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

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 , a novel pan-SR modulator with good antiproliferative activities toward a panel of different cancer cell lines. In the present study, we investigated the properties and pharmacological profile of in PC cell lines with the aim to identify a potential lead candidate for the treatment of this tumor. 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 . The apoptotic properties of 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 effect on cell migration. In addition, we delineated the pharmacokinetic profile and pancreas distribution of in male CD-1 mice. Panc-1, Capan-1, and Capan-2 express both SRs. exerts an antiproliferative and pro-apoptotic effect in all examined cell lines. Cells exposure to induces the increase of the expression of ER-UPR related proteins, and the inhibition of proteasome activity. Moreover, is able to decrease PC cell lines motility. The results show that is more concentrated in pancreas than plasma. Overall, our data evidenced that the pan-SR modulator is an optimal candidate for studies in animal models of PC.