Trifluoroibuprofen Inhibits α-Methylacyl Coenzyme A Racemase (AMACR/P504S), Reduces Cancer Cell Proliferation and Inhibits in vivo Tumor Growth in Aggressive Prostate Cancer Models
Giovanni Luca Gravina,
Ernesto Di Cesare,
Andrew J. Carnell.
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, trifluoroibuprofen, prostate cancer.
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