Tocotrienols, a subgroup within the vitamin E family of compounds, display potent antiproliferative and apoptotic activity against neoplastic mammary epithelial cells at treatment doses that have little or no effect on normal cell growth and function. Recent studies have shown that treatment with a growth inhibitory, but non-cytotoxic dose (4 microM) of gamma-tocotrienol inhibits phosphatidylinositol-3-kinase-dependent kinase (Pl3K)/Pl3K-dependent kinase 1 (PDK-1)/mitogenic signaling over a 2-3 day period following treatment exposure, and these effects were not found to be associated with an increased in either phosphatase and tensin homologue deleted from chromosome 10 (PTEN) or protein phosphatase type 2A (PP2A) phosphatase activity. In addition, this treatment caused a large decrease in NFKB transcriptional activity, apparently by suppressing I kappa B-kinase (IKK)-alpha/beta activation, an enzyme associated with inducing NFKB activation. Since Akt and NFkappaB are intimately involved in mammary tumor cell proliferation and survival, these findings strongly suggest that the antiproliferative effects of gamma-tocotrienol result, at least in part, from a reduction in Akt and NFkappa B activity. In contrast, treatment with 20 microM gamma-tocotrienol (cytotoxic dose) resulted in caspase-8 and -3 activation and apoptosis. It was also shown that this same treatment caused a rapid and large decrease in Pl3K/PDK/Akt signaling within 2-4h following treatment exposure, and a corresponding decrease in intracellular levels of FLIP, an antiapoptotic protein that inhibits caspase-8 activation. In summary, both the antiproliferative and apoptotic effects of gamma-tocotrienol appear to be mediated by a reduction in the Pl3K/PDK-1 /Akt signaling, an important pathway associated with cell proliferation and survival in neoplastic mammary epithelial cells.

中文翻译：

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介导γ-生育三烯酚在肿瘤乳腺上皮细胞中的抗增殖和凋亡作用的细胞内信号机制

生育三烯酚是维生素 E 化合物家族中的一个亚组，在对正常细胞生长和功能几乎没有影响或没有影响的治疗剂量下，对肿瘤性乳腺上皮细胞显示出有效的抗增殖和凋亡活性。最近的研究表明，用抑制生长但非细胞毒性剂量 (4 microM) 的 γ-生育三烯酚治疗可抑制磷脂酰肌醇 3-激酶依赖性激酶 (Pl3K)/Pl3K 依赖性激酶 1 (PDK-1)/促有丝分裂信号在治疗暴露后的 2-3 天期间，未发现这些影响与从 10 号染色体 (PTEN) 或 2A 型蛋白磷酸酶 (PP2A) 磷酸酶活性中删除的磷酸酶和张力蛋白同源物的增加有关。此外，这种处理导致 NFKB 转录活性的大幅下降，显然是通过抑制 IκB 激酶 (IKK)-α/β 激活，一种与诱导 NFKB 激活相关的酶。由于 Akt 和 NFkappaB 与乳腺肿瘤细胞的增殖和存活密切相关，因此这些发现强烈表明，γ-生育三烯酚的抗增殖作用至少部分来自 Akt 和 NFkappa B 活性的降低。相比之下，用 20 microM γ-生育三烯酚（细胞毒性剂量）治疗导致 caspase-8 和 -3 激活和细胞凋亡。还表明，同样的处理在处理暴露后 2-4 小时内导致 Pl3K/PDK/Akt 信号传导的快速和大量减少，以及细胞内 FLIP（一种抑制 caspase-8 激活的抗凋亡蛋白）水平的相应降低。总之，