Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption
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Haijun Zhao1,5,*, Pengcheng Shi1,*, Manman Deng2,*, Zhiwu Jiang3, Yin Li1, Vinodh Kannappan4, Weiguang Wang4, Peng Li3, Bing Xu1,2
1Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China
2Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, P. R. China
3Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P. R. China
4Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK
5Department of Hematology, Anqing Municipal Hospital of Anhui Medical University, Anqing, P. R. China
*These authors have contributed equally to this work
Bing Xu, email: [email protected]
Peng Li, email: [email protected]
Weiguang Wang, email: [email protected]
Keywords: triptolide, chemotherapy, drug resistance, DNA damage, acute lymphoblastic leukemia
Received: June 30, 2016 Accepted: October 19, 2016 Published: November 19, 2016
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.
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