Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption

2.50
Hdl Handle:
http://hdl.handle.net/2436/620386
Title:
Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption
Authors:
Zhao, Haijun; Shi, Pengcheng; Deng, Manman; Jiang, Zhiwu; Li, Yin; Kannappan, Vinodh; Wang, Weiguang; Li, Peng; Xu, Bing
Abstract:
Chemoresistance represents a major challenge for treatment of acute lymphoblastic leukemia (ALL). Thus, new drugs to overcome chemoresistance in ALL are urgently needed. To this end, we established a cytarabine (araC)-resistant ALL cell line (NALM-6/R), which interestingly displayed cross-resistance towards doxorubicin (ADM). Here we report that low dose of triptolide (TPL), a natural product used for treating inflammatory diseases such as arthritis, could reverse araC and ADM resistance and in NALM-6/R cells as well as primary cells from patients with relapsed or refractory (R/R) ALL, reflected by inhibition of cell proliferation and induction of apoptosis in vitro, and repression of tumor growth in vivo in a mouse xenograft model. Mechanistically, these events were associated with impaired mitochondrial membrane potential and increased reactive oxygen species (ROS) production. Co-treatment with TPL and araC or ADM upregulated pro-apoptotic caspase-9 protein, inhibited checkpoint kinase 1 (Chk1) and 2 (Chk2) phosphorylation, and induced γH2A.X (a DNA damage marker). Notably, the combination regimen of TPL and conventional chemotherapeutics also rapidly diminished tumor burden in a patient with R/R ALL. Together, these findings provide preclinical evidence for repurposing use of TPL in combination with chemotherapeutic agents to treat R/R ALL as an alternative salvage regimen.
Citation:
Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption 2016 Oncotarget
Publisher:
Elsevier
Journal:
Oncotarget
Issue Date:
19-Dec-2016
URI:
http://hdl.handle.net/2436/620386
DOI:
10.18632/oncotarget.13454
Additional Links:
http://www.oncotarget.com/abstract/13454
Type:
Article
Language:
en
ISSN:
1949-2553
Appears in Collections:
FSE

Full metadata record

DC FieldValue Language
dc.contributor.authorZhao, Haijunen
dc.contributor.authorShi, Pengchengen
dc.contributor.authorDeng, Manmanen
dc.contributor.authorJiang, Zhiwuen
dc.contributor.authorLi, Yinen
dc.contributor.authorKannappan, Vinodhen
dc.contributor.authorWang, Weiguangen
dc.contributor.authorLi, Pengen
dc.contributor.authorXu, Bingen
dc.date.accessioned2017-02-21T15:38:13Z-
dc.date.available2017-02-21T15:38:13Z-
dc.date.issued2016-12-19-
dc.identifier.citationLow dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption 2016 Oncotargeten
dc.identifier.issn1949-2553en
dc.identifier.doi10.18632/oncotarget.13454-
dc.identifier.urihttp://hdl.handle.net/2436/620386-
dc.description.abstractChemoresistance represents a major challenge for treatment of acute lymphoblastic leukemia (ALL). Thus, new drugs to overcome chemoresistance in ALL are urgently needed. To this end, we established a cytarabine (araC)-resistant ALL cell line (NALM-6/R), which interestingly displayed cross-resistance towards doxorubicin (ADM). Here we report that low dose of triptolide (TPL), a natural product used for treating inflammatory diseases such as arthritis, could reverse araC and ADM resistance and in NALM-6/R cells as well as primary cells from patients with relapsed or refractory (R/R) ALL, reflected by inhibition of cell proliferation and induction of apoptosis in vitro, and repression of tumor growth in vivo in a mouse xenograft model. Mechanistically, these events were associated with impaired mitochondrial membrane potential and increased reactive oxygen species (ROS) production. Co-treatment with TPL and araC or ADM upregulated pro-apoptotic caspase-9 protein, inhibited checkpoint kinase 1 (Chk1) and 2 (Chk2) phosphorylation, and induced γH2A.X (a DNA damage marker). Notably, the combination regimen of TPL and conventional chemotherapeutics also rapidly diminished tumor burden in a patient with R/R ALL. Together, these findings provide preclinical evidence for repurposing use of TPL in combination with chemotherapeutic agents to treat R/R ALL as an alternative salvage regimen.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.oncotarget.com/abstract/13454en
dc.rightsArchived with thanks to Oncotargeten
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjecttriptolideen
dc.subjectchemotherapyen
dc.subjectdrug resistanceen
dc.subjectDNA damageen
dc.subjectacute lymphoblastic leukemiaen
dc.titleLow dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruptionen
dc.typeArticleen
dc.identifier.journalOncotargeten
dc.date.accepted2016-10-
rioxxterms.funderNational Natural Science Foundation of China (No. 81570156 and No. 81400104) and the Guangdong Provincial Basic Research Program, P. R. China (No. 2015B020227003).en
rioxxterms.identifier.projectNo. 81570156 and No. 81400104) (No. 2015B020227003)en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttps://creativecommons.org/CC BY-NC-ND 4.0en
rioxxterms.licenseref.startdate2017-02-21en
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