Selective inhibition of fatty acid synthase for lung cancer treatment

ORITA HAJIME, Kuhajda Frank, Gabrielson Edward

doi:10.14789/pjmj.54.10

Fatty acid synthase (FAS) is highly expressed in many human cancers, including lung cancers. Our previous work has shown that blocking FAS activity by cerulenin, a natural antibiotic, or C75, a first-generation synthetic small molecule, leads to apoptosis in cells that overexpress this enzyme. However, the use of C75 is limited by dose-dependent anorexia that appears to be associated with stimulation of carnitine O-palmitoyltransferase-1 (CPT-1). Several second-generation novel FAS-inhibitory compounds have been synthesized that show significant inhibition of FAS, without parallel stimulation of CPT-1. Among the most promising compounds is C93, which inhibits FAS at a potency nearly equal to that of C75, but couses significantly less stimulation of CPT-1. According to pharmacological research, we administered C93 by intraperitoneal injection, which effectively reduces FAS activity in tumor xenograft tissues in a time-dependant manner. We demonstrated that, 1) fatty acid synthase is a therapeutic target for lung cancer, 2) inhibiting fatty acid synthase has significant antineoplastic effects in the absence of effects on fatty acid oxidation, and 3) anti-FAS treatment can apparently be accomplished without significant toxicity. In addition, we found that pharmacological inhibitors of FAS prevented the development of lung tumors in murine models of carcinogenesis. We conclude that inhibiting the FAS level, not only as treatment, but also for prevention will become a very important factor.

Selective inhibition of fatty acid synthase for lung cancer treatment

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