Fungal dimeric xanthones as anticancer agents by novelly stimulating sodium-calcium exchanger 1

Multitude of natural products have the ability to demonstrate inhibitory effects on cancer cells by regulating ion channels/transporters functions. Eighteen xanthone dimers (Xds), including five new dimers diaporxanthones H, I, J-L (1, 2, and 12-14), were isolated and characterized through co-culture and chemical conversion methods. ECD Cotton effect analyses and chemical communication method provided fundamental role in addressing the challenges of elucidating their absolute configurations. Structure-activity relationship (SAR) analysis showed that eight xanthone-xanthone Xds (2-7, 15 and 16) demonstrated marked cytotoxic effects against gastric cancer (GC) cell line AGS, with undetectable inhibition on human colon cancer cells. The anti-proliferative potency of Xds was 2-5 fold higher than positive control drug cisplatin. Mechanistic studies were conducted on a high-yield compound, 12-O-deacetyl-phomoxanthone A (4). Compound 4 activated Na⁺/Ca²⁺ exchanger 1 (NCX1), thereby causing an increase in cellular Ca²⁺ signaling and subsequent inhibition of the downstream PI3K/AKT/β-catenin pathway, ultimately leading to GC cell death. Like anti-GC, Xds also possessed anti-melanoma activity in vitro and in vivo. We demonstrate Xds have effective cytotoxic actions against GC and melanoma by targeting NCX1/Ca²⁺ signaling in cancer cells.