α-NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase-4 pathway

Chemotherapy resistance is one of the most common causes of death among patients with ovarian cancer, and identifying novel antitumor agents is a priority. Here, we report that the novel molecule 2-(anaphthoyl)ethyltrimethylammonium iodide (-NETA) induces epithelial ovarian cancer (EOC) cell pyroptosis through the gesdermin-d (GSDMD)/caspase-4 pathway. Furthermore, Cell Counting Kit-8 fluorescence-activated cell sorting analysis showed that alpha-NETA treatment led to cell death in different ovarian cancer cell lines, including Ho8910, Ho8910PM, and A2780. Morphologic examination by electron microscopy indicated that cells treated with alpha-NETA produced multiple microbubbles, typical of cells undergoing pyroptosis. alpha-NETA also significantly increased expression of pyroptosis-associated molecules including caspase-4 and GSDMD in EOC cells. Knockdown of either caspase-4 or GSDMD in ovarian cancer cells strongly interfered with alpha-NETA cell-killing activity, indicating that alpha-NETA acts through the pyroptosis pathway. In vivo, alpha-NETA treatment dramatically decreased the size of EOC tumors in mice. Our findings suggest that alpha-NETA represents a potential new antitumor molecule or lead compound for EOC chemotherapy.