KYP-2047, an Inhibitor of Prolyl-Oligopeptidase, Reduces GlioBlastoma Proliferation through Angiogenesis and Apoptosis Modulation

Sarah Adriana Scuderi; Giovanna Casili; Alessio Ardizzone; Stefano Forte; Lorenzo Colarossi; Serena Sava; Irene Paterniti; Emanuela Esposito; Salvatore Cuzzocrea; Michela Campolo

doi:10.3390/cancers13143444

KYP-2047, an Inhibitor of Prolyl-Oligopeptidase, Reduces GlioBlastoma Proliferation through Angiogenesis and Apoptosis Modulation

Cancers (Basel). 2021 Jul 9;13(14):3444. doi: 10.3390/cancers13143444.

Affiliations

¹ Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D' Alcontres, 31-98166 Messina, ME, Italy.
² IOM Ricerca Srl, Via Penninazzo 11, 95029 Viagrande, CT, Italy.
³ Istituto Oncologico del Mediterraneo, Via Penninazzo 7, 95029 Viagrande, CT, Italy.

Abstract

Glioblastoma (GB) is the most aggressive tumor of the central nervous system (CNS), characterized by excessive proliferation, necrosis and invasiveness. The survival rate for patients with GB still remains low. Angiogenesis and apoptosis play a key role in the development of GB. Thus, the modulation of angiogenesis and apoptosis processes represent a possible strategy to counteract GB progression. This study aimed to investigate the potential effect of KYP-2047, an inhibitor of the prolyl-oligopeptidase (POP), known to modulate angiogenesis, in an in vivo U87-xenograft model and in an in vitro study on human GB cells. Our results showed that KYP-2047 at doses of 2.5 mg/kg and 5 mg/kg was able to reduce tumor burden in the xenograft-model. Moreover, KYP-2047 significantly reduced vascular endothelial-growth-factor (VEGF), angiopoietins (Ang) and endothelial-nitric-oxide synthase (eNOS) expression. In vitro study revealed that KYP-2047 at different concentrations reduced GB cells' viability. Additionally, KYP-2047 at the concentrations of 50 µM and 100 µM was able to increase the pro-apoptotic protein Bax, p53 and caspase-3 expression whereas Bcl-2 expression was reduced. Thus, KYP-2047 could represent a potential therapeutic treatment to counteract or reduce GB progression, thanks its abilities to modulate angiogenesis and apoptosis pathways.

Keywords: angiopoietin (Ang); endothelial nitric oxide synthase (eNOS); glioblastoma (GB); prolyl-oligopeptidase (POP); transforming growth factor-β (TGF-β); vascular endothelial growth factor (VEGF).