Synergistic Impact of d‐δ‐Tocotrienol and Geranylgeraniol on the Growth and HMG CoA Reductase of Human DU145 Prostate Carcinoma Cells

Abstract

d‐δ‐Tocotrienol and geranylgeraniol suppress the growth of diverse types of tumors in vitro and in vivo. Their growth‐suppressive effect 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 and nuclear lamins. d‐δ‐Tocotrienol blocks the processing and nuclear localization of sterol regulatory element binding protein 2, the transcriptional factor for HMG CoA reductase, while d‐δ‐tocotrienol and geranylgeraniol collaboratively enhance the proteasome‐mediated degradation of HMG CoA reductase. We hypothesize that these agents have synergistic inhibitory impact on cell growth based on their complementary mechanisms of action with HMG CoA reductase. d‐δ‐Tocotrienol (0 – 40 μmol/L) and geranylgeraniol (0 – 100 μmol/L) each induced concentration‐dependent suppression of the growth of human DU145 prostate carcinoma cells as measured by CellTiter 96® AQueous One Solution. Blends of the two agents synergistically suppressed the growth of DU145 cells, with combination index values in the range of 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 at these concentrations 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 RAS protein induced by the blend. Our finding lends further support to the cancer chemopreventive action of plant‐based diets and their isoprenoid constituents. Properly formulated isoprenoid combinations and their derivatives with complementary mechanisms may provide novel approaches in prostate cancer therapy.Support or Funding InformationTDA FFRP, TWU REP, and American River Nutrition, Inc.