Inhibiting fatty acid synthase for chemoprevention of chemically induced lung tumors.
Fatty acid synthase (FAS) is overexpressed in lung cancer, and we have investigated the potential use of FAS inhibitors for chemoprevention of lung cancer. Expression of FAS was evaluated in preinvasive human lung lesions (bronchial squamous dysplasia and atypical adenomatous hyperplasia) and in murine models of lung tumorigenesis [4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone-induced and urethane-induced lung tumors in A/J mice]. Then, the ability of pharmacologic inhibitors of FAS to prevent development of the murine tumors was investigated. Finally, the effect of the FAS inhibitor treatment of levels of phosphorylated Akt in the murine tumors was evaluated by immunohistochemistry. Immunohistochemical studies show that human bronchial dysplasia and atypical adenomatous hyperplasia express high levels of FAS compared with normal lung tissues, suggesting that FAS might be a target for intervention in lung carcinogenesis. FAS is also expressed at high levels in chemically induced murine lung tumors, and the numbers and sizes of those murine tumors are significantly reduced by treating carcinogen-exposed mice with pharmacologic inhibitors of FAS, C75 and C93. C93 treatment is associated with reduced levels of phosphorylated Akt in tumor tissues, suggesting that inhibition of this signal transduction pathway might be involved in the chemopreventative activity of this compound. We conclude that increased levels of FAS are common in human preinvasive neoplasia of the lung. Based on studies in mouse models, it seems that inhibiting FAS is an effective strategy in preventing and retarding growth of lung tumors that have high expression of this enzyme.