Co-operation of ABT-199 and gemcitabine in impeding DNA damage repair and inducing cell apoptosis for synergistic therapy of T-cell acute lymphoblastic leukemia
| Autor: | Xu Bing, Fang Zhihong, Yu Lian, Deng Manman, Zhu Xiufeng, Zhou Yong, Bi Silei, Zhao Haijun |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research DNA Repair DNA repair DNA damage Poly ADP ribose polymerase Apoptosis Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Jurkat cells Deoxycytidine 03 medical and health sciences 0302 clinical medicine Antineoplastic Combined Chemotherapy Protocols medicine Tumor Cells Cultured Humans Pharmacology (medical) Cytotoxicity Cell Proliferation Pharmacology Sulfonamides Chemistry Cell growth Drug Synergism Bridged Bicyclo Compounds Heterocyclic Gemcitabine 030104 developmental biology Oncology 030220 oncology & carcinogenesis Case-Control Studies Cancer research medicine.drug DNA Damage |
| Zdroj: | Anti-cancer drugs. 30(2) |
| ISSN: | 1473-5741 |
| Popis: | T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia with limited therapeutic options available. Here, we evaluated the therapeutic potential of the combination of the Bcl-2 antagonist ABT-199 and cytotoxic agent gemcitabine in T-ALL cell lines. Our results showed that the combination of ABT-199 and gemcitabine exhibited synergistic cytotoxicity and induced significant apoptosis in human T-ALL cell lines (Jurkat and Molt4). The augmented apoptosis induced by combination treatment was accompanied by the greater extent of mitochondrial depolarization and enhanced DNA damage. Importantly, single agent induced DNA damage alone but did not inhibit RAD51/BRCA1-mediated repair for DNA double-strand breaks. In contrast, the combination of ABT-199 and gemcitabine disrupted RAD51/BRCA1-dependent DNA repair and remarkably activated caspase-3 and PARP to trigger apoptosis. Moreover, ABT-199 exerted an antagonistic action towards Bcl-2 and Bcl-xL, but to a certain extent moderately increased Mcl-1 level that could be compromised by gemcitabine. In conclusion, our study showed that the combination of ABT-199 and gemcitabine exhibited synergistic cytotoxicity in T-ALL cells by cooperatively targeting DNA damage repair pathway and Bcl-2 family proteins. |
| Databáze: | OpenAIRE |
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