Journal
ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY
Volume 13, Issue 7, Pages 1039-1047Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/18715206113139990116
Keywords
Vitamin E; tocotrienols; PI3K; Akt; breast cancer
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Funding
- NIH/NCI [CA86833]
- First Tec International Ltd. (Hong Kong)
- Malaysian Palm Oil Council (MPOC)
- Louisiana Cancer Foundation
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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 gamma-tocotrienol were associated with a suppression in PI3K/Akt signaling. Additional studies showed that cytotoxic LD50 doses of gamma-tocotrienol were 3-5-fold higher than growth inhibitory IC50 treatment doses, suggesting that cytotoxic and antiproliferative effects of gamma-tocotrienol might be mediated through different mechanisms. However, gamma-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 gamma-tocotrienol on PI3K/Akt signaling than normal cells, these findings suggest that gamma-tocotrienol may provide significant health benefits in reducing the risk of breast cancer in women. Studies have also shown that combined treatment of gamma-tocotrienol with other chemotherapeutic agents can result in a synergistic anticancer response. Combination therapy was most effective when the anticancer mechanism of action of gamma-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.
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