title: Divalproex sodium enhances the anti-leukemic effects of imatinib in chronic myeloid leukemia cells partly through SIRT1.
abstract: Imatinib (IM) represents a breakthrough in the treatment of chronic myeloid leukemia (CML) by inhibiting the activity of Bcr-Abl tyrosine kinase. However, many patients exhibit resistance to IM in the clinic. Recent studies have indicated that sirtuin 1 (SIRT1), a class III histone deacetylase (HDAC), plays an important role in leukemogenesis. In addition, some HDAC inhibitors are being tested to determine their anti-cancer activities in clinical trials. Divalproex sodium (DVPX), a first-line treatment for epilepsy, is also a HDAC inhibitor. However, it is unclear whether the anti-leukemic effects of IM in combination with DVPX on CML cells are related to SIRT1. The aim of this study was to investigate the effects of IM in combination with DVPX on cell viability, apoptosis, and cell cycle arrest in CML cells and to explore the underlying mechanisms. It was found that DVPX enhanced IM-induced cell growth inhibition, apoptosis and cell cycle arrest in K562-S and K562-G cells. Surprisingly, the level of p-Bcr-Abl was similar in K562-S and K562-G cells. Moreover, IM combined with DVPX had no effects on the phosphorylation of Bcr-Abl and its downstream target STAT5. Further study revealed that SIRT1 expression was higher in K562-G cells compared with K562-S cells. DVPX enhanced the inhibitory effect of IM on SIRT1 expression in K562-S and K562-G cells. Furthermore, knockdown of SIRT1 promoted apoptosis of K562-G cells treated with IM and DVPX. These results indicate that DVPX may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating SIRT1 expression.
authors.affiliation: Research Institute of Atherosclerotic Disease, Xi'an Jiaotong University Cardiovascular Research Center, Xi'an, Shaanxi 710061, China; Laboratory Animal Center, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Eighth Hospital of Xi'an City, Xi'an, Shaanxi 710061, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Yanxiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Yanhao
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pharmacology, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: zjy2011@mail.xjtu.edu.cn.
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: linrong63@aliyun.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D014635:Valproic Acid; D000068877:Imatinib Mesylate; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Bcr-Abl; Chronic myeloid leukemia; Divalproex sodium; Imatinib; SIRT1