Heteronemin Promotes Iron-Dependent Cell Death in Pancreatic Cancer

Abstract As the source of several anticancer drugs, the marine environment is a treasure trove for the discovery of new drugs. In this study, a sesterterpenoid-type natural product heteronemin was investigated as a potential ferroptotic agent in the pancreatic cancer cell line (Panc-1). The effect of heteronemin on lipid peroxidation and autophagy- and ferritin-related protein expressions was examined using spectrophotometric and immunoblotting techniques, respectively. As well, several preclinical cell-based tests were used for the anticancer assessment. Results: Heteronemin at 55 nM concentration reduced cell viability by 50%. Heteronemin-induced cell death was reversed by a ferroptosis inhibitor, Ferrostatin-1. The levels of ferroptosis markers and malondialdehyde (MDA) were upregulated by heteronemin treatment while glutathione peroxidase-4 (GPX4) protein expression was downregulated. Also, significant alterations in ferritinophagy- and iron-related proteins (Atg5, Atg7, FTL, STEAP3, and DMT-1) were observed in Panc-1 cells (p < 0.05). Conclusions: The obtained results indicated that heteronemin exerted its pharmacological effect via triggering ferroptosis in pancreatic cancer. The potent cytotoxic effect of heteronemin suggested its potential development as a drug lead in the war against cancer.