title: Garcinia benzophenones inhibit the growth of human colon cancer cells and synergize with sulindac sulfide and turmeric.
abstract: Previous studies indicate that extracts and purified components from Garcinia species inhibit the growth of human colon cancer cells. Garcinia benzophenones activate the expression of genes in the endoplasmic reticulum and cellular energy stress (mTOR) pathways. This study examines the growth inhibitory and synergistic effects of Garcinia benzophenones, alone or combined with chemopreventive agents, on human colon cancer cells. To find optimal combination treatments, HT29 colon cancer cells were treated with benzophenones alone, or combined with chemopreventive agents, and cell growth measured using the MTT assay. To reveal effects on signaling pathways, we assessed effects of the MEK inhibitor U0126 and the ER IP3 receptor antagonist heparin, as well as effects on the phosphorylation of 4E-BP-1 (mTOR pathway), using Western blot analysis. New and known benzophenones from Garcinia intermedia inhibited the growth of human colon cancer cells; an alcohol extract of Garcinia xanthochymus, as well as purified guttiferones (guttiferone E and xanthochymol), preferentially inhibited the growth of colon cancer versus nonmalignant intestinal epithelial cells. Guttiferone E exhibited synergy with the NSAID sulindac sulfide and xanthochymol, with the spice turmeric. Guttiferone A did not alter phosphorylation of 4E-BP-1, indicating that the mTORC1 pathway is not involved in its action. The effects of xanthochymol were enhanced by U0126, at low doses, and were blocked by heparin, indicating that the MEK pathway is involved, while the ER IP3 receptor is critical for its action. These studies indicate the potential of benzophenones, alone or combined with sulindac sulfide or turmeric, to prevent and treat colon cancer.
authors.forename: Linda Saxe
authors.initials: LS
authors.lastname: Einbond
authors.forename: Jason
authors.initials: J
authors.lastname: Mighty
authors.forename: Ryota
authors.initials: R
authors.lastname: Kashiwazaki
authors.forename: Mario
authors.initials: M
authors.lastname: Figueroa
authors.forename: Filza
authors.initials: F
authors.lastname: Jalees
authors.forename: Ulyana Munoz
authors.initials: UM
authors.lastname: Acuna
authors.forename: Onica
authors.initials: O
authors.lastname: Le Gendre
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
authors.affiliation: Lehman College and The Graduate Center, CUNY, Bronx, NY 10468, USA. Edward.Kennelly@lehman.cuny.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kennelly
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001577:Benzophenones / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D000068579:Celecoxib; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D030024:Curcuma; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D029760:Garcinia / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D001577:Benzophenones; D002070:Butadienes; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D046912:Multiprotein Complexes; D009570:Nitriles; D010750:Phosphoproteins; D010936:Plant Extracts; D011720:Pyrazoles; D013449:Sulfonamides; C113580:U 0126; D013467:Sulindac; C025462:sulindac sulfide; C012596:turmeric extract; D006493:Heparin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D000068579:Celecoxib