and Václav Suchý and Jan Vondrácek and Miroslav Machala},

doi = {10.1016/j.tox.2004.11.011},

issn = {0300-483X},

year  = {2005},

date = {2005-03-01},

journal = {Toxicology},

volume = {208},

number = {1},

pages = {81–93},

abstract = {Cytochrome P4501A activity, oxidative stress and inhibition of gap junctional intercellular communication (GJIC) are involved in metabolic activation of promutagens and tumor-promoting activity of various xenobiotics, and their prevention is considered to be an important characteristic of chemoprotective compounds. In this study, a series of 31 chalcones and their corresponding dihydroderivatives, substituted in 2,2'-, 3,3'-, 4- or 4'-position by hydroxyl or methoxy group, were tested for their ability to inhibit Fe(II)/NADPH-enhanced lipid peroxidation and cytochrome P4501A-dependent 7-cethoxyresorufin-O-deethylase (EROD) activity in rat hepatic microsomes. Effects of the compounds on GJIC were determined in rat liver epithelial WB-F344 cells. Most of the chalcones and dihydrochalcones inhibited EROD activity in a dose-dependent manner at the range 0.25-25 microM, which was comparable to model flavonoid inhibitors alpha-naphthoflavone and quercetin. The chalcones exhibited higher inhibition activity than the corresponding dihydroderivatives. Mono and dihydroxylated chalcones, and dihydrochalcones showed none or only a weak antioxidant activity; trihydroxyderivatives inhibited in vitro lipid peroxidation significantly only at 50 microM concentration. Potential adverse effects, namely inhibition of GJIC and/or cytotoxicity were detected after treatment of WB-F344 cells with a number of chalcone and dihydrochalcone derivatives, suggesting that they should be excluded from additional screening as chemoprotective compounds. Chalcones and dihydrochalcones substituted at 4- and/or 4'-position, which elicited no inhibition of GJIC, were further tested for the potential enhancing effects on GJIC. The present data seem to suggest that 4-hydroxy, 2',4'-dihydroxy-3-methoxy, 2,4,4'-trihydroxy, and 2',4,4'-trihydroxychalcone, 2',4-dihydroxy and 2'-hydroxy-3,4-dimethoxydihydrochalcone might be promising chemoprotective compounds against CYP1A activity, and partly also against oxidative damage without inducing adverse effects, such as GJIC inhibition. In general, determination of potencies of tested compounds to inhibit GJIC should be involved in any set of methods for the in vitro screening of chemoprotective characteristics of potential drugs, in order to reveal their potential adverse effects associated with tumor promotion.},

note = {Place: Ireland},

keywords = {Animals, Carcinogens/metabolism/*toxicity, Cell Communication/drug effects/physiology, Cell Line, Chalcones/*pharmacology/*toxicity, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System/*metabolism, Dose-Response Relationship, Drug, Epithelial Cells/drug effects/metabolism, Gap Junctions/drug effects/metabolism/physiology, In Vitro Techniques, Lipid Peroxidation/drug effects, Liver/drug effects/enzymology, Liver/drug effects/ultrastructure, Male, Microsomes, Rats, Structure-Activity Relationship, Wistar},

pubstate = {published},

tppubtype = {article}

}

@article{hoferova_effect_2002,

title = {The effect of nonsteroidal antiinflammatory drugs ibuprofen, flurbiprofen, and diclofenac on in vitro and in vivo growth of mouse fibrosarcoma.},

author = {Zuzana Hoferová and Peter Fedorocko and Jirina Hofmanová and Michal Hofer and Vladimír Znojil and Katerina Minksová and Karel Soucek and Alena Egyed and Alois Kozubík},

doi = {10.1081/cnv-120002149},

issn = {0735-7907},

year  = {2002},

date = {2002-01-01},

journal = {Cancer investigation},

volume = {20},

number = {4},

pages = {490–498},

abstract = {For suppression of primary G:5:113 fibrosarcoma growth, three structurally different cyclooxygenase (COX) inhibitors (ibuprofen, flurbiprofen, and diclofenac) were administered intraperitoneally (i.p.) in two regimens starting on day 5 after tumor-cell inoculation. Repeated application of 0.15 mg/mouse/day during 14 consecutive days significantly suppressed the tumor growth and increased the percentage of surviving mice. Similar tendency, however without significant differences, was observed when animals were given 0.5 mg/day for five consecutive days. These results suggest that a time schedule of drug application is important for the therapeutic effect. Suppressive effect of diclofenac and flurbiprofen on tumor growth was also observed under in vitro conditions. We conclude that suppressive effect of these drugs on tumor growth in vivo comprises both direct effects of COX inhibitors on fibrosarcoma cells and indirect effects that are presumably mediated by extratumoral sources. Our findings encourage the use of COX inhibitors in the therapy of fibrosarcoma.},

note = {Place: England},

keywords = {Animals, Anti-Inflammatory Agents, Cell Cycle/drug effects, Cell Division/drug effects, Cultured/*drug effects, Diclofenac/*therapeutic use, Experimental, Fibrosarcoma/*drug therapy/pathology, Flurbiprofen/*therapeutic use, Ibuprofen/*therapeutic use, In Vitro Techniques, Inbred C3H, Male, Mice, Neoplasms, Non-Steroidal/*therapeutic use, Survival Rate, Tumor Cells},

pubstate = {published},

tppubtype = {article}

}