TOFA suppresses ovarian cancer cell growth in vitro and in vivo

A characteristic feature of cancer cells is the activation of de novo fatty acid synthesis. Acetyl-CoA carboxylase (ACC) is a key enzyme in fatty acid synthesis, accelerating the reaction that carboxylates cytosolic acetyl-CoA to form malonyl-CoA. ACC is highly expressed in several types of human cancer and is important in breast and prostate cancer cell growth. The aim of the present study was to investigate the effects of 5-tetradecyloxy-2-furoic acid (TOFA), an allosteric inhibitor of ACC, on the proliferation and cell cycle progression of the ovarian cancer cell lines COC1 and COC1/DDP. TOFA was found to be cytotoxic to COC1 and COC1/DDP cells with a 50% inhibitory concentration (IC50) of similar to 26.1 and 11.6 mu g/ml, respectively. TOFA inhibited the proliferation of the cancer cells examined in a time-and dose-dependent manner, arrested the cells in the G0/G1 cell cycle phase and induced apoptosis. The expression of the cell cycle regulating proteins cyclin D1 and cyclin-dependent kinase (CDK) 4, as well as the expression of the apoptosis-related proteins caspase-3 and Bcl-2, were detected by western blot analysis. Cyclin D1, CDK4 and Bcl-2 protein expression was inhibited by TOFA, while caspase-3 was cleaved and activated. To the best of our knowledge, the present study demonstrated for the first time that TOFA inhibits COC1/DDP cell growth in ovarian tumor mouse xenografts. By inhibiting ACC, TOFA may be a promising small molecule agent for ovarian cancer therapy.