Effective elimination of adult B-lineage acute lymphoblastic leukemia by disulfiram/copper complex in vitro and in vivo in patient-derived xenograft models
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Manman Deng1,3,*, Zhiwu Jiang2,*, Yin Li3,*, Yong Zhou1, Jie Li3, Xiangmeng Wang3, Yao Yao4, Weiguang Wang5, Peng Li2, Bing Xu1
1Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, China
2Key Laboratory of Regenerative Biology, Southern China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
3Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
4Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
5Research Institute for Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
*These authors have contributed equally to this work
Bing Xu, e-mail: email@example.com
Peng Li, e-mail: firstname.lastname@example.org
Weiguang Wang, e-mail: email@example.com
Keywords: disulfiram, copper, adult B-cell acute lymphoblastic leukemia, p16 deletion, patient-derived xenograft
Received: January 6, 2016 Accepted: April 28, 2016 Published: May 17, 2016
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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