Synergistic Impact of d ‐δ‐Tocotrienol and Geranylgeraniol in Human DU145 Prostate Carcinoma Cells

Abstract

The mevalonate pathway produces essential intermediates for the post-translational prenylation and dolichylation of growth-associated proteins including Ras, nuclear lamins and growth factor receptors. Dysregulation and overexpression of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of this pathway, in malignant cells supports tumor growth and survival. d-δ-Tocotrienol, a vitamin E molecule with farnesyl side chain, and geranylgeraniol, a diterpene, accelerate the ubiquitination and proteasome-mediated degradation of HMG CoA reductase via complementary and collaborative mechanisms. We evaluated the impacts of these two isoprenoids in human DU145 prostate carcinoma cells. d-δ-Tocotrienol (IC50 = 15 μmol/L) and geranylgeraniol (IC50 = 60 μmol/L) individually induced concentration-dependent suppression of the viability of DU145 cells as measured by CellTiter 96® AQueous One Solution. Isobologram using CompuSyn software demonstrated the synergistic impact of the two agents in combination. Blends of d-δ-tocotrienol (7.5 μmol/L) and geranylgeraniol (30 μmol/L), each at half of their respective IC50 concentrations, cumulatively suppressed the level of membrane HMG CoA reductase and putatively as a consequence of reduced prenylation, that of membrane Ras protein. Synergistic impact of diverse isoprenoids on the mevalonate pathway and tumor cell viability may offer a potential therapeutic or preventive approach to prostate cancer. Supported by TWU REP and American River Nutrition, Inc.