Mevalonate suppression mediates the impact of geranylgeraniol on cell cycle arrest, apoptosis and differentiation in murine B16 melanoma cells
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The diterpene geranylgeraniol suppresses the growth of human liver, lung, ovary, pancreas, colon, stomach, and blood tumors with undefined mechanisms. We evaluated the growth-suppressive activity of geranylgeraniol in murine B16 melanoma cells. Geranylgeraniol induced dose-dependent suppression of B16 cell proliferation following a 48-h incubation in 96-well plates. Cell cycle arrest at the G1 and G2/M phases, measured by flow cytometry, and apoptosis, detected by Guava Nexin™ assay and fluorescence microscopy following acridine orange and ethidium bromide dual staining, contributed to the growth suppression. Geranylgeraniol also induced the activity of alkaline phosphatase activity, a biomarker for cell differentiation, in B16 cells. Mouse 3T3-L1 fibroblasts were more resistant than B16 cells to geranylgeraniol. The impact of geranylgeraniol on B16 cell proliferation, cell cycle arrest and apoptosis was attenuated by supplemental mevalonate, the product of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and an essential intermediate required for growth. Geranylgeraniol and d-d-tocotrienol, also a down-regulator of HMG CoA reductase activity, synergistically suppressed the proliferation of B16 cells. The anti-tumor activity of geranylgeraniol may be mediated by mevalonate starvation. Geranylgeraniol individually and in combination with other mevalonate suppressors may have potential in melanoma prevention and/or therapy.