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.

2.50
Hdl Handle:
http://hdl.handle.net/2436/620498
Title:
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.
Authors:
Xu, Bing; Wang, Shiyun; Li, Rongwei; Chen, Kai; He, Lingli; Deng, Manman; Kannappan, Vinodh; Zha, Jie; Dong, Huijuan; Wang, Weiguang
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:
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. 2017, 8 (5):e2797 Cell Death Dis
Publisher:
Nature Publishing Group
Journal:
Cell death & disease
Issue Date:
18-May-2017
URI:
http://hdl.handle.net/2436/620498
DOI:
10.1038/cddis.2017.176
PubMed ID:
28518151
Type:
Article
Language:
en
ISSN:
2041-4889
Appears in Collections:
FSE

Full metadata record

DC FieldValue Language
dc.contributor.authorXu, Bingen
dc.contributor.authorWang, Shiyunen
dc.contributor.authorLi, Rongweien
dc.contributor.authorChen, Kaien
dc.contributor.authorHe, Linglien
dc.contributor.authorDeng, Manmanen
dc.contributor.authorKannappan, Vinodhen
dc.contributor.authorZha, Jieen
dc.contributor.authorDong, Huijuanen
dc.contributor.authorWang, Weiguangen
dc.date.accessioned2017-06-07T14:31:23Z-
dc.date.available2017-06-07T14:31:23Z-
dc.date.issued2017-05-18-
dc.identifier.citationDisulfiram/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. 2017, 8 (5):e2797 Cell Death Disen
dc.identifier.issn2041-4889en
dc.identifier.pmid28518151-
dc.identifier.doi10.1038/cddis.2017.176-
dc.identifier.urihttp://hdl.handle.net/2436/620498-
dc.description.abstractAcute 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.en
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.rightsArchived with thanks to Cell death & diseaseen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleDisulfiram/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.en
dc.typeArticleen
dc.identifier.journalCell death & diseaseen
dc.date.accepted2017-03-21-
rioxxterms.funderinternalen
rioxxterms.identifier.projectUOW070617WWen
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-06-07en

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