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: Yong Guo, Yi Li, Qingqing Shan, Guangcui He, Juan Lin, Yuping Gong
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 65 Pg. 1-11 (Aug 2015) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 25979368 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Ltd.

Chemical References

• Imatinib Mesylate
• MTOR protein, human
• Fusion Proteins, bcr-abl
• TOR Serine-Threonine Kinases
• Curcumin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Curcumin (administration & dosage, pharmacology)
• Down-Regulation (drug effects)
• Drug Synergism
• Female
• Fusion Proteins, bcr-abl (biosynthesis, genetics)
• Gene Expression (drug effects)
• Humans
• Imatinib Mesylate (administration & dosage, pharmacology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Xenograft Model Antitumor Assays