title: Interaction between Gambogic acid and dihydrofolate reductase and synergistic lethal effects with methotrexate on hepatoma cells.
abstract: Gambogic acid (GA), a natural xanthone, has a wide spectrum of pharmacological activities, including repression of telomerase expression and induction of apoptosis of cancer cells. GA has also been reported to reduce the steady-state level of thymidylate synthetase mRNA in a gastric carcinoma cell line. Therefore, it has recently emerged as a candidate for use in cancer treatment. Using hepatoma cells with a dihydrofolate reductase (DHFR) gene amplification and cells transfected with an inducible DHFR transgene, we observed a negative relationship between DHFR expression and resistance to GA. Furthermore, DHFR assays in vitro indicated that in the presence of GA, DHFR activity was slightly inhibited and the affinity of the enzyme for dihydrofolate was markedly decreased. Treatment of rat hepatoma and other human and murine cancer cell lines with methotrexate and GA revealed that the two drugs displayed a marked synergistic lethal effect.
authors.affiliation: UMR 757 INSERM, University Paris-Sud, Orsay F-91405, France. jean.deschatrette@u-psud.fr
authors.forename: Jean
authors.initials: J
authors.lastname: Deschatrette
authors.forename: Kim
authors.initials: K
authors.lastname: Ng-Bonaventure
authors.forename: Laetitia
authors.initials: L
authors.lastname: Philippe
authors.forename: Claire
authors.initials: C
authors.lastname: Wolfrom
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005493:Folic Acid Antagonists / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D044004:Xanthones / Q000008:administration & dosage*
chemical_list: D005493:Folic Acid Antagonists; D044004:Xanthones; C052659:gambogic acid; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate