title: Curcumin potentiates the anti-leukemia effects of imatinib by downregulation of the AKT/mTOR pathway and BCR/ABL gene expression in Ph+ acute lymphoblastic leukemia.
abstract: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL and SRC family tyrosine kinases. They interact with each other and subsequently activate downstream growth-signaling pathways, including Raf/MEK/ERK, Akt/mTOR, and STAT5 pathways. Although imatinib is the standard treatment for Ph+ leukemia, response rate of Ph+ ALL to imatinib is low, relapse is frequent and quick. Studies have documented the potential anti-tumor activities of curcumin. However, whether curcumin can be used in the therapy for Ph+ ALL remains obscure. Here, we reported that curcumin induced apoptosis by inhibition of AKT/mTOR and ABL/STAT5 signaling, down-regulation of BCR/ABL expression, and induction of the BCL2/BAX imbalance. Curcumin exerted synergetic anti-leukemia effects with imatinib by inhibition of the imatinib-mediated overactivation of AKT/mTOR signaling and down-regulation of BCR/ABL gene expression. In primary samples from Ph+ ALL patients, curcumin inhibited cellular proliferation and down-regulated constitutive activation of growth-signaling pathways not only in newly diagnosed patients but also in imatinib-resistant patients. In Ph+ ALL mouse models, curcumin exhibited synergetic anti-leukemia effects with imatinib. These results demonstrated that curcumin might be a promising agent for Ph+ ALL patients.
authors.affiliation: Department of Hematology, West China Hospital of Sichuan University, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Human Sciences, Texas A&M University-Kingsville, Kingsville, TX 78363, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Hematology, West China Hospital of Sichuan University, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Shan
authors.affiliation: Department of Hematology, West China Hospital of Sichuan University, China.
authors.forename: Guangcui
authors.initials: G
authors.lastname: He
authors.affiliation: Department of Hematology, West China Hospital of Sichuan University, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Hematology, West China Hospital of Sichuan University, China. Electronic address: gongyuping94@aliyun.com.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068877:Imatinib Mesylate; C546842:MTOR protein, human; D016044:Fusion Proteins, bcr-abl; D058570:TOR Serine-Threonine Kinases; D003474:Curcumin
keywords: AKT/mTOR; Anti-leukemia effect; Curcumin; Imatinib; Philadelphia chromosome-positive acute lymphoblastic leukemia