1-Piperidine Propionic Acid Inhibits PAR2/SerpinB3 Signaling and Reduces Glioblastoma Tumor Aggressiveness

Glioblastoma multiforme is the most aggressive primary brain tumor in adults, which displays extremely poor prognosis. Protease-activated receptor 2 (PAR2) and its downstream effector SerpinB3 are overexpressed in aggressive glioblastomas. In this study we evaluated the antitumor activity of 1-piperidine propionic acid (1-PPA), an allosteric PAR2 inhibitor, in in vitro preclinical models of glioblastoma. PAR2 and SerpinB3 were analyzed at the transcriptional and protein level in glioblastoma cell lines and primary cultures. These were treated with 1-PPA alone or in association with temozolomide (TMZ) and the effects evaluated by Incucyte® technology. Pharmacokinetics and tissue distribution of 1-PPA were assessed in mice by LC-MS/MS. 1-PPA significantly reduced glioma cell proliferation, migration, and invasion, thus promoting apoptotic cell death, in a concentration-dependent manner. The combined treatment with TMZ led to a concentration-dependent decrease in cell proliferation (12–20%) compared to TMZ alone. Molecularly, 1-PPA downregulated PAR2 and SerpinB3 expression. Pharmacokinetic studies in healthy mice showed that 1-PPA is systemically bioavailable and distributes to several organs, including the brain. These data indicate that 1-PPA shows brain exposure and capability to affect different hallmarks of aggressiveness in glioblastoma cells, including hyperproliferation and invasion, supporting its further development as a novel therapeutic strategy in these tumors.