title: The modulating effect of ATM, ATR, DNA-PK inhibitors on the cytotoxicity and genotoxicity of benzo[a]pyrene in human hepatocellular cancer cell line HepG2.
abstract: The effect of inhibitors of phosphatidylinositol-3-kinase-related kinases (PIKK): ataxia-telangiectasia mutated (ATM), ATM- and Rad3-related (ATR) and DNA-dependent protein kinase (DNA-PK) on response of HepG2 human liver cancer cells to benzo[a]pyrene (BaP) was investigated. PIKK inhibitors: KU55933 (5 μM), NU7026 (10 μM) or caffeine (1 and 2mM) when used as single agents or in combinations (KU55933/NU7026 and caffeine/NU7026) did not significantly influence the BaP (3 μM) cytotoxicity (MTT reduction test). BaP induced a weak proapoptotic effect which was moderately enhanced by both inhibitor combinations. HepG2 cells exposed to BaP showed a strong S-phase arrest which was considerably diminished by both inhibitor combinations. The DNA damage (comet assay) induced after continuous 24h exposure to BaP was significantly diminished by both inhibitor combinations. Weak induction of reactive oxygen species by BaP was observed, which was not modulated by the inhibitor combinations. Similarly, no modulation of the glutathione levels was observed.
authors.affiliation: Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland. Electronic address: mstep@imp.lodz.pl.
authors.forename: Maciej
authors.initials: M
authors.lastname: Stępnik
authors.affiliation: Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland. Electronic address: sgajda@imp.lodz.pl.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Spryszyńska
authors.affiliation: Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland. Electronic address: smok@imp.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Smok-Pieniążek
authors.affiliation: Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland. Electronic address: mkomorow@imp.lodz.pl.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Ferlińska
authors.affiliation: Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland. Electronic address: joanna@imp.lodz.pl.
authors.forename: Joanna
authors.initials: J
authors.lastname: Roszak
authors.affiliation: Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Łódź, Poland. Electronic address: nocun@imp.lodz.pl.
authors.forename: Marek
authors.initials: M
authors.lastname: Nocuń
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002110:Caffeine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D009025:Morpholines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011753:Pyrones / Q000494:pharmacology; D000099317:Hippo Kinases
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D001564:Benzo(a)pyrene; D002110:Caffeine; D002867:Chromones; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011753:Pyrones; C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; C109163:STK24 protein, human; D000099317:Hippo Kinases; C576324:ATM protein, human; C576597:ATR protein, human
keywords: Benzo[a]pyrene; DNA damage signaling; HepG2; PIKK inhibitors