Celastrol, a novel HSP90 inhibitor, depletes Bcr-Abl and induces apoptosis in imatinib-resistant chronic myelogenous leukemia cells harboring T315I mutation.
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.
Lu
Zhongzheng
Z
Department of Pathophysiology, Sun Yat-sen University, Guangzhou, People's Republic of China.
Jin
Yanli
Y
Qiu
Lin
L
Lai
Yingrong
Y
Pan
Jingxuan
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D053978:Pentacyclic Triterpenes; D010879:Piperazines; D011743:Pyrimidines; D014315:Triterpenes; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C050414:celastrol