Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): therapeutic indication for prostate cancer

Abstract

Clioquinol (5-chloro-7-iodo-8-quinolinol) is a copper ionophore that was used primarily during the 1950-1970s as an oral antimicrobial agent. It has been established that clioquinol displays toxicity towards malignant cells, inducing caspase-dependent apoptosis. In the present study we therefore investigated the effect of clioquinol on the XIAP [X-linked IAP (inhibitor of apoptosis protein)], as one of its primary functions is to hinder caspase activity and suppress apoptotic cell death. Clioquinol treatment caused cytoplasmic XIAP to rapidly relocate to the nucleus in multiple human transformed (hyperplasic and carcinoma) prostate lines. Clioquinol also caused the cytoplasmic clearance of other IAP family members (cIAP1 and cIAP2). Copper, and no other relevant bivalent metal (e.g. zinc or iron), was exclusively required for clioquinol to elicit an effect on XIAP. We further demonstrated that clioquinol selectively targets and rapidly destroys transformed prostate lines without harming primary prostate epithelial cells. The toxicity of clioquinol was copper-dependent, positively correlated with the level of extracellular copper and could be abrogated by using the copper chelator TTM (tetrathiomolybdate). Clioquinol forced the profound accumulation of intracellular copper with ensuing toxicity influenced by key regulators of cellular copper homoeostasis. Taken together, our results provide significant insight into clioquinol toxicity and reveal an exciting therapeutic approach for the treatment of prostate cancer.