PACE4 inhibitors and their peptidomimetic analogs block prostate cancer tumor progression through quiescence induction, increased apoptosis and impaired neovascularisation

Abstract

// Christine Levesque 1, 2 , Frédéric Couture 1, 2 , Anna Kwiatkowska 1, 2 , Roxane Desjardins 1, 2 , Brigitte Guérin 2, 3 , Witold A. Neugebauer 2 , Robert Day 1, 2 1 Department of Surgery/Urology Division and Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada 2 Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada 3 Department of Nuclear Medicine and Radiobiology and Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada Correspondence to: Robert Day, e-mail: Robert.day@usherbrooke.ca Keywords: PACE4, Multi-Leu peptide, Prostate Cancer, Proprotein convertases, Peptide inhibitors Received: November 16, 2014      Accepted: December 14, 2014      Published: February 19, 2015 ABSTRACT Prostate cancer is the leading cancer in North American men. Current pharmacological treatments are limited to anti-androgen strategies and the development of new therapeutic approaches remains a challenge. As a fundamentally new approach, we propose the inhibition of PACE4, a member of the proprotein convertases family of enzymes, as a therapeutic target in prostate cancer. We developed an inhibitor named the Multi-Leu peptide, with potent in vitro anti-proliferative effects. However, the Multi-Leu peptide has not been tested under in vivo conditions and its potency under such conditions is most likely limited, due to the labile characteristics of peptides in general. Using a peptidomimetic approach, we modified the initial scaffold, generating the analog Ac-[DLeu]LLLRVK-Amba, which demonstrates increased inhibitory potency and stability. The systemic administration of this peptidomimetic significantly inhibits tumor progression in the LNCaP xenograft model of prostate cancer by inducing tumor cell quiescence, increased apoptosis and neovascularization impairment. Pharmacokinetic and biodistribution profiles of this inhibitor confirm adequate tumor delivery properties of the compound. We conclude that PACE4 peptidomimetic inhibitors could result in stable and potent drugs for a novel therapeutic strategy for prostate cancer.