Anti-tumor Efficacy Assessment of the Sigma Receptor Pan Modulator RC-106. A Promising Therapeutic Tool for Pancreatic Cancer

• Váldodahkkit: Anna Tesei (Dahkki), Michela Cortesi (Dahkki), Sara Pignatta (Dahkki), Chiara Arienti (Dahkki), Giulio Massimo Dondio (Dahkki), Chiara Bigogno (Dahkki), Alessio Malacrida (Dahkki), Mariarosaria Miloso (Dahkki), Cristina Meregalli (Dahkki), Alessia Chiorazzi (Dahkki), Valentina Carozzi (Dahkki), Guido Cavaletti (Dahkki), Marta Rui (Dahkki), Annamaria Marra (Dahkki), Daniela Rossi (Dahkki), Simona Collina (Dahkki)
• Materiálatiipa: Girji
• Almmustuhtton: Frontiers Media S.A., 2019-05-01T00:00:00Z.
• Fáttát: article
• Liŋkkat: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2019.00490
• Keywords: Pancreatic cancer; pan-sigma receptor modulators; endoplasmic reticulum stress; unfolded protein response; proteasome inhibition; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 10 (2019)

Introduction: Pancreatic cancer (PC) is one of the most lethal tumor worldwide, with no prognosis improvement over the past 20-years. The silent progressive nature of this neoplasia hampers the early diagnosis, and the surgical resection of the tumor, thus chemotherapy remains the only available therapeutic option. Sigma receptors (SRs) are a class of receptors proposed as new cancer therapeutic targets due to their over-expression in tumor cells and their involvement in cancer biology. The main localization of these receptors strongly suggests their potential role in ER unfolded protein response (ER-UPR), a condition frequently occurring in several pathological settings, including cancer. Our group has recently identified RC-106, a novel pan-SR modulator with good in vitro antiproliferative activities toward a panel of different cancer cell lines. In the present study, we investigated the in vitro properties and pharmacological profile of RC-106 in PC cell lines with the aim to identify a potential lead candidate for the treatment of this tumor.Methods: Pancreatic cancer cell lines Panc-1, Capan-1, and Capan-2 have been used in all experiments. S1R and TMEM97/S2R expression in PC cell lines was quantified by Real-Time qRT-PCR and Western Blot experiments. MTS assay was used to assess the antiproliferative effect of RC-106. The apoptotic properties of RC-106 was evaluated by TUNEL and caspase activation assays. GRP78/BiP, ATF4, and CHOP was quantified to evaluate ER-UPR. Proteasome activity was investigated by a specific fluorescent-based assay. Scratch wound healing assay was used to asses RC-106 effect on cell migration. In addition, we delineated the in vivo pharmacokinetic profile and pancreas distribution of RC-106 in male CD-1 mice.Results: Panc-1, Capan-1, and Capan-2 express both SRs. RC-106 exerts an antiproliferative and pro-apoptotic effect in all examined cell lines. Cells exposure to RC-106 induces the increase of the expression of ER-UPR related proteins, and the inhibition of proteasome activity. Moreover, RC-106 is able to decrease PC cell lines motility. The in vivo results show that RC-106 is more concentrated in pancreas than plasma.Conclusion: Overall, our data evidenced that the pan-SR modulator RC-106 is an optimal candidate for in vivo studies in animal models of PC.