Fatty Acid Synthase Inhibitor Cytotoxicity: Depletion of the Coenzyme-A Pool. Revision

摘要

Inhibition of fatty acid synthase (FAS) with C75 in human cancer cells leads to cytotoxicity without evidence of DNA damage. Based on this and other biochemical observations attention was focused on the cytoplasm as the site for the origin of C75 cytotoxicity to human cancer cells. We have shown that eukaryotic initiation factor 2 alpha (EIF2alpha), a key regulator of protein synthesis and the ER stress response is involved in the cytotoxic mechanism of C75 against human breast cancer cells. Based on these observations we synthesized a series of novel thiazolidinedione (TZD) compounds. TZD's likely induce cancer cell death through inhibition of translation initiation mediated by phosphorylation of eukaryotic initiation factor 20 (EIF2alpha) rendering it inactive. In summary our novel TZD are cytotoxic to human colon cancer cells in vitro and xenografts in athymic mice. These compounds also phosphorylate EIF2alpha similar to C75. Based on these observations novel class of potent TZD derivatives which may be useful for the treatment of a wide variety of human cancers.