17-Demethoxy-reblastatin, an Hsp90 inhibitor, induces mitochondria-mediated apoptosis through downregulation of Mcl-1 in human hepatocellular carcinoma cells View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2015-10

AUTHORS

Surong Zhao, Hongmei Li, Chenchen Jiang, Tao Ma, Chengzhu Wu, Qiang Huo, Hao Liu

ABSTRACT

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. More... »

PAGES

373-381

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10863-015-9620-1

DOI

http://dx.doi.org/10.1007/s10863-015-9620-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1023578366

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26323360


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