Trifluoroibuprofen inhibits α-Methylacyl Coenzyme A Racemase (AMACR/P504S), Reduces Cancer Cell Proliferation and Inhibits in Vivo Tumor Growth in Aggressive Prostate Cancer Models.

Abstract: Background: α-Methylacyl-CoA racemase (AMACR) participates in the oxidation of branched chain fatty acids and is highly expressed in prostate cancer (PCa). The aims of this study were to verify if the AMACR inhibitor trifluoroibuprofen (TFIP) had anticancer effects and to determine the best route for in vivo administration. Materials and Methods: In vitro effects of TFIP were verified by using three non-tumour prostate epithelial cell lines, a series of eight PCa cell lines and six cell derivatives. In vivo experiments were performed using PC3 and 22rv1 xenografts grown in nude mice with TFIP administered intraperitoneally or by oral gavage. Results: AMACR was expressed in PCa cell lines but was absent in normal and BPH cells. Although androgen-independent (AI) cell lines originating from androgen-dependent (AD) LnCaP cells displayed increased AMACR expression, the levels of this enzyme were higher in AI with respect to AD cell lines. TFIP induced: (1) down-modulation of AMACR expression; (2) suppression of the survival Akt/mTOR signalling pathway and (3) down-modulation of cyclin D1 and survivin with G2/M arrest and apoptosis. TFIP exhibited antitumour effects independently of the administration method. Nevertheless, oral administration was associated with acute toxicity at doses >75 mg/Kg/day. A dose of 75 mg/Kg administered biweekly reduced the toxicity whereas limited toxic effects were observed at 50 mg/Kg/day. Intraperitoneal administration of 75-100 mg/Kg/day was not toxic. Conclusions: AMACR is a good pharmacological target for treatment of PCa and TFIP is a suitable anticancer compound with parenteral administration being the preferred route. Keywords: AMACR and androgen independence, prostate cancer. INTRODUCTION Prostate cancer (PC) is the second most common cause of cancer death among men in the industrialized countries. Androgen deprivation therapies are indicated for advanced PCa. However, despite a rapid initial response in the majority of cases, PCa will ultimately progress to a hormone-refractory stage and metastatic disease [1]. Alpha-Methylacyl-CoA racemase (AMACR) is overexpressed in high-grade prostatic intraepithelial neoplasia and in the majority (60-100%) of prostate cancers compared with the lower expression observed in normal and benign hyperplastic lesions [2-10]. AMACR is involved in the β-oxidation of branched-chain fatty acids, and recent data show that the entire peroxisomal pathway for branched-chain substrates is up-regulated in prostate cancer [11, 12]. Interestingly, there is an established correlation between PCa risk and the consumption of dairy and beef products, which also contain marked quantities of phytol-derived branched fatty acids [5, 13, 14]. In this context, it has also been reported that sex steroids influence lipogenesis through the induction of fatty acid synthase (FASN). These findings indicate a potential role for AMACR and the possible influence of sex steroids in both the early development and subsequent progression of PCa.