title: Low dose triptolide reverses chemoresistance in adult acute lymphoblastic leukemia cells via reactive oxygen species generation and DNA damage response disruption.
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.
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China.|Department of Hematology, Anqing Municipal Hospital of Anhui Medical University, Anqing, P. R. China.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Shi
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, P. R. China.
authors.forename: Manman
authors.initials: M
authors.lastname: Deng
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P. R. China.
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Vinodh
authors.initials: V
authors.lastname: Kannappan
authors.affiliation: Research Institute in Healthcare Science, Faculty of Science and Engineering, University of Wolverhampton, Wolverhampton, UK.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P. R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, P. R. China.|Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen, P. R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology*; D004249:DNA Damage; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D010616:Phenanthrenes / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; C468783:H2AX protein, human; D006657:Histones; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; D003561:Cytarabine; C001899:triptolide; D004317:Doxorubicin; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C506433:CASP9 protein, human; D053453:Caspase 9
keywords: DNA damage; acute lymphoblastic leukemia; chemotherapy; drug resistance; triptolide