17-Demethoxy-reblastatin, an Hsp90 inhibitor, induces mitochondria-mediated apoptosis through downregulation of Mcl-1 in human hepatocellular carcinoma cells.
Heat shock protein 90 (Hsp90) is an attractive therapeutic target. Geldanamycin (GA), the first identified Hsp90 inhibitor, exhibited potent antitumor activity, but possessed significant hepatotoxicity. To overcome the hepatotoxicity derived from the quinone structure of GA, a non-quinone GA derivative 17-demethoxy-reblastatin (17-DR) was obtained from a genetically modified strain of Streptomyces hygroscopicus. In the present study, we examined the anticancer effects of 17-DR on human hepatocellular carcinoma (HCC) cell lines HepG2 and SMMC7721, and its underlying mechanisms. The results indicated that 17-DR could concentration-dependently inhibit the proliferation, and decrease the colony formation in HCC cells. It also induced significant apoptosis in HCC cells, which was mediated by mitochondria via a caspase-dependent pathway. The mechanisms involved in 17-DR-induced apoptosis included the downregulation of myeloid cell leukemia-1 (Mcl-1), and upregulation of Bcl-2 antagonist killer 1 (Bak). And the upregulated Bak expression resulted from downregulation of Mcl-1 played an essential role in this process. Taken together, these results indicated that 17-DR possessed potent anticancer effects on HCC cells by inhibiting cell proliferation and inducing apoptosis.
Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People's Republic of China.
Surong
S
Zhao
Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People's Republic of China.
Hongmei
H
Li
Priority Research Center for Cancer Research, University of Newcastle, Newcastle, Australia.
Chenchen
C
Jiang
Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People's Republic of China.
Tao
T
Ma
Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People's Republic of China.
Chengzhu
C
Wu
Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People's Republic of China. huoqiang3@sohu.com.
Qiang
Q
Huo
Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People's Republic of China. liuhao6886@foxmail.com.
Hao
H
Liu
D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis*
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein
17-Demethoxy-reblastatin; Apoptosis; Hepatocellular carcinoma; Myeloid cell leukemia-1