title: Subcellular localization and activity of gambogic acid.
abstract: The natural product gambogic acid (GA) has shown significant potential as an anticancer agent as it is 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. By thorough analysis of several cellular organelles, at both the morphological and functional levels, we demonstrate that the primary effect of GA is 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 localize specifically 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, and thus represents a new member of the mitocans.
authors.affiliation: Department of Cell Biology and Infection, Membrane Traffic and Pathogenesis Unit, Pasteur Institute, 25, rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Gianni
authors.initials: G
authors.lastname: Guizzunti
authors.forename: Ayse
authors.initials: A
authors.lastname: Batova
authors.forename: Oraphin
authors.initials: O
authors.lastname: Chantarasriwong
authors.forename: Marianna
authors.initials: M
authors.lastname: Dakanali
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Theodorakis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D044004:Xanthones / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D044004:Xanthones; C052659:gambogic acid