17-DMCHAG, a new geldanamycin derivative, inhibits prostate cancer cells through Hsp90 inhibition and survivin downregulation.

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the stability of many client proteins, including androgen receptor (AR) and survivin, making Hsp90 an attractive molecular therapeutic target for prostate cancer. Several Hsp90 inhibitors have shown antitumor activity in various preclinical models and in clinical trials. Geldanamycin is a well-known inhibitor of Hsp90, but its associated liver toxicity limited its clinical development. Here, we report a highly effective and low-hepatotoxic geldanamycin derivative that exhibits antitumor activity against human prostate cancer cells. Treatment of cells with 17-DMCHAG (17-(6-(3,4-dimethoxycinnamamido)hexylamino)-17-demethoxy-geldanamycin) dose-dependently suppressed the proliferation, reduced colony formation and induced apoptosis of human prostate cancer cell lines. 17-DMCHAG exhibits anti-invasive and anti-migratory activities in prostate cancer cells through down-regulating of transcription factors Zeb1, Snail1, Slug, and mesenchymal marker Vimentin, while up-regulating the epithelial marker of E-cadherin. Furthermore, 17-DMCHAG treatment damaged the Hsp90/AR and Hsp90/survivin complexes and induced the proteasome-dependent degradation of AR and survivin, then inhibited the activity of these two proteins. In vivo, we observed that 17-DMCHAG showed strong antitumor effects in LNCaP and DU-145 cell-xenografted nude mice. Thus, 17-DMCHAG is a potential treatment for prostate cancer.

• Authors: Jifeng Wang, Zhenyu Li, Zhiyuan Lin, Baobing Zhao, Yang Wang, Ruixian Peng, Meifang Wang, Chunhua Lu, Guowei Shi, Yuemao Shen
• Journal: Cancer letters (Cancer Lett) Vol. 362 Issue 1 Pg. 83-96 (Jun 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25813406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• 17-(6-(3,4-dimethoxycinnamamido)hexylamino)-17-demethoxy-geldanamycin
• Antibiotics, Antineoplastic
• BIRC5 protein, human
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Inhibitor of Apoptosis Proteins
• Lactams, Macrocyclic
• Survivin

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Benzoquinones (pharmacology)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Lactams, Macrocyclic (pharmacology)
• Male
• Mice
• Mice, Nude
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism)
• Random Allocation
• Survivin
• Xenograft Model Antitumor Assays