TOCOTRIENOLS INHIBIT THE GROWTH OF HUMAN BREAST-CANCER CELLS IRRESPECTIVE OF ESTROGEN-RECEPTOR STATUS

Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estr ogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unre sponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alpha T). The tocotrienol-ric h fraction (TRF) of palm oil inhibited growth of MCF7 cells in both th e presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 mu g/mL. M DA-MB-231 cells were also inhibited by TRF but with a linear dose-resp onse such that 20 mu g/mL TRF was needed for complete growth suppressi on. Separation of the TRF into individual tocotrienols revealed that a ll fractions could inhibit growth of both ER+ and ER-cells and of ERcells in both the presence and absence of estradiol. However, the gamm a- and delta-fractions were the most inhibitory. Complete inhibition o f MCF7 cell growth was achieved at 6 mu g/mL of gamma-tocotrienol/delt a-tocotrienol (gamma T-3/delta T-3) in the absence of estradiol and 10 mu g/mL of delta T-3 in the presence of estradiol, whereas complete s uppression of MDA-MB-231 cell growth was not achieved even at concentr ations of 10 mu g/mL of delta T-3. By contrast to these inhibitory eff ects of tocotrienols, alpha T had no inhibitory effect on MCF7 cell gr owth in either the presence or the absence of estradiol, nor on MDA-MB -231 cell growth. These results confirm studies using other sublines o f human breast cancer cells and demonstrate that tocotrienols can exer t direct inhibitory effects on the growth of breast cancer cells. In s earching for the mechanism of inhibition, studies of the effects of TR F on estrogen-regulated p52 gene expression in MCF7 cells showed that tocotrienols do not act via an estrogen receptor-mediated pathway and must therefore act differently from estrogen antagonists. Furthermore, tocotrienols did not increase levels of growth-inhibitory insulin-lik e growth factor binding proteins (IGFBP) in MCF7 cells, implying also a different mechanism from that proposed for retinoic acid inhibition of estrogen-responsive breast cancer cell growth. Inhibition of the gr owth of breast cancer cells by tocotrienols could have important clini cal implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells coul d be growth-inhibited in the presence as well as in the absence of est radiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to g rowth inhibition by antiestrogens and retinoic acid.