Investigating the Activity of Novel Sigma‐2 Receptor Analogs in Pancreatic Ductal Adenocarcinoma Cell Lines

Abstract

Pancreatic cancer is an aggressive cancer that is highly resistant to most chemotherapy agents and has an estimated 5‐year survival rate of less than 10%. Sigma‐2 receptors (S2Rs) are highly upregulated in many cancers, including pancreatic. Specifically, S2Rs are overexpressed in pancreatic cancer cells, while minimally expressed in normal pancreatic cells, which makes them a potentially selective drug target. Additionally, pancreatic ductal adenocarcinoma cell (PDAC) lines have been found to be sensitive to SR2‐ligand binding, which initiates an apoptotic response. The selective estrogen receptor modifier, tamoxifen, has been shown to have affinity for S2Rs. We developed a series of analogs based on tamoxifen’s scaffold, with the intent to increase sigma‐2 receptor activity while decreasing estrogen receptor affinity and activity.Previously, we have shown the analogs in our sigma receptor library presented here have low micromolar IC50 values in glioblastoma, melanoma, breast, and colorectal cancer cell lines. These analogs do not display selectivity between cancerous and noncancerous cell lines of normal human astrocytes and mammary epithelium.Here we present additional screening data of SP‐1, SP‐5, SP‐6, and SP‐9 in three PDAC lines, ASPC‐1, BXPC‐3, and Su86.86. SP‐1, SP‐5, and SP‐9 all demonstrate similar efficacy with IC50 values ranging from 30 to 50 μM in each of the three PDAC lines. These findings are in line with previous studies with this library in the other cell lines listed above. Interestingly, the SP‐6 analog was much less active with IC50 values of 100 μM or greater in all three PDAC lines.In summary, we found that our sigma‐2 analogs have low micromolar IC50 values in multiple PDAC lines. In the future, we would like to assess selectivity against non‐cancerous pancreatic cells and measure binding affinity of these analogs for S2R and estrogen receptors. Lastly, we would like to explore the mechanisms by which these analogs induce cell death in pancreatic cells.