INHIBITION OF PROLIFERATION OF ESTROGEN RECEPTOR-NEGATIVE MDA-MB-435 AND RECEPTOR-POSITIVE MCF-7 HUMAN BREAST-CANCER CELLS BY PALM OIL TOCOTRIENOLS AND TAMOXIFEN, ALONE AND IN COMBINATION

Tocotrienols are a form of vitamin E, having an unsaturated isoprenoid side-chain rather than the saturated side-chain of tocopherols. The t ocotrienol-rich fraction (TRF) from palm oil coritains alpha-tocophero l and a mixture of alpha-, gamma- and delta-tocotrienols. Earlier stud ies have shown that tocotrienols display anticancer activity. We previ ously reported that TRF, alpha-, gamma- and delta-tocotrienols inhibit ed proliferation of estrogen receptor-negative MDA-MB-435 human breast cancer cells with 50% inhibitory concentrations (IC50) of 180, 90, 30 and 90 mu g/mL, respectively, whereas alpha-tocopherol had no effect at concentrations up to 500 mu g/mL. Further experiments with estrogen receptor-positive MCF-7 cells showed that tocotrienols also inhibited their proliferation, as measured by [H-3] thymidine incorporation. Th e IC(50)s for TRF, alpha-tocopherol, alpha-, gamma- and delta-tocotrie nols were 4, 125, 6, 2 and 2 mu g/mL, respectively. Tamoxifen, a widel y used synthetic antiestrogen inhibits the growth of MCF-7 cells with an IC50 of 0.04 mu g/mL. We tested 1:1 combinations of TRF, alpha-toco pherol and the individual tocotrienols with tamoxifen in both cell lin es. In the MDA-MB-435 cells, all of the combinations were found to be synergistic. In the MCF-7 cells, only 1:1 combinations of gamma- or de lta-tocotrienol with tamoxifen showed a synergistic inhibitory effect on the proliferative rate and growth of the cells. The inhibition by t ocotrienols was not overcome by addition of excess estradiol to the me dium. These results suggest that tocotrienols are effective inhibitors of both estrogen receptor-negative and -positive cells and that combi nations with tamoxifen should be considered as a possible improvement in breast cancer therapy.