A Src/Abl kinase inhibitor, bosutinib, downregulates and inhibits PARP enzyme and sensitizes cells to the DNA damaging agents

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dc.contributor.authorKirmizibayrak P.B.
dc.contributor.authorIlhan R.
dc.contributor.authorYilmaz S.
dc.contributor.authorGunal S.
dc.contributor.authorTepedelen B.E.
dc.date.accessioned2024-07-22T08:09:54Z
dc.date.available2024-07-22T08:09:54Z
dc.date.issued2018
dc.description.abstractBackground: 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.
dc.identifier.DOI-ID10.1515/tjb-2017-0095
dc.identifier.issn02504685
dc.identifier.urihttp://akademikarsiv.cbu.edu.tr:4000/handle/123456789/14974
dc.language.isoEnglish
dc.publisherTurkish Biochemistry Society
dc.rightsAll Open Access; Gold Open Access
dc.subjectbosutinib
dc.subjectBRCA2 protein
dc.subjectcheckpoint kinase 1
dc.subjectdoxorubicin
dc.subjectetoposide
dc.subjectnicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1
dc.subjectArticle
dc.subjectBRCA2 gene
dc.subjectCapan-1 cell line
dc.subjectcontrolled study
dc.subjectDNA damage response
dc.subjectDNA repair
dc.subjectdrug sensitization
dc.subjectenzyme inhibition
dc.subjectfluorometry
dc.subjectgene expression
dc.subjectHeLa cell line
dc.subjecthuman
dc.subjecthuman cell
dc.subjectimmunoblotting
dc.subjectMRC-5 cell line
dc.subjectMTT assay
dc.subjectoxidative stress
dc.subjectpancreas adenocarcinoma
dc.subjectprotein phosphorylation
dc.subjectreceptor down regulation
dc.subjecttumor gene
dc.titleA Src/Abl kinase inhibitor, bosutinib, downregulates and inhibits PARP enzyme and sensitizes cells to the DNA damaging agents
dc.typeArticle

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