title: Synergistic Impact of d-δ-Tocotrienol and Geranylgeraniol on the Growth and HMG CoA Reductase of Human DU145 Prostate Carcinoma Cells.
abstract: The growth-suppressive effect of d-δ-tocotrienol and geranylgeraniol is at least partially attributed to their impact on 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that provides essential intermediates for the posttranslational modification of growth-related proteins including RAS. We hypothesize that these agents synergistically impact cell growth based on their complementary mechanisms of action with HMG CoA reductase. d-δ-tocotrienol (0-40 µmol/L; half maximal inhibitory concentration [IC50] = 15 µmol/L) and geranylgeraniol (0-100 µmol/L; IC50= 60 µmol/L) each induced concentration-dependent suppression of the growth of human DU145 prostate carcinoma cells. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values ranging 0.67-0.75. While 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol individually had no impact on cell cycle distribution in DU145 cells, a blend of the agents induced cell cycle arrest at the G1 phase. The synergistic downregulation of the expression of HMG CoA reductase by 7.5 µmol/L d-δ-tocotrienol and 30 µmol/L geranylgeraniol was accompanied by a reduction in membrane K-RAS protein. Our finding supports the cancer chemopreventive action of plant-based diets and their isoprenoid constituents. Properly formulated isoprenoids and derivatives may provide novel approaches in prostate cancer prevention and therapy.
authors.affiliation: a Department of Nutrition and Food Sciences , Texas Woman's University , Denton , Texas , USA.|b Department of Molecular Genetics , University of Texas Southwestern Medical Center , Dallas , Texas , USA.
authors.forename: Hoda
authors.initials: H
authors.lastname: Yeganehjoo
authors.affiliation: b Department of Molecular Genetics , University of Texas Southwestern Medical Center , Dallas , Texas , USA.
authors.forename: Russell
authors.initials: R
authors.lastname: DeBose-Boyd
authors.affiliation: c Department of Kinesiology , Health Promotion, and Recreation, University of North Texas , Denton , Texas , USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: McFarlin
authors.affiliation: d Department of Nutrition , Byrdine F. Lewis School of Nursing and Health Professions, Georgia State University , Atlanta , Georgia , USA.|e Center for Obesity Reversal, Georgia State University , Atlanta , Georgia , USA.
authors.forename: Huanbiao
authors.initials: H
authors.lastname: Mo
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C117307:KRAS protein, human; D014810:Vitamin E; C082097:tocotrienol, delta; C017338:geranylgeraniol; D006903:Hydroxymethylglutaryl CoA Reductases; D016283:Proto-Oncogene Proteins p21(ras)