Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo

Zhang,Chong; Zhou,Shuang-Shuang; Li,Xiang-Rong; Wang,Bao-Ming; Lin,Neng-Ming; Feng,Lin-Yi; Zhang,Da-Yong; Zhang,Li-Huang; Wang,Jun-Bo; Pan,Jian-Ping

doi:10.3892/or.2013.2405

Enhanced antitumor activity by the combination of dasatinib and combretastatin A-4 in vitro and in vivo

Authors:
- Chong Zhang
- Shuang-Shuang Zhou
- Xiang-Rong Li
- Bao-Ming Wang
- Neng-Ming Lin
- Lin-Yi Feng
- Da-Yong Zhang
- Li-Huang Zhang
- Jun-Bo Wang
- Jian-Ping Pan
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Affiliations: School of Medicine, Zhejiang University City College, Hangzhou, Zhejiang 310015, P.R. China, Laboratory of Clinical Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
Published online on: April 12, 2013 https://doi.org/10.3892/or.2013.2405
Pages: 2275-2282

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Abstract

The present study showed that the combination of dasatinib and combretastatin A-4 (CA-4) exhibited synergistic cytotoxicity in multiple types of cancer, including ovarian, hepatocellular, lung and prostate carcinoma. The enhanced apoptosis induced by dasatinib plus CA-4 was accompanied by a greater extent of mitochondrial depolarization, caspase-3 activation and PARP cleavage in HO-8910 cells. Furthermore, elevated expression of Mcl-1 led to a reduced apoptosis induced by dasatinib plus CA-4, highlighting that downregulated Mcl-1 was necessary for the potentiating effect of dasatinib to CA-4-triggered apoptosis. A clear increase in γ-H2AX expression was observed in the dasatinib + CA-4 group compared with the mono-treatment groups, indicating that dasatinib plus CA-4 may induce double-strand breaks (DSBs) in HO-8910 cells. Moreover, the increased anticancer efficacy of dasatinib combined with CA-4 was further validated in a human HO-8910 ovarian cancer xenograft model in nude mice. Our study is the first to show that the combination of dasatinib with CA-4 could be a novel and promising therapeutic approach for the treatment of cancer.

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