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Journals / Türk Biyokimya Dergisi / 2018 / Cilt: 43 - Sayı: 2

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

Src/Abl kinaz inhibitörü bosutinib PARP enzim seviyesini azaltıp inhibe eder ve hücreleri DNA hasar verici ajanlara karşı hassaslaştırır

Burcu ERBAYKENT TEPEDELEN
Petek BALLAR KIRMIZIBAYRAK
Sinem YILMAZ
Recep İLHAN
Selin GÜNAL
Pages
101–109
Publication Date
2022-11-05
DOI
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AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Bosutinib was foundto be more cytotoxic on Capan1 cells with BRCA2 mutation.Furthermore by acting as a chemosensitizer, bosutinibenhanced the cytotoxicity of doxorubicin (DOXO) andetoposide (ETP) by decreasing phosphorylation of DNArepair enzymes checkpoint kinase 1 (Chk1) and ataxiatelangiectasiamutated (ATM).Conclusion: By inhibition of both PARP and DNA damagecheckpoint kinases, bosutinib increased the phospho-H2AXlevels, an early indicator of DNA double strand breaks.

📌 3 Key Takeaways

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Objective & Hypothesis:Background: Poly(ADP-ribosyl)ation (PARylation) catalyzedmainly by PARP1 is a highly regulated posttranslationalmodification associated with several pathways in cellularphysiology and genotoxic deoxyribonucleic acid (DNA)damage response.
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Key Findings & Data:The cytotoxic and chemosensitizing effects wereassessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay.
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Conclusion & Impact:Bosutinib was foundto be more cytotoxic on Capan1 cells with BRCA2 mutation.Furthermore by acting as a chemosensitizer, bosutinibenhanced the cytotoxicity of doxorubicin (DOXO) andetoposide (ETP) by decreasing phosphorylation of DNArepair enzymes checkpoint kinase 1 (Chk1) and ataxiatelangiectasiamutated (ATM).Conclusion: By inhibition of both PARP and DNA damagecheckpoint kinases, bosutinib increased the phospho-H2AXlevels, an early indicator of DNA double strand breaks.
🔬Design:Research Article
📍Scope:Comprehensive Sample
⚙️Variables:Domain Parameters

Abstract

Background: Poly(ADP-ribosyl)ation (PARylation) catalyzedmainly by PARP1 is a highly regulated posttranslationalmodification associated with several pathways in cellularphysiology and genotoxic deoxyribonucleic acid (DNA)damage response. PAR polymers and PARP enzyme functionin DNA integrity maintenance and several PARP inhibitorshave entered clinical phase studies for cancer therapies.Material and methods: The effect of bosutinib, a dual Src/Abl kinase inhibitor, on PARylation was fluorometricallymeasured. The cytotoxic and chemosensitizing effects wereassessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. The levels of DNA repair proteinsand PARP enzyme were examined by immunoblotting.Results: In this study, bosutinib is characterized as anovel PARP inhibitor. Bosutinib inhibited oxidativestress-induced cellular PARylation and nuclear foci formationby downregulating PARP1 levels. Bosutinib was foundto be more cytotoxic on Capan1 cells with BRCA2 mutation.Furthermore by acting as a chemosensitizer, bosutinibenhanced the cytotoxicity of doxorubicin (DOXO) andetoposide (ETP) by decreasing phosphorylation of DNArepair enzymes checkpoint kinase 1 (Chk1) and ataxiatelangiectasiamutated (ATM).Conclusion: By inhibition of both PARP and DNA damagecheckpoint kinases, bosutinib increased the phospho-H2AXlevels, an early indicator of DNA double strand breaks.

Özet

Amaç: Başlıca PARP1 enzimi ile katalize edilen poli(ADP-ribozil) asyon (PARilasyon), oldukça sıkı regüle edilen bir posttranslasyonal modifikasyon olup hücresel fizyoloji ve genotoksik DNA hasar yanıtındaki çeşitli yolaklar ile ilişkilendirilmiştir. PAR polimerleri ve PARP enzimi, DNA bütünlüğünün korunmasında fonksiyon göstermektedir ve çeşitli PARP inhibitörleri kanser terapisi için klinik faz çalışmalarına dahil edilmiştir. Gereç ve Yöntem: Bir Src/Abl kinaz inhibitörü olan bosutinibin PARilasyona etkisi fluorometrik olarak ölçülmüştür. Sitotoksik ve kemohassaslaştırıcı etki, 3-(4,5dimetilmiazoll- 2-yl)-2,5-difeniltetrazolyum bromit (MTT) yöntemi ile değerlendirilmiştir. DNA onarım proteinleri ve PARP enzim seviyesi immunoblotlama ile incelenmiştir. Bulgular: Bu çalışmada, bosutinib yeni bir PARP inhibitörü olarak karakterize edilmiştir. Bosutinib, PARP1 protein seviyesini azaltarak oksidatif stres ile indüklenmiş hücresel PARilasyonu ve nüklear odak oluşumunu inhibe etmektedir. Bosutinib, BRCA2 mutasyonu içeren Capan1 hücrelerinde daha fazla sitotoksik bulunmuştur. Kemohassaslaştırıcı olarak davranan bosutinib, DNA tamir enzimlerinden Chk1 ve ATM fosforilasyonunu inhibe ederek doksorubisin (DOXO) ve etoposidin (ETP) sitotoksisitesini arttırmaktadır. Hem PARP hem de DNA hasar tamir kinazlarının inhibisyonu ile bosutinib, DNA çift zincir kırıklarının erken bir belirteci olan fosfo-H2AX seviyesini arttırmaktadır. Sonuç: Bu çalışmadaki verilerimiz bosutinibin bir PARP inhibitörü olarak davrandığını ve kemohassaslaştırıcı etkisinin hem PARP hem de DNA tamir proteinlerinin inhibisyonu sonucu gözlendiğini önermektedir.

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Cite This Article

TEPEDELEN, B. E., KIRMIZIBAYRAK, P. B., YILMAZ, S., İLHAN, R., GÜNAL, S. (2022). A Src/Abl kinase inhibitor, bosutinib, downregulates and inhibits PARP enzyme and sensitizes cells to the DNA damaging agents. Türk Biyokimya Dergisi, Cilt: 43 - Sayı: 2, 101–109. https://ajindex.com/articles/620940

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