Celastrol, a novel HSP90 inhibitor, depletes Bcr–Abl and induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation

Lu, Zhongzheng; Jin, Yanli; Qiu, Lin; Lai, Yingrong; Pan, Jingxuan

doi:10.1016/j.canlet.2009.09.006

« Previous Next »Cancer Letters
Volume 290, Issue 2 , Pages 182-191, 28 April 2010

Celastrol, a novel HSP90 inhibitor, depletes Bcr–Abl and induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation

Zhongzheng Lu
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510089, People’s Republic of China
Yanli Jin
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510089, People’s Republic of China
Lin Qiu
- Harbin Institute of Hematology and Oncology, Harbin, People’s Republic of China
Yingrong Lai
- Department of Pathology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510089, People’s Republic of China
Jingxuan Pan
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou 510089, People’s Republic of China
- Corresponding author. Tel./fax: +86 20 8733 2788.

Received 10 July 2009; received in revised form 5 September 2009; accepted 7 September 2009. published online 12 October 2009.

Abstract

T315I Bcr–Abl in chronic myelogenous leukemia (CML) is the most notorious point mutations to elicit acquired resistance to imatinib. In the present study, we investigated the effect of celastrol on CML cells bearing wild-type Bcr–Abl or T315I-mutant. The results revealed that celastrol potently downregulated the protein levels of Bcr–Abl, and inhibited the growth in CML cells in vitro and in nude mouse xenografts regardless of Bcr–Abl mutation status. Celastrol induced mitochondrial-dependent apoptosis. In conclusion, celastrol exhibits potent activity against CML cells bearing wild-type Bcr–Abl or -the T315I-mutant.

Keywords: CML, Bcr–Abl, T315I mutation, Imatinib, Celastrol, Apoptosis