Latest Publications

@article{zapletal_butyrate_2017,

title = {Butyrate alters expression of cytochrome P450 1A1 and metabolism of benzo[a]pyrene via its histone deacetylase activity in colon epithelial cell models.},

author = {Ondřej Zapletal and Zuzana Tylichová and Jiří Neča and Jiří Kohoutek and Miroslav Machala and Alena Milcová and Michaela Pokorná and Jan Topinka and Mary Pat Moyer and Jiřina Hofmanová and Alois Kozubík and Jan Vondráček},

doi = {10.1007/s00204-016-1887-4},

issn = {1432-0738 0340-5761},

year  = {2017},

date = {2017-05-01},

journal = {Archives of toxicology},

volume = {91},

number = {5},

pages = {2135–2150},

abstract = {Butyrate, a short-chain fatty acid produced by fermentation of dietary fiber, is an important regulator of colonic epithelium homeostasis. In this study, we investigated the impact of this histone deacetylase (HDAC) inhibitor on expression/activity of cytochrome P450 family 1 (CYP1) and on metabolism of carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP), in colon epithelial cells. Sodium butyrate (NaBt) strongly potentiated the BaP-induced expression of CYP1A1 in human colon carcinoma HCT116 cells. It also co-stimulated the 7-ethoxyresorufin-O-deethylase (EROD) activity induced by the 2,3,7,8-tetrachlorodibenzo-p-dioxin, a prototypical ligand of the aryl hydrocarbon receptor. Up-regulation of CYP1A1 expression/activity corresponded with an enhanced metabolism of BaP and formation of covalent DNA adducts. NaBt significantly potentiated CYP1A1 induction and/or metabolic activation of BaP also in other human colon cell models, colon adenoma AA/C1 cells, colon carcinoma HT-29 cells, or in NCM460D cell line derived from normal colon mucosa. Our results suggest that the effects of NaBt were due to its impact on histone acetylation, because additional HDAC inhibitors (trichostatin A and suberanilohydroxamic acid) likewise increased both the induction of EROD activity and formation of covalent DNA adducts. NaBt-induced acetylation of histone H3 (at Lys14) and histone H4 (at Lys16), two histone modifications modulated during activation of CYP1A1 transcription, and it reduced binding of HDAC1 to the enhancer region of CYP1A1 gene. This in vitro study suggests that butyrate, through modulation of histone acetylation, may potentiate induction of CYP1A1 expression, which might in turn alter the metabolism of BaP within colon epithelial cells.},

note = {Place: Germany},

keywords = {Benzo(a)pyrene/metabolism/*pharmacokinetics, beta Catenin/metabolism, Butyrate, Butyric Acid/*pharmacology, Colon epithelial cells, Colon/*drug effects/metabolism, CYP1A1, Cytochrome P-450 CYP1A1/genetics/*metabolism, DNA adducts, DNA Adducts/drug effects/metabolism, Enhancer Elements, Genetic/drug effects, HCT116 Cells, Histone Deacetylase 1/antagonists & inhibitors/metabolism, Histone Deacetylase Inhibitors/pharmacology, Histone deacetylases, Histones/metabolism, HT29 Cells, Humans, Inactivation, Metabolic, Polycyclic aromatic hydrocarbons},

pubstate = {published},

tppubtype = {article}

}

@article{tylichova_activation_2017,

title = {Activation of autophagy and PPARγ protect colon cancer cells against apoptosis induced by interactive effects of butyrate and DHA in a cell type-dependent manner: The role of cell differentiation.},

author = {Zuzana Tylichová and Nicol Straková and Jan Vondráček and Alena Hyršlová Vaculová and Alois Kozubík and Jiřina Hofmanová},

doi = {10.1016/j.jnutbio.2016.09.006},

issn = {1873-4847 0955-2863},

year  = {2017},

date = {2017-01-01},

journal = {The Journal of nutritional biochemistry},

volume = {39},

pages = {145–155},

abstract = {The short-chain and n-3 polyunsaturated fatty acids exhibit anticancer properties, and they may mutually interact within the colon. However, the molecular mechanisms of their action in colon cancer cells are still not fully understood. Our study focused on the mechanisms responsible for the diverse effects of sodium butyrate (NaBt), in particular when interacting with docosahexaenoic acid (DHA), in distinct colon cancer cell types, in which NaBt either induces cell differentiation or activates programmed cell death involving mitochondrial pathway. NaBt activated autophagy both in HT-29 cells, which are sensitive to induction of differentiation, and in nondifferentiating HCT-116 cells. However, autophagy supported cell survival only in HT-29 cells. Combination of NaBt with DHA-promoted cell death, especially in HCT-116 cells and after longer time intervals. The inhibition of autophagy both attenuated differentiation and enhanced apoptosis in HT-29 cells treated with NaBt and DHA, but it had no effect in HCT-116 cells. NaBt, especially in combination with DHA, activated PPARγ in both cell types. PPARγ silencing decreased differentiation and increased apoptosis only in HT-29 cells, therefore we verified the role of caspases in apoptosis, differentiation and also PPARγ activity using a pan-caspase inhibitor. In summary, our data suggest that diverse responses of colon cancer cells to fatty acids may rely on their sensitivity to differentiation, which may in turn depend on distinct engagement of autophagy, caspases and PPARγ. These results contribute to understanding of mechanisms underlying differential effects of NaBt, when interacting with other dietary fatty acids, in colon cancer cells.},

note = {Place: United States},

keywords = {Antineoplastic Agents/pharmacology, Apoptosis/*drug effects, Autophagy, Autophagy/*drug effects, Butyrate, Butyrates/*pharmacology, Butyric Acid/pharmacology, Caspase 3/genetics/metabolism, Cell Differentiation/drug effects, Colon cancer, Colonic Neoplasms/*pathology, Differentiation, Docosahexaenoic acid, Docosahexaenoic Acids/*pharmacology, HCT116 Cells, HT29 Cells, Humans, Mitochondria/drug effects/metabolism, PPAR gamma/genetics/*metabolism, PPARγ},

pubstate = {published},

tppubtype = {article}

}

@article{svihalkova-sindlerova_-12_2010,

title = {LA-12 overcomes confluence-dependent resistance of HT-29 colon cancer cells to Pt (II) compounds.},

author = {Lenka Svihálková-Sindlerová and Vendula Foltinová and Alena Vaculová and Viktor Horváth and Karel Soucek and Petr Sova and Jirina Hofmanová and Alois Kozubík},

issn = {1791-7530 0250-7005},

year  = {2010},

date = {2010-04-01},

journal = {Anticancer research},

volume = {30},

number = {4},

pages = {1183–1188},

abstract = {BACKGROUND: LA-12 is a new platinum (IV) drug with promising cytotoxic effects in a wide range of cancer cell lines. Its confluence-dependent effects were compared with cisplatin (CDDP) and oxaliplatin (L-OHP) in HT-29 cells. MATERIALS AND METHODS: Cytotoxicity was determined by MTT test, eosin exclusion assay, and cell number quantification. The cell cycle was analysed using propidium iodide DNA staining (flow cytometry), apoptosis by phosphatidylserine externalisation (annexin-V assay), mitochondrial membrane potential by flow cytometry, nuclear morphology by means of fluorescence microscopy, and PARP cleavage by Western blotting. RESULTS: While L-OHP and CDDP were practically inactive in the subconfluent cell population, LA-12 showed a similar toxicity in both subconfluent and growing populations. All compounds induced apoptosis, although with different potentials. CONCLUSION: LA-12 was able to overcome confluence-dependent resistance of HT-29 cells observed for other platinum compounds, which may have potential therapeutic use in slowly growing tumours.},

note = {Place: Greece},

keywords = {Adenocarcinoma/*drug therapy, Amantadine/*analogs & derivatives/pharmacology, Antineoplastic Agents/*pharmacology, Apoptosis/drug effects, Cell Adhesion/drug effects, Cisplatin/pharmacology, Colonic Neoplasms/*drug therapy/pathology, Dose-Response Relationship, Drug, Drug resistance, HT29 Cells, Humans, Neoplasm, Organoplatinum Compounds/*pharmacology, Oxaliplatin},

pubstate = {published},

tppubtype = {article}

}

@article{jendzelovsky_drug_2009,

title = {Drug efflux transporters, MRP1 and BCRP, affect the outcome of hypericin-mediated photodynamic therapy in HT-29 adenocarcinoma cells.},

author = {Rastislav Jendzelovský and Jaromír Mikes and Ján Koval' and Karel Soucek and Jirina Procházková and Martin Kello and Veronika Sacková and Jirina Hofmanová and Alois Kozubík and Peter Fedorocko},

doi = {10.1039/b9pp00086k},

issn = {1474-9092 1474-905X},

year  = {2009},

date = {2009-12-01},

journal = {Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology},

volume = {8},

number = {12},

pages = {1716–1723},

abstract = {Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.},

note = {Place: England},

keywords = {Adenocarcinoma/*drug therapy/secondary, Anthracenes, ATP Binding Cassette Transporter, ATP-Binding Cassette Transporters/*metabolism, Caspase 3/metabolism, Caspase 9/metabolism, Colonic Neoplasms/*drug therapy, Enzyme Inhibitors/pharmacology, HT29 Cells, Humans, Light, Member 1/metabolism, Member 2, Membrane Potential, Mitochondrial/drug effects, Mixed Function Oxygenases/metabolism, Multidrug Resistance-Associated Proteins/*metabolism, Neoplasm Proteins/*metabolism, Perylene/*analogs & derivatives/pharmacology, Photochemotherapy, Photosensitizing Agents/*pharmacology, Proadifen/pharmacology, Reactive Oxygen Species/metabolism, Subfamily B, Subfamily G},

pubstate = {published},

tppubtype = {article}

}

@article{maioli_rottlerin_2009,

title = {Rottlerin inhibits ROS formation and prevents NFkappaB activation in MCF-7 and HT-29 cells.},

author = {Emanuela Maioli and Lucedio Greci and Karel Soucek and Martina Hyzdalova and Alessandra Pecorelli and Vittoria Fortino and Giuseppe Valacchi},

doi = {10.1155/2009/742936},

issn = {1110-7251 1110-7243},

year  = {2009},

date = {2009-01-01},

journal = {Journal of biomedicine & biotechnology},

volume = {2009},

pages = {742936},

abstract = {Rottlerin, a polyphenol isolated from Mallotus Philippinensis, has been recently used as a selective inhibitor of PKC delta, although it can inhibit many kinases and has several biological effects. Among them, we recently found that Rottlerin inhibits the Nuclear Factor kappaB (NFkappaB), activated by either phorbol esters or H(2)O(2). Because of the redox sensitivity of NFkappaB and on the basis of Rottlerin antioxidant property, we hypothesized that Rottlerin could prevent NFkappaB activation acting as a free radicals scavenger, as other natural polyphenols. The current study confirms the antioxidant property of Rottlerin against the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) in vitro and against oxidative stress induced by H(2)O(2) and by menadione in culture cells. We also demonstrate that Rottlerin prevents TNFalpha-dependent NFkappaB activation in MCF-7 cells and in HT-29 cells transfected with the NFkappaB-driven plasmid pBIIX-LUC, suggesting that Rottlerin can inhibit NFkappaB via several pathways and in several cell types.},

note = {Place: United States},

keywords = {Acetophenones/chemistry/*pharmacology, Benzopyrans/chemistry/*pharmacology, Biphenyl Compounds/metabolism, Cell Nucleus/drug effects/metabolism, DNA/metabolism, Electron Spin Resonance Spectroscopy, Free Radical Scavengers/pharmacology, Genetic/drug effects, HT29 Cells, Humans, Hydrogen Peroxide/metabolism, Intracellular Space/drug effects/metabolism, NF-kappa B/*metabolism, Picrates/metabolism, Protein Binding/drug effects, Protein Transport/drug effects, Reactive Oxygen Species/*metabolism, Spectrophotometry, Transcription, Transfection, Tumor Necrosis Factor-alpha/pharmacology, Ultraviolet},

pubstate = {published},

tppubtype = {article}

}

@article{vaculova_different_2006,

title = {Different modulation of TRAIL-induced apoptosis by inhibition of pro-survival pathways in TRAIL-sensitive and TRAIL-resistant colon cancer cells.},

author = {Alena Vaculová and Jirina Hofmanová and Karel Soucek and Alois Kozubík},

doi = {10.1016/j.febslet.2006.11.004},

issn = {0014-5793},

year  = {2006},

date = {2006-12-01},

journal = {FEBS letters},

volume = {580},

number = {28-29},

pages = {6565–6569},

abstract = {Epithelial cells can be manipulated to undergo apoptosis depending on the balance between pro-survival and apoptotic signals. We showed that TRAIL-induced apoptosis may be differentially regulated by inhibitors of MEK ERK (U0126) or PI3K/Akt (LY294002) pathway in TRAIL-sensitive (HT-29) and TRAIL-resistant (SW620) human epithelial colon cancer cells. U0126 or LY294002 significantly enhanced TRAIL-induced apoptosis in HT-29 cells, but not in SW620 cells. We report a different regulation of the level of an anti-apoptotic Mcl-1 protein under MEK/ERK or PI3K/Akt pathway inhibition and suggest the mechanisms involved. A special attention was paid to the role of the ERK1/2, Akt, and glycogen synthase kinase 3beta.},

note = {Place: England},

keywords = {Apoptosis/*drug effects, Caspase 8/metabolism, Cell Survival/drug effects, Colonic Neoplasms/*pathology, Enzyme Activation/drug effects, Enzyme Inhibitors/pharmacology, Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors, Glycogen Synthase Kinase 3 beta, Glycogen Synthase Kinase 3/metabolism, HT29 Cells, Humans, Keratin-18/metabolism, Mitogen-Activated Protein Kinase 1/antagonists & inhibitors, Mitogen-Activated Protein Kinase 3/antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins/metabolism, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation/drug effects, Poly(ADP-ribose) Polymerases/metabolism, Proto-Oncogene Proteins c-akt/antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2/metabolism, TNF-Related Apoptosis-Inducing Ligand/*pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{vaculova_ethanol_2004,

title = {Ethanol acts as a potent agent sensitizing colon cancer cells to the TRAIL-induced apoptosis.},

author = {Alena Vaculová and Jirina Hofmanová and Karel Soucek and Ladislav Andera and Alois Kozubík},

doi = {10.1016/j.febslet.2004.10.013},

issn = {0014-5793},

year  = {2004},

date = {2004-11-01},

journal = {FEBS letters},

volume = {577},

number = {1-2},

pages = {309–313},

abstract = {Identification of mechanisms of modulation of the TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is important for its potential use in anticancer therapy. Ethanol can induce cell death in vitro and in vivo by different signalling pathways. Its effect in combination with death ligands is unknown. We investigated how ethanol modulates the effects of TRAIL in colon cancer cells. After combined TRAIL and ethanol treatment, a potentiation of caspase-8, -9, -3 activation, a proapoptotic Bid protein cleavage, a decrease of mitochondrial membrane potential, a complete poly(ADP)ribose polymerase cleavage, and disappearance of antiapoptotic Mcl-1 protein were demonstrated. Ethanol acts as a potent agent sensitizing colon cancer cells to TRAIL-induced apoptosis.},

note = {Place: England},

keywords = {Apoptosis Regulatory Proteins, Apoptosis/*drug effects/physiology, BH3 Interacting Domain Death Agonist Protein, Blotting, Carrier Proteins/metabolism, Caspases/metabolism, Colonic Neoplasms/enzymology/metabolism/*pathology, Ethanol/*pharmacology, HT29 Cells, Humans, Membrane Glycoproteins/*physiology, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins/metabolism, Proto-Oncogene Proteins c-bcl-2/metabolism, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor-alpha/*physiology, Western},

pubstate = {published},

tppubtype = {article}

}