Journal of Bioenergetics and Biomembranes

, Volume 47, Issue 5, pp 373–381 | Cite as

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

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


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.


Hepatocellular carcinoma 17-Demethoxy-reblastatin Apoptosis Myeloid cell leukemia-1 



This work was supported by the National Natural Science Foundation of China (81372899, 81302671), the Natural Science Foundation of Anhui Province (1408085QH162), and the Natural Science Foundation of Bengbu Medical College (BYKY1408ZD).

Conflicts of interest

The authors declare that they have no conflict of interests regarding the publication of this paper.

Supplementary material

10863_2015_9620_MOESM1_ESM.tif (730 kb)
Fig. S1 Proliferation of HCC cells inhibited by GA. HepG2 and SMMC7721 cells were treated with different concentrations of GA (2.5, 5, 10, 20, 40 μM) or DMSO for 48 h. Cell viability was measured by MTT assay. **p < 0.01 versus no GA treatment (TIFF 730 kb)
10863_2015_9620_MOESM2_ESM.tif (991 kb)
Fig. S2 Effects of GA and 17-DR on the viability of normal liver cells. a L-02 cells were treated with different concentrations of GA (5, 10, 20, 40, 80 μM) or DMSO for 48 h. b L-02 cells were treated with different concentrations of 17-DR (25, 50, 100, 200, 400 μM) or DMSO for 48 h. Cell viability was measured by MTT assay. *p < 0.05 and **p < 0.01 versus no GA or 17-DR treatment. (TIFF 991 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Faculty of PharmacyBengbu Medical CollegeBengbuPeople’s Republic of China
  2. 2.Priority Research Center for Cancer ResearchUniversity of NewcastleNewcastleAustralia

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