Impact of d‐δ‐Tocotrienol on Human A2058 and A375 Melanoma Cells

Abstract

The rate‐limiting activity 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 lamins, Ras and growth factor receptors. d‐δ‐Tocotrienol, a post‐transcriptional down‐regulator of HMG CoA reductase, suppresses the proliferation of murine B16 melanoma cells and human blood, breast, cervix, colon, liver, lung, lymph gland, nerve, pancreas, and prostate tumor cells. Dietary d‐δ‐tocotrienol suppresses the growth of implanted B16 melanomas without toxicity to host mice. We evaluated d‐δ‐tocotrienol in human A2058 and A375 melanoma cells. d‐δ‐Tocotrienol induced dose‐dependent suppression of the cell proliferation following 72 h incubation in 96‐well plates with IC50 values of 48 (A2058) and 22 (A375) μmol/L, respectively. Morphological changes detected by fluorescence microscopy following acridine orange and ethidium bromide dual staining showed d‐δ‐tocotrienol‐induced apoptosis in A2058 cells. The impact of d‐δ‐tocotrienol on A2058 cell proliferation was potentiated by lovastatin (IC50=3 μmol/L), a competitive inhibitor of HMG CoA reductase. d‐δ‐Tocotrienol may have potential application in melanoma chemoprevention and/or therapy. TDA, TWU REP & Summer Stipend Award.