Malonyl-coenzyme-A is a potential mediator of cytotoxicity induced by fatty-acid synthase inhibition in human breast cancer cells and xenograft

A biologically aggressive subset of human breast cancers and other malignan cies is characterized by elevated fatty-acid synthase (FAS) enzyme expressi on, elevated fatty acid (FA) synthesis, and selective sensitivity to pharma cological inhibition of FAS activity by cerulenin or the novel compound C75 , In this study, inhibition of FA synthesis at the physiologically regulate d step of carboxylation of acetyl-CoA to malonyl-CoA by 5-(tetradecyloxy)-2 -furoic acid (TOFA) was not cytotoxic to breast cancer cells in clonogenic assays. FAS inhibitors induced a rapid increase in intracellular malonyl-Co A to several fold above control Levels, whereas TOFA reduced intracellular malonyl-CoA by 60%, Simultaneous exposure of breast cancer cells to TOFA an d an FAS inhibitor resulted in significantly reduced cytotoxicity and apopt osis, Subcutaneous xenografts of MCF7 breast cancer cells in nude mice trea ted with C75 showed FA synthesis inhibition, apoptosis, and inhibition of t umor growth to less than 1/8 of control volumes, without comparable toxicit y in normal tissues, The data suggest that differences in intermediary meta bolism render tumor cells susceptible to toxic fluxes in malonyl-CoA, both in vitro and in vivo.