Trifluoroibuprofen inhibits α-methylacyl coenzyme A racemase (AMACR/P504S), reduces cancer cell proliferation and inhibits in vivo tumor growth in aggressive prostate cancer models.
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.


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.
Claudio
C
Festuccia
Giovanni Luca
GL
Gravina
Andrea
A
Mancini
Paola
P
Muzi
Ernesto Di
ED
Cesare
Ralph
R
Kirk
Matthew
M
Smith
Shaun
S
Hughes
Robert
R
Gibson
Lu-Yun
LY
Lian
Enrico
E
Ricevuto
Dipartimento di Medicina Sperimentale, Radiobiology Laboratory, Universita dell'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italia. claudio.festuccia@univaq.it.
Andrew J
AJ
Carnell
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D064593:Heterografts; D006801:Humans; D007052:Ibuprofen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology / Q000473:pathology; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C000598189:3,3,3-trifluoro-2-(4-isobutylphenyl)propanoic acid; D000970:Antineoplastic Agents; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase; D007052:Ibuprofen