The influence of ATM, ATR, DNA-PK inhibitors on the cytotoxic and genotoxic effects of dibenzo[def,p]chrysene on human hepatocellular cancer cell line HepG2.
PBN-AR
Instytucja
Instytut Medycyny Pracy im. prof. dr. med. Jerzego Nofera
Informacje podstawowe
Główny język publikacji
EN
Czasopismo
Mutation Research. Genetic Toxicology and Environmental Mutagenesis
ISSN
1383-5718
EISSN
Wydawca
URL
Rok publikacji
2015
Numer zeszytu
Strony od-do
12-24
Numer tomu
791
Link do pełnego tekstu
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
PL
Dibenzo[def,p]chryzenu
inhibitory PIKK
sygnał uszkodzenia DNA
Streszczenia
Język
EN
Treść
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 the response of HepG2 human liver cancer cells to dibenzo[def,p]chrysene (DBC) was investigated. High cytotoxicity of DBC (IC50= 0.1 M) was observed after 72 h incubation. PIKK inhibitors: KU55933 (5 M), NU7026 (10 M) or caffeine (1 and 2 mM) when used alone did not significantly influence the cytotoxicity. However, two combinations: KU55933/NU7026 and caffeine/NU7026 significantly increased HepG2 viability (by 25%) after treatment with DBC at 0.5 M. The cytoprotective effect was confirmed by cell cycle and apoptosis/necrosis analysis. DNA damage level after exposure to DBC assessed by comet assay (single strand breaks) showed a long persistence and significant decrease after incubation of the cells in the presence the inhibitors (the combination of KU55933 + NU7026 showed the strongest effect). Weak induction of reactive oxygen species (ROS) by DBC (0.5 M) was observed. Although, KU55933 and NU7026 when used alone did not increase ROS levels in the cells, their combination induced the ROS increase and moderately enhanced ROS generation by DBC. We propose a mechanism how cells with damaged DNA after exposure to DBC and under the condition of PIKK inhibition, may be at higher risk of undergoing malignant transformation.
Inne
System-identifier
100 331 983
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