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

Festuccia, Claudio, Gravina, Giovanni, Mancini, Andrea, Muzi, Paola, Cesare, Ernesto, Kirk, Ralph, Smith, Matthew, Hughes, Shaun, Gibson, Robert, Lian, Lu-Yun, Ricevuto, Enrico and Carnell, Andrew (2014) Trifluoroibuprofen Inhibits alpha-Methylacyl Coenzyme A Racemase (AMACR/P504S), Reduces Cancer Cell Proliferation and Inhibits in vivo Tumor Growth in Aggressive Prostate Cancer Models. Anti-Cancer Agents in Medicinal Chemistry, 14 (7). pp. 1031-1041. ISSN 18715206

Item Type: Article

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.

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More Information

Depositing User: Matt Smith

Identifiers

Item ID: 16346
Identification Number: https://doi.org/10.2174/1871520614666140327152607
ISSN: 18715206
URI: http://sure.sunderland.ac.uk/id/eprint/16346
Official URL: http://dx.doi.org/10.2174/187152061466614032715260...

Users with ORCIDS

ORCID for Matthew Smith: ORCID iD orcid.org/0000-0003-1903-7607

Catalogue record

Date Deposited: 09 Aug 2023 13:02
Last Modified: 09 Aug 2023 13:02

Contributors

Author: Matthew Smith ORCID iD
Author: Claudio Festuccia
Author: Giovanni Gravina
Author: Andrea Mancini
Author: Paola Muzi
Author: Ernesto Cesare
Author: Ralph Kirk
Author: Shaun Hughes
Author: Robert Gibson
Author: Lu-Yun Lian
Author: Enrico Ricevuto
Author: Andrew Carnell

University Divisions

Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

Subjects

Sciences > Chemistry

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