Identification of ferroptosis as a novel mechanism for antitumor activity of natural product derivative a2 in gastric cancer

Abstract

Ferroptosis is a type of cell death accompanied by iron-dependent lipid peroxidation, thus stimulating ferroptosis may be a potential strategy for treating gastric cancer, therapeutic agents against which are urgently required. Jiyuan oridonin A (JDA) is a natural compound isolated from Jiyuan <i>Rabdosia rubescens</i> with anti-tumor activity, unclear anti-tumor mechanisms and limited water solubility hamper its clinical application. Here, we showed <b>a2</b>, a new JDA derivative, inhibited the growth of gastric cancer cells. Subsequently, we discovered for the first time that <b>a2</b> induced ferroptosis. Importantly, compound <b>a2</b> decreased GPX4 expression and overexpressing GPX4 antagonized the anti-proliferative activity of <b>a2</b>. Furthermore, we demonstrated that <b>a2</b> caused ferrous iron accumulation through the autophagy pathway, prevention of which rescued <b>a2</b> induced ferrous iron elevation and cell growth inhibition. Moreover, <b>a2</b> exhibited more potent anti-cancer activity than 5-fluorouracil in gastric cancer cell line-derived xenograft mice models. Patient-derived tumor xenograft models from different patients displayed varied sensitivity to <b>a2</b>, and GPX4 downregulation indicated the sensitivity of tumors to <b>a2</b>. Finally, <b>a2</b> exhibited well pharmacokinetic characteristics. Overall, our data suggest that inducing ferroptosis is the major mechanism mediating anti-tumor activity of <b>a2</b>, and <b>a2</b> will hopefully serve as a promising compound for gastric cancer treatment.