Inhibition of fatty acid synthase by Orlistat accelerates gastric tumor cell apoptosis in culture and increases survival rates in gastric tumor bearing mice in vivo.

Orlistat, an anti-obesity drug, is a potent inhibitor of fatty acid synthase (FAS) and tumor cell viability. It can also induce apoptotic cancer cell death. We examined the effects of Orlistat on cultured NUGC-3 gastric cancer cells. We identified that inhibition of FAS via Orlistat exposure results in rapid cellular damage preceded by a direct but short-lived autophagic response. The Orlistat induced damage can be reversed through the addition of lipid containing media in a process that normally leads to cell death. By limiting exogenous lipid availability and inhibiting FAS using Orlistat, we demonstrated both a greater sensitivity and amplified cancer cell death by activation of apoptosis. We have identified "windows of opportunity" at which time apoptosis can be aborted and cells can be reversed from the death pathway. However, when challenged beyond the window of recovery, cell death becomes all but certain as the ability to be rescued decreases considerably. In vivo examination of Orlistat's ability to inhibit gastrointestinal cancer was examined using heterozygous male C57BL/6J APC-Min mice, which spontaneously develop a fatal gastrointestinal cancer. Mice were fed either a high fat (11%) or low fat (1.2%) diet containing no Orlistat or 0.5 mg Orlistat/g of chow. Orlistat treated mice fed the high fat, but not low fat diet, survived 7-10% longer than the untreated controls.