Biphenylalkylacetylhydroquinone Ethers Suppress the Proliferation of Murine B16 Melanoma Cells

Hydroquinone, an activator of caspase-9 activity via reactive oxygen species, and farnesol, a post-translational downregulator of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity suppress the growth of murine B16 melanoma cells. Our previous studies have shown that farnesyl-O-acetylhydroquinone has a markedly greater growth-suppressive activity than that predicted by the responses to the parent compounds. Perillyl alcohol, a modulator of small G-protein activity, and biphenyl compounds, activators of Fas-mediated death pathways, suppress B16 growth. A similar synergistic increase in the potency of each compound when ether-linked to acetylhydroquinone is reported. Perillyl-O-acetylhydroquinone, biphenylethyl-O-acetylhydroquinone and biphenylpropyl-O-acetylhydroquinone had dose-dependent impacts on the proliferation of B16 cells with 50% inhibitory concentration (IC50) values of 8.0, 4.2 and 1.4 Ìmol/L, respectively. The growth-suppression effected by biphenylpropyl-Oacetylhydroquinone was accompanied by a dose-dependent arrest at the G1/S interface of the cell cycle, an impact greater than that previously reported for farnesyl-O-acetylhydroquinone (IC50=2.5 Ìmol/L). These new hydroquinone derivatives may have potential in cancer chemoprevention and/or therapy

d-β-Tocotrienol-mediated cell cycle arrest and apoptosis in human melanoma cells

Background: 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. d-δ-Tocotrienol, a post-transcriptional downregulator of HMG CoA reductase, suppresses the proliferation of murine B16 melanoma cells. Dietary d-δ- tocotrienol suppresses the growth of implanted B16 melanomas without toxicity to host mice. Materials and Methods: The proliferation of human A2058 and A375 melanoma cells following a 72 h incubation in 96-well plates was measured by CellTiter 96® Aqueous One Solution. Cell cycle distribution was determined by flow cytometry. Fluorescence microscopy following acridine orange and ethidium bromide dual staining and procaspase-3 cleavage were used to detect apoptosis. Western-blot was employed to measure protein expression. Results: d-δ-Tocotrienol induced dose-dependent suppression of cell proliferation with 50% inhibitory concentrations (IC50) of 37.5±1.4 (A2058) and 22.3±1.8 (A375) μmol/l, respectively (data are reported as mean±standard deviation). d-δ-Tocotrienol-mediated cell cycle arrest at the G1 phase was accompanied by reduced expression of cyclin-dependent kinase 4. Concomitantly, d- δ-tocotrienol induced caspase-3 activation and apoptosis. The impact of d-δ-tocotrienol on A2058 cell proliferation was potentiated by lovastatin (IC50=3.1±0.5 μmol/l), a competitive inhibitor of HMG CoA reductase. Conclusion: d-δ-Tocotrienol may have potential application in melanoma chemoprevention and/or therapy