Isoprenylated Coumarin Exhibits Anti-proliferative Effects in Pancreatic Cancer Cells Under Nutrient Starvation by Inhibiting Autophagy.

Abstract

Due to the lack of early detection methods and effective treatments, pancreatic cancer has one of the lowest five-year survival rates among all cancers. We have previously identified novel isoprenylated coumarin compounds that exhibit preferential cytotoxicity against pancreatic adenocarcinoma cell line PANC-1 exclusively under glucose deprivation conditions. Using cell cytotoxicity assays, we investigated the anti-proliferative mechanism of our most potent isoprenylated coumarin compound of the series, DCM-MJ-I-21, with respect to time, against two other pancreatic cancer cell lines, BxPC-3 and Capan-2. We used western blotting to quantify the autophagic flux influenced by our compound, autophagy inducers (starvation and Rapamycin), and autophagy inhibitors (chloroquine and wortmannin). We observed a clear dependence on glucose in DCM-MJ-I-21 in BxPC-3 and Capan-2 pancreatic cancer cell lines, suggesting that our compound targets a pathway shared by these cancer cell lines when glycolysis is not an option for survival. Our lead compound increased the conversion of LC3-I to LC3-II in PANC-1, similar to the effect of chloroquine, an autophagy inhibitor. In addition, Spautin-1, another autophagy inhibitor, showed almost the same anti-proliferative activities at the same concentration under nutrient-deprived conditions as our lead compound in both 2D and 3D cell cultures. Our lead isoprenylated coumarin compound induces selective pancreatic cancer cell death under nutrient-deprived conditions through inhibition of autophagy, potentially providing insights into new therapeutic options.