title: PACE4 inhibitors and their peptidomimetic analogs block prostate cancer tumor progression through quiescence induction, increased apoptosis and impaired neovascularisation.
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.
authors: Department of Surgery/Urology Division and Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.|Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors: Christine
authors: C
authors: Levesque
authors: Department of Surgery/Urology Division and Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.|Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors: Frédéric
authors: F
authors: Couture
authors: Department of Surgery/Urology Division and Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.|Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors: Anna
authors: A
authors: Kwiatkowska
authors: Department of Surgery/Urology Division and Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.|Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors: Roxane
authors: R
authors: Desjardins
authors: Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.|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.
authors: Brigitte
authors: B
authors: Guérin
authors: Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors: Witold A
authors: WA
authors: Neugebauer
authors: Department of Surgery/Urology Division and Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.|Institut de Pharmacologie de Sherbrooke, Faculté de Médecine et Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
authors: Robert
authors: R
authors: Day
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D057786:Peptidomimetics / Q000494:pharmacology*; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D012697:Serine Endopeptidases; D023041:Xenograft Model Antitumor Assays
chemical_list: D057786:Peptidomimetics; C080654:PCSK6 protein, human; D043484:Proprotein Convertases; D012697:Serine Endopeptidases