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.
From: Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, 4100 John R Road, Detroit, MI 48201, USA.
Cancer research
- Publish Date: Feb 2007
- ISSN: 0008-5472
- Volume: 67
- Issue: 4
- Pages: 1636-44
- Medium: Print
- Language: English
- Citation (JAMA): Chen Di, Cui Qiuzhi Cindy, Yang Huanjie, et al. 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.. Cancer Res. Feb 2007;67:1636-44
Abstract
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.
Mesh Headings (Keywords): Animals, Apoptosis, Cell Line, Tumor, Clioquinol, Copper, Humans, Male, Mice, Mice, Nude, Neoplasms, Hormone-Dependent, Neovascularization, Pathologic, Prostatic Neoplasms, Protease Inhibitors, Proteasome Endopeptidase Complex, Receptors, Androgen, Xenograft Model Antitumor Assays
Check for Full Text / PubMed Unique Identifier (PMID): 17308104
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on January 1st, 1970 and may not reflect the most current and accurate data available from NLM.