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The Impact of d‐δ‐Tocotrienol and Geranylgeraniol on Cell Cycle Progression and Apoptosis in Human and Murine Melanoma Cells
Author(s) -
Fernandes Nicolle V,
Katuru Rajasekhar,
Dutta Dibyendu,
Mills Nathaniel,
Mo Huanbiao
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb237
Subject(s) - geranylgeraniol , mevalonate pathway , apoptosis , farnesyl pyrophosphate , tocotrienol , cell growth , cell cycle , chemistry , biology , microbiology and biotechnology , biochemistry , farnesol , vitamin e , reductase , tocopherol , atp synthase , antioxidant , enzyme
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.