Clioquinol, a Therapeutic Agent for Alzheimer's Disease, Has Proteasome-Inhibitory, Androgen Receptor–Suppressing, Apoptosis-Inducing, and Antitumor Activities in Human Prostate Cancer Cells and Xenografts
| Autor: | Huanjie Yang, Q. Ping Dou, Shijie Sheng, G. Prem Veer Reddy, Di Chen, Qiuzhi Cindy Cui, Fazlul H. Sarkar, Raúl A. Barrea, Bing Yan |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Neoplasms Hormone-Dependent Mice Nude Apoptosis Mice Prostate cancer Cell Line Tumor Internal medicine LNCaP Androgen Receptor Antagonists medicine Animals Humans Protease Inhibitors Neovascularization Pathologic business.industry Clioquinol Prostatic Neoplasms Cancer medicine.disease Xenograft Model Antitumor Assays Androgen receptor Endocrinology Oncology Proteasome Dihydrotestosterone Cancer cell Cancer research business Proteasome Inhibitors Copper medicine.drug |
| Zdroj: | Cancer Research. 67:1636-1644 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-06-3546 |
| Popis: | Tumor growth and metastasis depend on angiogenesis that requires the cofactor copper. Consistently, high levels of copper have been found in many types of human cancers, including prostate, breast, colon, and lung. Recent studies suggest that copper could be used as a novel selective target for cancer therapies. Clioquinol is capable of forming stable complexes with copper and currently used in clinics for treatment of Alzheimer's disease. Most recently, it has been reported that clioquinol possesses antitumor effects. However, the underlying molecular mechanism is unclear. We report here that after binding to copper, clioquinol can inhibit the proteasomal chymotrypsin-like activity, repress androgen receptor (AR) protein expression, and induce apoptotic cell death in human prostate cancer LNCaP and C4-2B cells. In addition, clioquinol alone exhibits similar effects in prostate cancer cell lines with elevated copper at concentrations similar to those found in patients. Addition of dihydrotestosterone did not affect clioquinol-mediated proteasome inhibition in both prostate cancer cell lines. However, dihydrotestosterone partially inhibited clioquinol-induced AR suppression and apoptosis only in androgen-dependent LNCaP cells. Animal studies show that clioquinol treatment significantly inhibits the growth of human prostate tumor C4-2B xenografts (by 66%), associated with in vivo proteasome inhibition, AR protein repression, angiogenesis suppression, and apoptosis induction. Our study provides strong evidence that clioquinol is able to target tumor proteasome in vivo in a copper-dependent manner, resulting in formation of an active AR inhibitor and apoptosis inducer that is responsible for its observed antiprostate tumor effect. [Cancer Res 2007;67(4):1636–44] |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|