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

Christine Levesque,Anna Kwiatkowska,Roxane Desjardins,Frédéric Couture,Witold A Neugebauer,Robert Day,Brigitte Guérin

doi:10.18632/oncotarget.2918

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.

Highlights

The proprotein convertases (PCs) are increasingly implicated in various types of cancers, as well as cancer hallmarks
The peptide resulting from combination of both modifications Ac-[DLeu]LLLRVK-Amba is a low nanomolar PACE4 inhibitor in vitro (Ki 4.9 ± 0.9 nM) with a 4-fold increase in potency when compared to a control ML inhibitor (Ki 22 ± 6 nM)
What is known so far, is that PCs act by cleaving cancer-related substrates, such as growth factors, receptors, proteases and adhesion molecules, mostly in activating functions

Summary

Introduction

The proprotein convertases (PCs) are increasingly implicated in various types of cancers, as well as cancer hallmarks. The PCs have been extensively studied and linked to malignant phenotypes and disease progression in models of colon carcinoma [5,6,7], melanoma [8], cervical cancer [9], head and neck squamous carcinoma [10,11,12], breast [13, 14], ovarian [15, 16] and prostate carcinoma [17, 18] Through this accumulating evidence, it is clear that PCs are essential participants in the multi-step processes of carcinogenesis through the activation of a variety of cancer-related substrates [2,3,4]. There is a need for new therapeutic targets that could complement or follow the current anti-androgen strategies [17, 18]

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Conclusion