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{samadder_synthesis_2017,

title = {Synthesis and Profiling of a Novel Potent Selective Inhibitor of CHK1 Kinase Possessing Unusual N-trifluoromethylpyrazole Pharmacophore Resistant to Metabolic N-dealkylation.},

author = {Pounami Samadder and Tereza Suchánková and Ondřej Hylse and Prashant Khirsariya and Fedor Nikulenkov and Stanislav Drápela and Nicol Straková and Petr Vaňhara and Kateřina Vašíčková and Hana Kolářová and Lucia Binó and Miroslava Bittová and Petra Ovesná and Peter Kollár and Radek Fedr and Milan Ešner and Josef Jaroš and Aleš Hampl and Lumír Krejčí and Kamil Paruch and Karel Souček},

doi = {10.1158/1535-7163.MCT-17-0018},

issn = {1538-8514 1535-7163},

year  = {2017},

date = {2017-09-01},

journal = {Molecular cancer therapeutics},

volume = {16},

number = {9},

pages = {1831–1842},

abstract = {Checkpoint-mediated dependency of tumor cells can be deployed to selectively kill them without substantial toxicity to normal cells. Specifically, loss of CHK1, a serine threonine kinase involved in the surveillance of the G(2)-M checkpoint in the presence of replication stress inflicted by DNA-damaging drugs, has been reported to dramatically influence the viability of tumor cells. CHK1's pivotal role in maintaining genomic stability offers attractive opportunity for increasing the selectivity, effectivity, and reduced toxicity of chemotherapy. Some recently identified CHK1 inhibitors entered clinical trials in combination with DNA antimetabolites. Herein, we report synthesis and profiling of MU380, a nontrivial analogue of clinically profiled compound SCH900776 possessing the highly unusual N-trifluoromethylpyrazole motif, which was envisioned not to undergo metabolic oxidative dealkylation and thereby provide greater robustness to the compound. MU380 is a selective and potent inhibitor of CHK1 which sensitizes a variety of tumor cell lines to hydroxyurea or gemcitabine up to 10 times. MU380 shows extended inhibitory effects in cells, and unlike SCH900776, does not undergo in vivo N-dealkylation to the significantly less selective metabolite. Compared with SCH900776, MU380 in combination with GEM causes higher accumulation of DNA damage in tumor cells and subsequent enhanced cell death, and is more efficacious in the A2780 xenograft mouse model. Overall, MU380 represents a novel state-of-the-art CHK1 inhibitor with high potency, selectivity, and improved metabolic robustness to oxidative N-dealkylation. Mol Cancer Ther; 16(9); 1831-42. ©2017 AACR.},

note = {Place: United States},

keywords = {Animal, Animals, Antineoplastic Agents/*chemical synthesis/*pharmacology, Apoptosis/drug effects, Biomarkers, Cell Cycle Checkpoints/drug effects, Cell Cycle/drug effects, Cell Line, Checkpoint Kinase 1/*antagonists & inhibitors, Dealkylation/drug effects, Disease Models, Dose-Response Relationship, Drug, Drug resistance, Humans, Methylation, Mice, Molecular Structure, Neoplasm/*drug effects, Protein Kinase Inhibitors/*chemical synthesis/*pharmacology, Pyrazoles/pharmacology, Pyrimidines/pharmacology, Tumor, Xenograft Model Antitumor Assays},

pubstate = {published},

tppubtype = {article}

}

@article{palkova_aryl_2015,

title = {The aryl hydrocarbon receptor-mediated and genotoxic effects of fractionated extract of standard reference diesel exhaust particle material in pulmonary, liver and prostate cells.},

author = {Lenka Pálková and Jan Vondráček and Lenka Trilecová and Miroslav Ciganek and Kateřina Pěnčíková and Jiří Neča and Alena Milcová and Jan Topinka and Miroslav Machala},

doi = {10.1016/j.tiv.2014.12.002},

issn = {1879-3177 0887-2333},

year  = {2015},

date = {2015-04-01},

journal = {Toxicology in vitro : an international journal published in association with BIBRA},

volume = {29},

number = {3},

pages = {438–448},

abstract = {Diesel exhaust particles (DEP) and the associated complex mixtures of organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), or their derivatives, have been suggested to exert deleterious effects on human health. We used a set of defined cellular models representing liver, lung and prostate tissues, in order to compare non-genotoxic and genotoxic effects of crude and fractionated extract of a standard reference DEP material - SRM 1650b. We focused on the aryl hydrocarbon receptor (AhR)-mediated activity, modulation of cell proliferation, formation of DNA adducts, oxidative DNA damage, and induction of DNA damage responses, including evaluation of apoptosis, and phosphorylation of p53 tumor suppressor and checkpoint kinases (Chk). Both PAHs and the polar aromatic compounds contributed to the AhR-mediated activity of DEP-associated organic pollutants. The principal identified AhR agonists included benzo[k]fluoranthene, indeno[1,2,3-c,d]pyrene, chrysene and several non-priority PAHs, including benzochrysenes and methylated PAHs. In contrast to PAHs, polar compounds contributed more significantly to overall formation of DNA adducts associated with phosphorylation of p53, Chk1 or Chk2, and partly with apoptosis. Therefore, more attention should be paid to identification of DEP-associated polar organic compounds, contributing to the AhR activation and cytotoxic/genotoxic effects of complex airborne mixtures of organic contaminants produced by diesel engines.},

note = {Place: England},

keywords = {Air Pollutants/*toxicity, Air pollution, Animals, Apoptosis, Apoptosis/drug effects, Aryl Hydrocarbon/*drug effects, Cell Cycle/drug effects, Cell Death/drug effects, Cell Proliferation, DNA adducts, DNA Damage, DNA damage response, Liver/*pathology, Lung/*pathology, Male, Mutagens/*toxicity, PAHs, Particulate Matter/*toxicity, Prostate/*pathology, Rats, Receptors, SRM 1650b, Vehicle Emissions/*toxicity},

pubstate = {published},

tppubtype = {article}

}

@article{hruba_gene_2011,

title = {Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands.},

author = {Eva Hrubá and Jan Vondráček and Helena Líbalová and Jan Topinka and Vítězslav Bryja and Karel Souček and Miroslav Machala},

doi = {10.1016/j.toxlet.2011.07.011},

issn = {1879-3169 0378-4274},

year  = {2011},

date = {2011-10-01},

journal = {Toxicology letters},

volume = {206},

number = {2},

pages = {178–188},

abstract = {Carcinogenic polycyclic aromatic hydrocarbons (PAHs) are known as efficient mutagens and ligands of the aryl hydrocarbon receptor (AhR), which has been suggested to play an important role in prostate carcinogenesis. In order to evaluate the complex relationship between the genotoxicity and the AhR-mediated activity of PAHs in prostate cells, we selected benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as model genotoxic and nongenotoxic AhR ligands, respectively, to explore global changes in gene expression in LNCaP cells by microarray analysis. We identified 112 genes that were differentially expressed in cells treated for 24h with BaP, TCDD or both compounds. Our data indicated that the impacts of BaP and TCDD on transcriptome of LNCaP cells significantly overlap, since over 64% of significantly up-regulated genes and 47% of down-regulated genes were similarly affected by both AhR ligands. This suggested that the activation of AhR played a prominent role in the nongenotoxic effects of BaP in the prostate carcinoma cell model LNCaP. Both AhR ligands suppressed expression of genes associated with cell cycle progression, DNA replication, spindle assembly checkpoint or DNA repair, which probably occurred secondary to inhibition of cell cycle progression. In contrast, we identified Wnt5a, an important regulator of prostate cancer progression, to be induced as early as 6h after exposure to both AhR ligands. The AhR ligand-induced Wnt5a upregulation, together with other observed alterations of gene expression, may further contribute to enhanced cell plasticity of prostate carcinoma cells.},

note = {Place: Netherlands},

keywords = {Aryl Hydrocarbon/*agonists, Benzo(a)pyrene/*toxicity, Carcinogens, Carcinoma/metabolism, Cell Cycle/drug effects, Cell Line, DNA Repair/drug effects, DNA Replication/drug effects, Environmental/*toxicity, Gene Expression Profiling, Gene Expression Regulation, Humans, Ligands, Male, Mutagens/*toxicity, Neoplastic/*drug effects, Oligonucleotide Array Sequence Analysis, Polychlorinated Dibenzodioxins/*toxicity, Prostatic Neoplasms/*metabolism, Proto-Oncogene Proteins/genetics/metabolism, Receptors, Spindle Apparatus/drug effects, Time Factors, Tumor, Wnt Proteins/genetics/metabolism, Wnt-5a Protein},

pubstate = {published},

tppubtype = {article}

}

@article{trilecova_toxic_2011,

title = {Toxic effects of methylated benzo[a]pyrenes in rat liver stem-like cells.},

author = {Lenka Trilecová and Simona Krčková and Soňa Marvanová and Kateřina Pĕnčíková and Pavel Krčmář and Jiří Neča and Petra Hulinková and Lenka Pálková and Miroslav Ciganek and Alena Milcová and Jan Topinka and Jan Vondráček and Miroslav Machala},

doi = {10.1021/tx200049x},

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

year  = {2011},

date = {2011-06-01},

journal = {Chemical research in toxicology},

volume = {24},

number = {6},

pages = {866–876},

abstract = {The methylated benzo[a]pyrenes (MeBaPs) are present at significant levels in the environment, especially in the sediments contaminated by petrogenic PAHs. However, the existing data on their toxic effects in vitro and/or in vivo are still largely incomplete. Transcription factor AhR plays a key role in the metabolic activation of PAHs to genotoxic metabolites, but the AhR activation may also contribute to the tumor promoting effects of PAHs. In this study, the AhR-mediated activity of five selected MeBaP isomers was estimated in the DR-CALUX reporter gene assay performed in rat hepatoma cells. Detection of other effects, including induction of CYP1A1, CYP1B1, and AKR1C9 mRNAs, DNA adduct formation, production of reactive oxygen species, oxidation of deoxyguanosine, and cell cycle modulation and apoptosis, was performed in the rat liver epithelial WB-F344 cell line, a model of liver progenitor cells. We identified 1-MeBaP as the most potent inducer of AhR activation, stable DNA adduct formation, checkpoint kinase 1 and p53 phosphorylation, and apoptosis. These effects suggest that 1-MeBaP is a potent genotoxin eliciting a typical sequence of events ascribed to carcinogenic PAHs: induction of CYP1 enzymes, formation of high levels of DNA adducts, activation of DNA damage responses (including p53 phosphorylation), and cell death. In contrast, 10-MeBaP, representing BaP isomers substituted with the methyl group in the angular ring, elicited only low levels DNA adduct formation and apoptosis. Other MeBaPs under study also elicited strong apoptotic responses associated with DNA adduct formation as the prevalent mode of toxic action of these compounds in liver cells. MeBaPs induced a weak production of ROS, which did not lead to significant oxidative DNA damage. Importantly, 1-MeBaP and 3-MeBaP were found to be potent AhR agonists, one order of magnitude more potent than BaP, thus suggesting that the AhR-dependent modulations of gene expression, deregulation of cell survival mechanisms, and further nongenotoxic effects associated with AhR activation may further contribute to their tumor promotion and carcinogenicity.},

note = {Place: United States},

keywords = {Animals, Apoptosis/drug effects, Aryl Hydrocarbon/*metabolism, Benzo(a)pyrene/*chemistry/*toxicity, Cell Cycle/drug effects, Cell Line, Checkpoint Kinase 1, DNA Adducts/metabolism, Epithelial Cells/drug effects/metabolism, Gene Expression Regulation/drug effects, Liver/*cytology, Methylation, Mutagens/*chemistry/*toxicity, Oxidative Stress/drug effects, Protein Kinases/metabolism, Rats, Receptors, Stem Cells/drug effects/metabolism, Tumor, Tumor Suppressor Protein p53/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{benes_inhibition_2011,

title = {Inhibition of topoisomerase IIα: novel function of wedelolactone.},

author = {Petr Benes and Lucia Knopfova and Filip Trcka and Alice Nemajerova and Diana Pinheiro and Karel Soucek and Miroslav Fojta and Jan Smarda},

doi = {10.1016/j.canlet.2011.01.002},

issn = {1872-7980 0304-3835},

year  = {2011},

date = {2011-04-01},

journal = {Cancer letters},

volume = {303},

number = {1},

pages = {29–38},

abstract = {The naturally occurring coumestan wedelolactone has been previously shown to reduce growth of various cancer cells. So far, the growth-suppressing effect of wedelolactone has been attributed to the inhibition of the NFκB transcription factor and/or androgen receptors. We found that wedelolactone suppressed growth and induced apoptosis of androgen receptor-negative MDA-MB-231 breast cancer cells at concentrations that did not inhibit the NFκB activity. The cells responded to wedelolactone by the S and G2/M phase cell cycle arrest and induction of the DNA damage signaling. Wedelolactone interacted with dsDNA and inhibited the activity of DNA topoisomerase IIα. We conclude that wedelolactone can act as growth suppressor independently of NFκB and androgen receptors.},

note = {Place: Ireland},

keywords = {Antigens, Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Breast Neoplasms/*drug therapy/enzymology/pathology, Cell Cycle/drug effects, Cell Growth Processes/drug effects, Cell Line, Cell Survival/drug effects, Coumarins/*pharmacology, DNA Damage, DNA Topoisomerases, DNA-Binding Proteins/*antagonists & inhibitors/metabolism, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoblotting, Neoplasm/metabolism, Signal Transduction, Topoisomerase Inhibitors/*pharmacology, Tumor, Type II/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{prochazkova_differential_2011,

title = {Differential effects of indirubin and 2,3,7,8-tetrachlorodibenzo-p-dioxin on the aryl hydrocarbon receptor (AhR) signalling in liver progenitor cells.},

author = {Jiřina Procházková and Alois Kozubík and Miroslav Machala and Jan Vondráček},

doi = {10.1016/j.tox.2010.10.003},

issn = {1879-3185 0300-483X},

year  = {2011},

date = {2011-01-01},

journal = {Toxicology},

volume = {279},

number = {1-3},

pages = {146–154},

abstract = {In the present study, we investigated the effects of potential endogenous ligand indirubin on the aryl hydrocarbon receptor (AhR) signalling, with a focus on the AhR-dependent gene expression and cell cycle progression in rat liver progenitor cells, and compared them with the effects of a model toxic AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The low (picomolar and nanomolar) doses of indirubin, corresponding to expected endogenous levels, induced a transient translocation of AhR to the nucleus, while high (micromolar) doses induced a long-term AhR nuclear translocation, followed by its degradation, similar to the effects of TCDD. Whereas high doses of indirubin recruited AhR/ARNT1 dimer to rat Cyp1a1 promoter, the low doses did not induce its DNA binding, as revealed by the chromatin immunoprecipitation assay. This corresponded with the fact that the micromolar doses of indirubin significantly increased Cyp1a1/1b1 mRNA in a way similar to TCDD, while the low doses of indirubin were only poor inducers of Cyp1a1/1b1 expression. Comparable patterns of expression were observed also for other AhR gene targets, such as Nqo1 and Nrf2. Also, only micromolar doses of indirubin were able to mimic the effects of TCDD on cell cycle and proliferation of liver progenitor cells or hepatoma cells. Nevertheless, indirubin at low concentrations may have unique effects on gene expression in non-tumorigenic cells. Although both TCDD and the high doses of indirubin repressed plakoglobin (Jup) expression, the picomolar doses of indirubin, unlike the equimolar doses of TCDD, increased mRNA levels of this important desmosomal and adherens junctions constituent. These present data suggest that the outcome of AhR activation induced by indirubin at concentrations expected in vivo may differ from the AhR signalling triggered by exogenous toxic ligands, such as TCDD.},

note = {Place: Ireland},

keywords = {Animals, Aryl Hydrocarbon/*drug effects/metabolism, Carcinoma, Cell Cycle/drug effects, Cell Nucleus/metabolism, Cell Proliferation/drug effects, Cells, Chromatin Immunoprecipitation, Cultured, Dose-Response Relationship, Drug, Gene Expression Regulation/*drug effects, Hepatocellular/pathology, Indoles/administration & dosage/metabolism/pharmacology, Liver Neoplasms/pathology, Liver/cytology/drug effects/metabolism, Polychlorinated Dibenzodioxins/*toxicity, Protein Transport, Rats, Receptors, Signal Transduction/drug effects, Stem Cells/drug effects/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{horvath_platinumiv_2006,

title = {Platinum(IV) complex with adamantylamine overcomes intrinsic resistance to cisplatin in ovarian cancer cells.},

author = {Viktor Horváth and Olga Blanárová and Lenka Svihálková-Sindlerová and Karel Soucek and Jirina Hofmanová and Petr Sova and Ales Kroutil and Peter Fedorocko and Alois Kozubík},

doi = {10.1016/j.ygyno.2005.11.016},

issn = {0090-8258},

year  = {2006},

date = {2006-07-01},

journal = {Gynecologic oncology},

volume = {102},

number = {1},

pages = {32–40},

abstract = {OBJECTIVES: The resistance of tumor cells to cisplatin remains a major cause of treatment failure in cancer patients. In this study, the ability of Pt(IV) complex with adamantylamine-LA-12 and its reduced counterpart with lower oxidation state Pt(II)-LA-9 to overcome intrinsic cisplatin resistance was investigated. METHODS: The ovarian adenocarcinoma SK-OV-3 cells were exposed to cisplatin, LA-9, or LA-12 for 72 h and the effects of drug concentrations that caused 10% or 50% inhibition of cell proliferation were determined. After 24-72 h of sustained exposure viability, apoptosis and inhibition of proliferation were analyzed. DNA synthesis and cell cycle analysis were performed simultaneously in order to determine the modulation of cell cycle after platinum complexes treatment. RESULTS: Lung Resistance-related Protein (LRP/MVP) was detected in SK-OV-3 cells but not in the other two ovarian cancer lines with different sensitivity to cisplatin. LRP/MVP overexpression may be an important factor contributing to intrinsic cisplatin resistance. Interestingly, Pt(IV) complex-LA-12 had approximately 2.7-fold lower IC(50) concentration than LA-9 or cisplatin in SK-OV-3 cells. Moreover, LA-12 caused persistent accumulation of cells in S-phase of the cell cycle while LA-9 and cisplatin treatment-induced S-phase arrest was transient and shifted to G(2)/M-phase at later intervals. Apoptosis seemed to be not the dominant type of cell death caused by such the derivatives, but it was the most intensive after LA-12 treatment. CONCLUSIONS: We found strong differences between effects of Pt(IV) complex-LA-12 and Pt(II) derivatives-LA-9 and cisplatin on cytokinetic parameters. Overall, LA-12 but not its reduced Pt(II) counterpart LA-9 is the compound effective in p53 null human ovarian cancer cells and it is able to overcome intrinsic cisplatin resistance in these cells.},

note = {Place: United States},

keywords = {Adenocarcinoma/*drug therapy/metabolism/pathology, Amantadine/administration & dosage/analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols/*pharmacology, Blotting, Cell Cycle/drug effects, Cell Growth Processes/drug effects, Cell Line, Cisplatin/administration & dosage, DNA, Drug resistance, Female, Humans, Neoplasm, Neoplasm Proteins/biosynthesis, Neoplasm/biosynthesis, Organoplatinum Compounds/administration & dosage/*pharmacology, Ovarian Neoplasms/*drug therapy/metabolism/pathology, Poly(ADP-ribose) Polymerases/metabolism, Tumor, Vault Ribonucleoprotein Particles/biosynthesis, Western},

pubstate = {published},

tppubtype = {article}

}

@article{soucek_transforming_2006,

title = {Transforming growth factor-beta1 inhibits all-trans retinoic acid-induced apoptosis.},

author = {Karel Soucek and Jirí Pacherník and Lukás Kubala and Jan Vondrácek and Jirina Hofmanová and Alois Kozubík},

doi = {10.1016/j.leukres.2005.09.007},

issn = {0145-2126},

year  = {2006},

date = {2006-05-01},

journal = {Leukemia research},

volume = {30},

number = {5},

pages = {607–623},

abstract = {The interaction between retinoids and transforming growth factor-beta1 (TGF-beta1) leading to regulation of proliferation, differentiation and apoptosis is not still fully understood. In this study, we demonstrated that a combination treatment with all-trans retinoic acid (ATRA) and TGF-beta1 led to the enhancement of ATRA-induced suppression of cell proliferation, which is accompanied by inhibition of ATRA-induced apoptosis in human leukemia HL-60 cells. This effect was preceded by the arrest of cells in G0/G1 cell cycle phase linked with pRb protein dephosphorylation, continuous accumulation of p21 and transiently increased level of p27, inhibitors of cyclin-dependent kinases. Inhibition of ATRA-induced apoptosis by TGF-beta1 was associated with an increased level of Mcl-1 protein, an anti-apoptotic member of Bcl-2 family, but not with inhibition of mitochondrial membrane depolarization. Levels of other Bcl-2 family proteins (Bcl-2, Bcl-X(L), Bad, Bak, Bax) were unaffected by simultaneous ATRA and TGF-beta1 treatment, when compared to ATRA alone. Upregulation of c-FLIP(L) protein, an inhibitor of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), correspond with inhibition of ATRA-induced (autocrine TRAIL-mediated) caspase-8 activation and apoptosis. These results suggest that apoptosis inhibition associated with proliferation block could depend on modulation of the TRAIL apoptotic pathway and regulation of the Mcl-1 protein level. In summary, we demonstrate that the balance of processes leading to regulation of proliferation and differentiation of myeloid cells can modulate cell sensitivity to apoptosis-inducing stimuli.},

note = {Place: England},

keywords = {Apoptosis Regulatory Proteins/metabolism/pharmacology, Apoptosis/*drug effects/physiology, bcl-2-Associated X Protein/drug effects/metabolism, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 3, Caspase 8, Caspases/drug effects/metabolism, CD11b Antigen/biosynthesis/drug effects, Cell Cycle/drug effects, Cell Differentiation/drug effects, Cell Proliferation/drug effects, Cell Survival/drug effects, Cultured, Cyclin-Dependent Kinase Inhibitor p21/biosynthesis/drug effects, Drug Synergism, Enzyme Activation/drug effects, G1 Phase/drug effects, Granulocytes/drug effects/physiology, HL-60 Cells, Humans, Intracellular Signaling Peptides and Proteins/drug effects/metabolism, Membrane Glycoproteins/metabolism/pharmacology, Mitochondrial Membranes/drug effects/physiology, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins/drug effects/metabolism, Phosphorylation, Proto-Oncogene Proteins c-bcl-2/drug effects/metabolism, Reactive Oxygen Species/metabolism, Resting Phase, Retinoblastoma Protein/drug effects/metabolism, TNF-Related Apoptosis-Inducing Ligand, Transforming Growth Factor beta/*pharmacology, Transforming Growth Factor beta1, Tretinoin/*antagonists & inhibitors/pharmacology, Tumor Cells, Tumor Necrosis Factor-alpha/metabolism/pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{andrysik_activation_2006,

title = {Activation of ERK1/2 and p38 kinases by polycyclic aromatic hydrocarbons in rat liver epithelial cells is associated with induction of apoptosis.},

author = {Zdenek Andrysík and Miroslav Machala and Katerina Chramostová and Jirina Hofmanová and Alois Kozubík and Jan Vondrácek},

doi = {10.1016/j.taap.2005.06.007},

issn = {0041-008X},

year  = {2006},

date = {2006-03-01},

journal = {Toxicology and applied pharmacology},

volume = {211},

number = {3},

pages = {198–208},

abstract = {Deregulation of various signaling pathways, linked either to induction of cell proliferation or to modulation of cellular differentiation and apoptosis, has been proposed to contribute to carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). In the present study, we investigated effects of the PAHs previously shown to induce cell proliferation and/or apoptosis in contact-inhibited rat liver epithelial WB-F344 cells, with an aim to define the role of mitogen-activated protein kinases in both events. We found that only strong genotoxin dibenzo[a,l]pyrene (DBalP) activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 kinase, but not c-Jun N-terminal kinases (JNKs), at concentrations inducing both apoptosis and phosphorylation of p53 tumor suppressor at serine 15 residue. In contrast, the PAHs stimulating cell proliferation in WB-F344 cell line had no effect on activation of ERK1/2, p38 or JNKs. Synthetic inhibitors of ERK1/2 activation (U0126) or p38 kinase activity (SB203580) prevented both apoptosis and induction of p53 phosphorylation by DBalP. Pifithrin-alpha, inhibitor of p53 transcriptional activity, prevented induction of apoptosis and activation of ERK1/2 and p38. Taken together, our data suggest that both ERK1/2 and p38 are activated in response to DBalP and that they might be involved in regulation of cellular response to DNA damage induced by DBalP, while neither kinase is involved in the release from contact inhibition induced by PAHs.},

note = {Place: United States},

keywords = {*Epithelial Cells/cytology/drug effects/enzymology, *Liver/cytology/drug effects/enzymology, Animals, Apoptosis/*drug effects, Cell Cycle/drug effects, Cell Line, Cell Proliferation/drug effects, Enzyme Activation/drug effects, Enzyme Inhibitors/pharmacology, Extracellular Signal-Regulated MAP Kinases/*metabolism, JNK Mitogen-Activated Protein Kinases/metabolism, p38 Mitogen-Activated Protein Kinases/*metabolism, Phosphorylation, Polycyclic Aromatic Hydrocarbons/*toxicity, Rats},

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}

}

@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{kovarikova_effects_2004,

title = {The effects of TNF-alpha and inhibitors of arachidonic acid metabolism on human colon HT-29 cells depend on differentiation status.},

author = {Martina Kovaríková and Jirina Hofmanová and Karel Soucek and Alois Kozubík},

doi = {10.1111/j.1432-0436.2004.07201006.x},

issn = {0301-4681},

year  = {2004},

date = {2004-02-01},

journal = {Differentiation; research in biological diversity},

volume = {72},

number = {1},

pages = {23–31},

abstract = {The level of differentiation could influence sensitivity of colonic epithelial cells to various stimuli. In our study, the effects of TNF-alpha, inhibitors of arachidonic acid (AA) metabolism (baicalein, BA; indomethacin, INDO; niflumic acid, NA; nordihydroguaiaretic acid, NDGA), and/or their combinations on undifferentiated or sodium butyrate (NaBt)-differentiated human colon adenocarcinoma HT-29 cells were compared. NaBt-treated cells became growth arrested (blocked in G0/G1 phase of the cell cycle), and showed down-regulated Bcl-xL and up-regulated Bak proteins and increased expression of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). These cells were more perceptive to anti-proliferative and apoptotic effects of TNF-alpha. Both inhibitors of LOX (BA and NDGA) and COX (INDO and NA) in higher concentrations modulated cell cycle changes accompanying NaBt-induced differentiation and induced various level of cell death in undifferentiated and differentiated cells. Most important is our finding that TNF-alpha action on proliferation and cell death can be potentiated by co-treatment of cells with AA metabolism inhibitors, and that these effects were more significant in undifferentiated cells. TNF-alpha and INDO co-treatment was associated with accumulation of cells in G0/G1 cell cycle phase, increased reactive oxygen species production, and elevated caspase-3 activity. These results indicate the role of differentiation status in the sensitivity of HT-29 cells to the anti-proliferative and proapoptotic effects of TNF-alpha, AA metabolism inhibitors, and their combinations, and imply promising possibility for novel anti-cancer strategies.},

note = {Place: England},

keywords = {*Flavanones, Adenocarcinoma/drug therapy/pathology, Arachidonate 5-Lipoxygenase/metabolism, Arachidonic Acid/*metabolism, Butyrates/pharmacology, Caspase 3, Caspases/drug effects/metabolism, Cell Cycle/drug effects, Cell Differentiation/*drug effects, Cell Division/drug effects, Colonic Neoplasms/drug therapy/metabolism/pathology, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors/*pharmacology, Drug Synergism, Flavonoids/pharmacology, HT29 Cells/drug effects, Humans, Indomethacin/pharmacology, Isoenzymes/antagonists & inhibitors/metabolism, Lipoxygenase Inhibitors/*pharmacology, Masoprocol/pharmacology, Membrane Proteins, Niflumic Acid/pharmacology, Prostaglandin-Endoperoxide Synthases/metabolism, Tumor Necrosis Factor-alpha/*pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{bryja_lipoxygenase_2003,

title = {Lipoxygenase inhibitors enhance tumor suppressive effects of jun proteins on v-myb-transformed monoblasts BM2.},

author = {Vítezslav Bryja and Jirí Sedlácek and Eva Zahradnícková and Sabina Sevcíková and Jirí Pacherník and Karel Soucek and Jirina Hofmanová and Alois Kozubík and Jan Smarda},

doi = {10.1016/s1098-8823(03)00052-2},

issn = {1098-8823},

year  = {2003},

date = {2003-11-01},

journal = {Prostaglandins & other lipid mediators},

volume = {72},

number = {3-4},

pages = {131–145},

abstract = {Inhibitors of arachidonic acid (AA) conversion were described as suppressors of proliferation and inducers of differentiation of various leukemic cells. Certain AA metabolites have been shown to cooperate with Jun proteins that are important factors controlling cell proliferation, differentiation and apoptosis. Using lipoxygenase (LOX) inhibitors of various specifity we studied possible participation of lipoxygenase pathway in regulation of proliferation and apoptosis of v-myb-transformed chicken monoblasts BM2 and its functional interaction with Jun proteins. We found that nordihydroguaiaretic acid (NDGA) and esculetin (Esc) negatively regulate proliferation of BM2 cells causing accumulation in either G0/G1-phase (nordihydroguaiaretic acid) or S-phase (esculetin) of the cell cycle. BM2 cells can be also induced to undergo growth arrest and partial differentiation by ectopic expression of Jun proteins. We demonstrated that lipoxygenase inhibitors further enforce tumor suppressive capabilities of Jun proteins by inducing either more efficient cell cycle block and/or apoptosis in BM2 cells. This suggests that there is a cross-talk between the lipoxygenase- and Jun-directed pathways in regulation of differentiation and proliferation of monoblastic cells. Thus pharmacologic agents that specifically block lipoxygenase-catalyzed activity and enforce the effects of differentiation-inducers may be important components in anti-tumor therapies.},

note = {Place: United States},

keywords = {*Genes, 11, 14-Eicosatetraynoic Acid/metabolism, 5, 8, Animals, Antioxidants/pharmacology, Apoptosis, Arachidonic Acids/metabolism, Cell Cycle/drug effects, Cell Division/*drug effects, Cells, Chickens, Cultured, Humans, Lipoxygenase Inhibitors/*pharmacology, Lipoxygenase/*metabolism, Masoprocol/pharmacology, Monocytes/cytology/*drug effects/physiology, myb, Proto-Oncogene Proteins c-jun/genetics/*metabolism, Umbelliferones/pharmacology},

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}

}