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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

Xiufeng, Zhua,*; Haijun, Zhaoa,*; Silei, Bia,*; Manman, Denga; Yong, Zhoua; Lian, Yub; Zhihong, Fanga; Bing, Xua

doi: 10.1097/CAD.0000000000000702
PRECLINICAL REPORTS
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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.

aDepartment of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, Xiamen

bDepartment of Hematology and Rheumatology, Longyan First Hospital Affiliated to Fujian Medical University, Longyan, People’s Republic of China

*Zhu Xiufeng, Zhao Haijun and Bi Silei contributed equally to the writing of this article.

Correspondence to Xu Bing, MD, PhD, Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, Medical College of Xiamen University, Xiamen 361003, People’s Republic of China Tel: +86 187 5091 8842; fax: +86 05 922 137 177; e-mail: xubingzhangjian@126.com

Received January 20, 2018

Accepted September 18, 2018

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