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Synergistic killing effect of imatinib and simvastatin on imatinib-resistant chronic myelogenous leukemia cells

Oh, Boraa,b; Kim, Tae Y.a,b; Min, Hyun J.b; Kim, Miyoungc; Kang, Myung S.e; Huh, Ji Y.f; Kim, Youngsood; Lee, Dong S.b,c

doi: 10.1097/CAD.0b013e32835a0fbd
Preclinical Reports

The antiproliferative effect of simvastatin on tumor cells has been speculated to be by intracellular signal inhibition through 3-hydroxy-3-methylglutaryl acetyl coenzyme A reductase. We examined the killing effect of simvastatin on imatinib-sensitive and resistant chronic myelogenous leukemia (CML) cells (three kinds of CML cell lines representative of each hematopoietic lineage: K562, KCL22, and LAMA84) and T315I and E255K site-directed mutant cells (Ba/F3). The in-vivo effect of simvastatin was determined in K562-xenografted nude mice. Cotreatment with imatinib and simvastatin in imatinib-resistant CML cells showed a synergistic killing effect in K562-R, KCL22-R, LAMA84-R, and E255K mutant cells, but only an additive effect in the T315I mutant cell, although a single treatment of simvastatin strongly inhibited T315I mutant cells. Mechanisms of killing were an induction of apoptosis and cell cycle arrest, through inhibition of tyrosine phosphorylation, and activated STAT5 and STAT3. Simvastatin suppressed the growth of K562-transplanted tumors, and cotreatment with imatinib was more effective in reducing tumor size. Simvastatin also killed primary CD34+ cells from patients with CML more efficiently, compared with CD34 CML cells. Our study shows a synergic effect of imatinib and simvastatin both in imatinib-sensitive and imatinib-resistant cells, but more effective synergism in resistant cells. On the basis of these findings, we suggest that a combination of simvastatin and imatinib may be a potential candidate for the treatment of imatinib-resistant CML.

aDepartment of Molecular and Clinical Oncology

bCancer Research Institute

cDepartment of Laboratory Medicine

dDepartment of Molecular Genomic Medicine, Seoul National University College of Medicine

eDepartment of Laboratory Medicine, CHA Gangnam Medical Center, Seoul

fDepartment of Laboratory Medicine, CHA Bundang Medical Center, Sungnam, Republic of Korea

All supplementary digital content is available directly from the corresponding author.

Correspondence to Dong S. Lee, MD, Department of Laboratory Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, 110 744 Seoul, Republic of Korea Tel: +82 2 2072 3986; fax: +82 2 766 0827; e-mail: soonlee@snu.ac.kr

Received April 18, 2012

Accepted September 4, 2012

© 2013 Lippincott Williams & Wilkins, Inc.