title: BJ-B11, a novel Hsp90 inhibitor, induces apoptosis in human chronic myeloid leukemia K562 cells through the mitochondria-dependent pathway.
abstract: In the past few years heat shock protein 90 (Hsp90) inhibitors have been reported to possess significant antitumor activity. We investigated, for the first time, the antitumor activity of a novel Hsp90 inhibitor 2-(4-acetyloxycyclohexylamino)-4-(3, 6, 6-trimethyl-4-oxo-4, 5, 6, 7-tetrahydro-1H-indazol-1-yl)-benzamide (BJ-B11) and the molecular mechanism underlying the apoptosis it induces in human chronic myeloid leukemia K562 cells. The results revealed that BJ-B11 triggered growth inhibition in K562 cells and other malignant cell lines in vitro with only minor toxicity in a normal human cell line. BJ-B11 inhibited the proliferation of K562 cells in a concentration- and time-dependent manner, with IC(50) values of 1.1 ± 0.2 μM and 0.4 ± 0.1 μM after 48 and 72 h incubations respectively. This most likely results from cell cycle arrest at the G(0)/G(1) phase and the induction of apoptosis. In addition, BJ-B11 degraded the Hsp90 client proteins Bcr-Abl and Akt, induced activation of caspase-9 and caspase-3, and subsequent cleavage of PARP. The caspase signals may originate from mitochondrial dysfunction, which is supported by the finding of cytochrome c release. In addition, inactivation of the Akt signaling pathway may be involved in the process of BJ-B11-induced apoptosis. Taken together, our data provide a putative molecular mechanism for the anticancer effect of BJ-B11 on K562 cells, and suggest a potential application for BJ-B11 in chronic myeloid leukemia therapy.
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, PR China.
authors.forename: Huai-Qiang
authors.initials: HQ
authors.lastname: Ju
authors.forename: Shao-Xiang
authors.initials: SX
authors.lastname: Wang
authors.forename: Yang-Fei
authors.initials: YF
authors.lastname: Xiang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.forename: Jin-Yun
authors.initials: JY
authors.lastname: Liu
authors.forename: Zhen-Ping
authors.initials: ZP
authors.lastname: Chen
authors.forename: Fan-Li
authors.initials: FL
authors.lastname: Zeng
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.forename: Zong-Hua
authors.initials: ZH
authors.lastname: Liu
authors.forename: Guo-Wen
authors.initials: GW
authors.lastname: Xing
authors.forename: Sha-Yan
authors.initials: SY
authors.lastname: Wang
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C559135:2-(4-acetyloxycyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007191:Indazoles; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases