title: Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status.
abstract: Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estrogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unresponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alphaT). The tocotrienol-rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 microg/mL. MDA-MB-231 cells were also inhibited by TRF but with a linear dose-response such that 20 microg/mL TRF was needed for complete growth suppression. Separation of the TRF into individual tocotrienols revealed that all fractions could inhibit growth of both ER+ and ER- cells and of ER+ cells in both the presence and absence of estradiol. However, the gamma- and delta-fractions were the most inhibitory. Complete inhibition of MCF7 cell growth was achieved at 6 microg/mL of gamma-tocotrienol/delta-tocotrienol (gammaT3/deltaT3) in the absence of estradiol and 10 microg/mL of deltaT3 in the presence of estradiol, whereas complete suppression of MDA-MB-231 cell growth was not achieved even at concentrations of 10 microg/mL of deltaT3. By contrast to these inhibitory effects of tocotrienols, alphaT had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA-MB-231 cell growth. These results confirm studies using other sublines of human breast cancer cells and demonstrate that tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. In searching for the mechanism of inhibition, studies of the effects of TRF on estrogen-regulated pS2 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-like 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 growth of breast cancer cells by tocotrienols could have important clinical implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth-inhibited in the presence as well as in the absence of estradiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to growth inhibition by antiestrogens and retinoic acid.
authors.affiliation: Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, England. sarnesar@porim.gov.my
authors.forename: K
authors.initials: K
authors.lastname: Nesaretnam
authors.forename: R
authors.initials: R
authors.lastname: Stephen
authors.forename: R
authors.initials: R
authors.lastname: Dils
authors.forename: P
authors.initials: P
authors.lastname: Darbre
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000032:analysis*; D024508:Tocotrienols; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D011960:Receptors, Estrogen; D024508:Tocotrienols; D014810:Vitamin E; C082097:tocotrienol, delta; C082089:tocotrienol, beta; D004958:Estradiol; C082032:tocotrienol, alpha