The Impact of d‐δ‐Tocotrienol and Geranylgeraniol on Cell Cycle Progression and Apoptosis in Human and Murine Melanoma Cells

Abstract

The mevalonate pathway provides essential intermediates for the prenylation or dolichylation of growth‐related proteins including nuclear lamins, Ras and growth factor receptors. d‐δ‐Tocotrienol, a vitamin E isomer with farnesyl side chain, and geranylgeraniol, a diterpene, are suppressors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG CoA) reductase, the rate‐limiting activity of the mevalonate pathway. We evaluated the impact of d‐δ‐tocotrienol and geranylgeraniol on cell cycle progression and apoptosis in human A375 and A2058 melanoma cells and murine B16 melanoma cells. d‐δ‐Tocotrienol (11–38 μmol/L) and geranylgeraniol (30–90 μmol/L) induced concentration‐dependent cell cycle arrest at the G1 phase and apoptosis as detected by flow cytometry and fluorescence microscopy; the impacts were accompanied by decreased levels of cyclin‐dependent kinase 4 and cyclin D1 proteins and the activation of caspases‐3. d‐δ‐Tocotrienol also suppressed the level of Ras protein in A375 and A2058 cells. Blends of d‐δ‐tocotrienol and geranylgeraniol suppressed the growth of murine B16 melanoma cells to greater extents than the sum of individual impacts, suggesting a synergistic effect. The tocotrienols, geranylgeraniol and other mevalonate suppressors may have potential application in melanoma prevention and therapy. TDA & TWU REP.