College of Pharmacy, University of Louisiana at Monroe, 700 University Ave, Monroe, LA 71209-0470, USA.
Anticancer Agents Med Chem. 2013 Sep;13(7):1039-47. doi: 10.2174/18715206113139990116.
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.
PI3K/Akt 信号通路介导各种类型癌细胞中的有丝分裂原依赖性生长和存活，抑制该通路会导致肿瘤细胞生长停滞和凋亡。生育三烯酚是维生素 E 的天然形式，在治疗剂量下具有很强的抗癌活性，而对正常细胞活力几乎没有影响。机制研究表明，γ-生育三烯酚的抗癌作用与 PI3K/Akt 信号的抑制有关。进一步的研究表明，γ-生育三烯酚的细胞毒性 LD50 剂量比生长抑制 IC50 治疗剂量高 3-5 倍，这表明 γ-生育三烯酚的细胞毒性和抗增殖作用可能通过不同的机制介导。然而，γ-生育三烯酚诱导的乳腺癌细胞中的 caspase 激活和凋亡也与细胞内 PI3K/Akt 信号的抑制以及随后的 FLIP（caspase 加工和激活的内源性抑制剂）下调有关。由于乳腺癌细胞对 γ-生育三烯酚抑制 PI3K/Akt 信号的作用比正常细胞更为敏感，这些发现表明 γ-生育三烯酚可能在降低女性患乳腺癌的风险方面提供显著的健康益处。研究还表明，γ-生育三烯酚与其他化疗药物联合治疗可导致协同抗癌反应。当 γ-生育三烯酚的抗癌作用机制与其他药物互补时，联合治疗最为有效，可在预防和/或治疗乳腺癌方面提供显著的健康益处，同时避免与高剂量单一疗法相关的肿瘤耐药或毒性作用。
