Xenograft Studies of Fatty Acid Synthesis Inhibition as Novel Therapy for Breast Cancer

摘要

Many common human cancers express high levels of fatty acid synthase (FAS), the primary enzyme responsible for the synthesis of fatty acids. Compared to cancer, fatty acid synthesis is highly down- regulated in normal tissues by dietary fat leading to a potential therapeutic index. Inhibition of FAS with cerulenin, a suicide inhibitor of FAS, induced apoptosis in cancer cells in vitro, demonstrating that cancer cells are dependent upon active fatty acid synthesis. To test the systemic effect of FAS inhibition on human cancer xenografts, synthesis of a chemically stable inhibitor was required. Based on the probable mechanism of action of cerulenin and the theoretical transition- state of the of the Beta-ketoacyl synthase reaction, we synthesized the first chemically stable inhibitor of FAS, C75. C75 is a slow-binding inhibitor of Type I mammalian FAS. In addition to its in vitro activity against cancer cells, C75 demonstrated significant anti-cancer activity in the MDA435/LCC6 and MCF-7 human breast cancer xenografts. C75 induced transient inanition which led to weight loss reversible with nutritional support. No other significant toxicity was identified. These data illustrates C75 anti-tumor activity, and demonstrate that the fatty acid synthesis pathway and FAS in particular are novel targets for breast cancer therapy.