Selective cytotoxicity of epidithiodiketopiperazine DC1149B, produced by marine-derived Trichoderma lixii on the cancer cells adapted to glucose starvation

AbstractThe core of solid tumors is characterized by hypoxia and a nutrient-starved microenvironment and has gained much attention as targets of anti-cancer drugs. In the course of search for selective growth inhibitors against the cancer cells adapted to nutrient starvation, epidithiodiketopiperazine DC1149B (1) together with structurally related compounds, trichodermamide A (2) and aspergillazine A (3), were isolated from culture extract of marine-derivedTrichoderma lixii. Compounds1 exhibited potent selective cytotoxic activity against human pancreatic carcinoma PANC-1 cells cultured under glucose-starved conditions with IC50 values of 0.02  µM. The selective index of the compound1 was found to be 35,500-fold higher for cells cultured under glucose-starved conditions than those under the general culture conditions. The mechanistic analysis indicated that compound1 inhibited the response of the ER stress signaling. In addition, these effects of compound1 could be mediated by inhibiting complex II in the mitochondrial electron transport chain.
Source: Journal of Natural Medicines - Category: Drugs & Pharmacology Source Type: research