Sterigmatocystin, 5-Methoxysterigmatocistin, and Their Combinations are Cytotoxic and Genotoxic to A549 and HepG2 Cells and Provoke Phosphorylation of Chk2, but not FANCD2 Checkpoint Proteins

Toxins

Sanja Dabelić¹  Domagoj Kifer²  Daniela Jakšić³  Maja Šegvić Klarić³  Nevenka Kopjar⁴ 

[1] Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia;Department of Biophysics, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia;Department of Microbiology, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia;Mutagenesis Unit, Institute for Medical Research and Occupational Health, 10000 Zagreb, Croatia;

关键词: Sterigmatocystin;    5-methoxysterigmatocystin;    checkpoint proteins;    cytotoxicity;    genotoxicity;    mycotoxin interactions;   

DOI  :  10.3390/toxins13070464

来源: DOAJ

【 摘 要 】

Sterigmatocystin (STC) and 5-methoxysterigmatocystin (5-M-STC) are structurally related mycotoxins with cytotoxic and genotoxic properties. In the present study, we hypothesized that DNA damage induced by non-cytotoxic concentrations of single and combined mycotoxins could alter the phosphorylation of the checkpoint proteins Chk2 and FANCD2 (ELISA) in HepG2 and A549 cells. The cytotoxic potential (MTT test) of single and combined STC and 5-M-STC, the nature of their interaction (additivity, antagonism, or synergy) and DNA damage level (alkaline comet assay) in HepG2 and A549 cells were also investigated. All experiments were performed after 24 h of mycotoxin treatment. 5-M-STC was 10-folds more cytotoxic than STC to both HepG2 and A549 cells. Both mycotoxins are genotoxic to HepG2 and A549 cells by inducing both double and single DNA strand breaks that activate Chk2 (especially in HepG2 cells) but not the FANCD2 protein. STC exerted higher genotoxic potential than 5-M-STC in HepG2 and A549 cells when both toxins were applied individually at the same concentration. Dual combinations of non-cytotoxic mycotoxin concentrations showed additive to antagonizing cytotoxic and genotoxic effects. The absence and low activation of checkpoint proteins during prolonged exposure to non-cytotoxic concentrations of STC and 5-M-STC could support cell proliferation and carcinogenesis.

【 授权许可】

Unknown