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Effective elimination of adult B-lineage acute lymphoblastic leukemia by disulfiram/copper complex in vitro and in vivo in patient-derived xenograft models
Deng, Manman Jiang, Zhiwu Li, Yin Zhou, Yong Li, Jie Wang, Xiangmeng Yao, Yao Wang, Weiguang Li, Peng Xu, Bing
Deng, Manman
Jiang, Zhiwu
Li, Yin
Zhou, Yong
Li, Jie
Wang, Xiangmeng
Yao, Yao
Wang, Weiguang
Li, Peng
Xu, Bing
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2016-05-17
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Abstract
Disulfiram (DS), a clinically used drug to control alcoholism, has displayed promising anti-cancer activity against a wide range of tumors. Here, we demonstrated that DS/copper (Cu) complex effectively eliminated adult B-ALL cells in vitro and in vivo in patient-derived xenograft (PDX) humanized mouse models, reflected by inhibition of cell proliferation, induction of apoptosis, suppression of colony formation, and reduction of PDX tumor growth, while sparing normal peripheral blood mononuclear cells. Mechanistically, these events were associated with disruption of mitochondrial membrane potential and down-regulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL. Further analysis on B-ALL patients’ clinical characteristics revealed that the ex vivo efficacy of DS/Cu in primary samples was significantly correlated to p16 gene deletion and peripheral blood WBC counts at diagnosis, while age, LDH level, extramedullary infiltration, status post intensive induction therapy, immune phenotype, risk category, and Ph chromosome had no effect. Together, these findings indicate that disulfiram, particularly when administrated in combination with copper, might represent a potential repurposing agent for treatment of adult B-ALL patients, including those clinically characterized by one or more adverse prognostic factors.
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Deng, M., Jiang, Z., Li, Y., Zhou, Y., Li, J., Wang, X., Yao, Y., Wang, W., Li, P., and Xu, B. (2016) Effective elimination of adult B-lineage acute lymphoblastic leukemia by disulfiram/copper complex in vitro and in vivo in patient-derived xenograft models, Oncotarget, 2016; 7, pp. 82200-82212. https://doi.org/10.18632/oncotarget.9413
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Journal article
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en
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1949-2553