| The rate-limiting enzyme of the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, provides essential intermediates for the prenylation or dolichylation of growth-related proteins including nuclear Ras, nuclear lamins, and growth factor receptors. d-delta-tocotrienol, a post-transcriptional down-regulator of HMG CoA reductase, suppresses the proliferation of marine B16 melanoma cells and human blood, breast, cervix, colon, liver, lung, lymph gland, nerve, pancreas, and prostate tumor cells.;Dietary d-delta-tocotrienol suppresses the growth of implanted B16 melanomas without toxicity to host mice. We evaluated the impact of d-delta-tocotrienol on the proliferation of human A2058 and A375 melanoma cells. d-delta-tocotrienol induced dose-dependent suppression of the cell proliferation following 72 h incubation in 96-well plates with 50% inhibitory concentrations (IC50) of 37.5 +/- 1.4 (A2058) and 22.3 +/- 1.8 (A375) mumol/L, respectively. d-delta-tocotrienol-mediated cell cycle arrest at the G1 phase was accompanied by decreased expression of cyclin-dependent kinase 4. Concomitantly, procaspase-3 cleavage and morphological changes detected by fluorescence microscopy following acridine orange and ethidium bromide dual staining showed d-delta-tocotrienol-induced apoptosis in melanoma cells. Consequent to mevalonate deprivation and the putatively reduced prenylation and biological half-life of Ras protein, d-delta-tocotrienol induced concentration- and time dependent decrease in the expression of Ras. The impact of d-8-tocotrienol on A2058 cell proliferation was potentiated by lovastatin (IC50 = 3.1+/- 0.5 mumol/L), a competitive inhibitor of HMG CoA reductase. d-delta-tocotrienol may have potential application in melanoma chemoprevention and/or therapy. |
