A Src/Abl kinase inhibitor, bosutinib, downregulates and inhibits PARP enzyme and sensitizes cells to the DNA damaging agents
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Date
2018
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Abstract
Background: Poly(ADP-ribosyl)ation (PARylation) catalyzed mainly by PARP1 is a highly regulated posttranslational modification associated with several pathways in cellular physiology and genotoxic deoxyribonucleic acid (DNA) damage response. PAR polymers and PARP enzyme function in DNA integrity maintenance and several PARP inhibitors have entered clinical phase studies for cancer therapies. Material and methods: The effect of bosutinib, a dual Src/ Abl kinase inhibitor, on PARylation was fluorometrically measured. The cytotoxic and chemosensitizing effects were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT) assay. The levels of DNA repair proteins and PARP enzyme were examined by immunoblotting. Results: In this study, bosutinib is characterized as a novel PARP inhibitor. Bosutinib inhibited oxidative stress-induced cellular PARylation and nuclear foci formation by downregulating PARP1 levels. Bosutinib was found to be more cytotoxic on Capan1 cells with BRCA2 mutation. Furthermore by acting as a chemosensitizer, bosutinib enhanced the cytotoxicity of doxorubicin (DOXO) and etoposide (ETP) by decreasing phosphorylation of DNA repair enzymes checkpoint kinase 1 (Chk1) and ataxia-telangiectasia mutated (ATM). Conclusion: By inhibition of both PARP and DNA damage checkpoint kinases, bosutinib increased the phospho-H2AX levels, an early indicator of DNA double strand breaks. © 2018 Turkish Biochemistry Society. All rights reserved.
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bosutinib , BRCA2 protein , checkpoint kinase 1 , doxorubicin , etoposide , nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1 , Article , BRCA2 gene , Capan-1 cell line , controlled study , DNA damage response , DNA repair , drug sensitization , enzyme inhibition , fluorometry , gene expression , HeLa cell line , human , human cell , immunoblotting , MRC-5 cell line , MTT assay , oxidative stress , pancreas adenocarcinoma , protein phosphorylation , receptor down regulation , tumor gene