The selective Hsp90 inhibitor BJ-B11 exhibits potent antitumor activity             via induction of cell cycle arrest, apoptosis and autophagy in Eca-109 human esophageal             squamous carcinoma cells.
BJ-B11 is a selective heat shock protein 90 (Hsp90) inhibitor that has been reported to possess significant antitumor activity in multiple types of cancer cells; however, the mechanism of action needs to be further clarified. We investigated, for the first time, the antitumor activity and the molecular mechanism underlying growth inhibition in Eca-109 cells. The results revealed that BJ-B11 inhibited the proliferation of Eca-109 cells in a time- and concentration-dependent manner, with 50% inhibitory concentration (IC(50)) values of 0.31±0.01 µM after 48-h incubation. BJ-B11 induced concentration-dependent G2/M cell cycle arrest and apoptosis. The cleavage of caspase 3 and PARP signals detected might originate from mitochondrial dysfunction, which was supported by the results of reactive oxygen species (ROS) production, cytochrome c release and the mitochondrial membrane potential (MMP) reduction. The general caspase inhibitor Z-VAD-fmk did not completely abolish BJ-B11-induced cell death. Furthermore, inhibition of the Akt/mTOR/p70S6K signaling pathway might be involved in the process of BJ-B11-induced autophagy, which was characterized by the production of autophagic vacuoles and upregulation of LC3-II protein in a time- and concentration-dependent manner. Meanwhile, the general autophagy inhibitor 3-MA decreased the apoptotic ratio. Furthermore, BJ-B11 induced the polymerization of cytoskeleton β-tubulin and F-actin. Taken together, our results suggest that the growth inhibition of Eca-109 cells induced by BJ-B11 may result from the induction of G2/M cell cycle arrest, apoptosis and autophagy.
Institute of Biomedicine, Jinan University, Guangzhou 510632, PR China.
Kai-Sheng
KS
Liu
Yi
Y
Zhang
Wei-Chao
WC
Ding
Shao-Xiang
SX
Wang
Yang-Fei
YF
Xiang
Pan
P
Yang
Zhen-Ping
ZP
Chen
Kai
K
Zheng
Zhong
Z
Liu
Min
M
Xia
Yi-Fei
YF
Wang
D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014404:Tubulin / Q000378:metabolism
C559135:2-(4-acetyloxycyclohexylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)-benzamide; D000199:Actins; D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007191:Indazoles; D014404:Tubulin; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020169:Caspases