The PI3K/Akt signaling pathway mediates mitogen-dependent growth and survival in various types of cancer cells, and
inhibition of this pathway results in tumor cell growth arrest and apoptosis. Tocotrienols are natural forms of vitamin E that displays
potent anticancer activity at treatment doses that had little or no effect on normal cell viability. Mechanistic studies revealed that the
anticancer effects of γ-tocotrienol were associated with a suppression in PI3K/Akt signaling. Additional studies showed that cytotoxic
LD50 doses of γ-tocotrienol were 3-5-fold higher than growth inhibitory IC50 treatment doses, suggesting that cytotoxic and
antiproliferative effects of γ-tocotrienol might be mediated through different mechanisms. However, γ-tocotrienol-induced caspase
activation and apoptosis in mammary tumor cells was also found to be associated with suppression in intracellular PI3K/Akt signaling
and subsequent down-regulation of FLIP, an endogenous inhibitor of caspase processing and activation. Since breast cancer cells are
significantly more sensitive to the inhibitory effects of γ-tocotrienol on PI3K/Akt signaling than normal cells, these findings suggest that
γ-tocotrienol may provide significant health benefits in reducing the risk of breast cancer in women. Studies have also shown that
combined treatment of γ-tocotrienol with other chemotherapeutic agents can result in a synergistic anticancer response. Combination
therapy was most effective when the anticancer mechanism of action of γ-tocotrienol is complimentary to that of the other drug and can
provide significant health benefits in the prevention and/or treatment of breast cancer, while at the same time avoiding tumor resistance
or toxic effects that is commonly associated with high dose monotherapy.
Keywords: Vitamin E, tocotrienols, PI3K, Akt, breast cancer.
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