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.

Funding

This work was partially supported by the Texas Department of Agriculture Food and Fiber Research Program, Texas Woman's University Research Enhancement Program and Human Nutrition Research Fund, and American River Nutrition, Inc.

Authors' contributions

All authors participated in the design, interpretation of the studies and analysis of the data, and review of the manuscript. HY, BM, and HM conducted the experiments; RAD supplied antibody to HMG CoA reductase and LPDS; and HY, RAD, BM, and HM wrote the manuscript.