Striking Growth-inhibitory Effects of Minocycline on Human Prostate Cancer Cell Lines

Abstract

To elucidate a hypothetical link between retinoic acid (RA) signaling and minocycline for targeting prostate carcinoma (PCA). RA signaling has been implicated in growth-inhibition of malignant PCA, and intracellular RA homeostasis has been investigated as a potential therapeutic target. Minocycline is a tetracycline antibiotic with pleiotropic actions in many tissues and reaches comparably high levels in human prostate tissue. Interestingly, minocycline exhibits the rare side effect of a pseudotumor cerebri, which is otherwise known to occur from vitamin A intoxication or in retinoid therapy. Therefore, we hypothesized minocycline to putatively interact with intracellular RA homeostasis in PCA. Using LN-CAP, DU-145, and PC-3 cell lines, effects of minocycline on microsomal RA metabolism and on cell growth were assessed in vitro. Minocycline was identified to potently inhibit cell growth, at concentrations within the range of tissue levels readily reached under standard therapeutic conditions. In vitro inhibition experiments revealed inhibition of RA breakdown, yet only at comparably high concentrations of minocycline. Using all trans-RA, RA metabolism inhibitor liarozole, and different retinoid receptor antagonists, the putative RA-dependent effects of minocycline were further evaluated and confirmed to be independent of RA signaling. Our findings add to the growing body of evidence for the many pleiotropic actions of minocycline. In view of the striking effects of minocycline on cell growth in PCA cell lines in vitro and its relatively safe side effect profile, the use of minocycline for targeting PCA should be timely clinically evaluated.