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
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
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ABT-199与吉西他滨阻碍DNA损伤修复并诱导细胞凋亡协同治疗T细胞急性淋巴细胞白血病
DOI：
10.1097/cad.0000000000000702
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发表时间：
2019-02
影响因子：
2.3
通讯作者：
Xu Bing
中科院分区：
文献类型：
--
作者：
Zhu Xiufeng;Zhao Haijun;Bi Silei;Deng Manman;Zhou Yong;Yu Lian;Fang Zhihong;Xu Bing
t细胞急性淋巴母细胞白血病（T-ALL）是急性淋巴母细胞白血病的高风险亚型，治疗选择有限。在这里，我们评估了Bcl-2拮抗剂ABT-199和细胞毒性药物吉西他滨在T-ALL细胞系中的联合治疗潜力。我们的研究结果表明，ABT-199和吉西他滨联合使用对人T-ALL细胞株（Jurkat和Molt4）具有协同细胞毒性，并诱导了显著的细胞凋亡。联合治疗后细胞凋亡增强，线粒体去极化程度加重，DNA损伤增强。重要的是，单一药物单独诱导DNA损伤，但不抑制RAD51/ brca1介导的DNA双链断裂修复。相比之下，ABT-199和吉西他滨联合使用可破坏RAD51/ brca1依赖性DNA修复，显著激活caspase-3和PARP，从而引发细胞凋亡。此外，ABT-199对Bcl-2和Bcl-xL具有拮抗作用，但在一定程度上适度升高Mcl-1水平，而这种水平可能被吉西他滨破坏。综上所述，我们的研究表明，ABT-199与吉西他滨联用通过协同靶向DNA损伤修复途径和Bcl-2家族蛋白，对T-ALL细胞具有协同细胞毒性。
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.
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低剂量雷公藤甲素通过活性氧生成和 DNA 损伤反应破坏逆转成人急性淋巴细胞白血病细胞的化疗耐药性
影响因子：
--
作者：
Zhao H;Shi P;Deng M;Jiang Z;Li Y;Kannappan V;Wang W;Li P;Xu B
通讯作者：
Xu B
影响因子：
2.7
作者：
Garcia TB;Fosmire SP;Porter CC
通讯作者：
Porter CC
影响因子：
6.5
作者：
Sutton, Rosemary;Shaw, Peter J.;O'Brien, Tracey A.
通讯作者：
O'Brien, Tracey A.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8
作者：
Wu X;Wang L;Qiu Y;Zhang B;Hu Z;Jin R
通讯作者：
Jin R