Subcellular Localization and Activity of Gambogic Acid

The natural product Gambogic Acid (GA) has shown significant potential as an anti-cancer agent being able to induce apoptosis in multiple tumor cell lines, including multidrug resistant cell lines, as well as displaying antitumor activity in animal models. Despite the fact that GA has entered phase I clinical trials, the primary cellular target and mode of action of this compound remain unclear, although many proteins have been shown to be affected by it. Via a thorough analysis of several cellular organelles, both at a morphological and a functional level, we demonstrate that the primary effect of GA is directed at the mitochondria. We found that GA induces mitochondrial damage within minutes of incubation at low micromolar concentrations. Moreover, a fluorescent derivative of GA was able to specifically localize to the mitochondria and was displaced from these organelles after competition with unlabeled GA. These findings indicate that GA directly targets the mitochondria to induce the intrinsic pathway of apoptosis thus representing a new member of mitocans.