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Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2
Xu, Bing Wang, Shiyun Li, Rongwei Chen, Kai He, Lingli Deng, Manman Kannappan, Vinodh Zha, Jie Dong, Huijuan Wang, Weiguang
Xu, Bing
Wang, Shiyun
Li, Rongwei
Chen, Kai
He, Lingli
Deng, Manman
Kannappan, Vinodh
Zha, Jie
Dong, Huijuan
Wang, Weiguang
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2017-05-18
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Abstract
Acute myeloid leukemia (AML) is a heterogeneous malignancy. Despite the advances in past decades, the clinical outcomes of AML patients remain poor. Leukemia stem cells (LSCs) is the major cause of the recurrence of AML even after aggressive treatment making, promoting development of LSC-targeted agents is an urgent clinical need. Although the antitumor activity of disulfiram (DS), an approved anti-alcoholism drug, has been demonstrated in multiple types of tumors including hematological malignancies such as AML, it remains unknown whether this agent would also be able to target cancer stem cells like LSCs. Here, we report the in vitro and in vivo activity of DS in combination with copper (Cu) against CD34(+)/CD38(+) leukemia stem-like cells sorted from KG1α and Kasumi-1 AML cell lines, as well as primary CD34(+) AML samples. DS plus Cu (DS/Cu) displayed marked inhibition of proliferation, induction of apoptosis, and suppression of colony formation in cultured AML cells while sparing the normal counterparts. DS/Cu also significantly inhibited the growth of human CD34(+)/CD38(+) leukemic cell-derived xenografts in NOD/SCID mice. Mechanistically, DS/Cu-induced cytotoxicity was closely associated with activation of the stress-related ROS-JNK pathway as well as simultaneous inactivation of the pro-survival Nrf2 and nuclear factor-κB pathways. In summary, our findings indicate that DS/Cu selectively targets leukemia stem-like cells both in vitro and in vivo, thus suggesting a promising LSC-targeted activity of this repurposed agent for treatment of relapsed and refractory AML.
Citation
Xu B., Wang S., Li R., Chen K., He L., Deng M., Kannappan V., Zha J., Dong H., Wang W. (2017) 'Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2', Cell Death & Disease. 8 (5) p. e2797
doi: 10.1038/cddis.2017.176
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PubMed ID
28518151
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Journal article
Language
en
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© 2017 The Authors. Published by Nature Publishing Group. This is an open access article available under a Creative Commons licence.
The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1038/cddis.2017.176
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2041-4889