γ-Tocotrienol Inhibits Neoplastic Mammary Epithelial Cell Proliferation by Decreasing Akt and Nuclear Factor κB Activity

Abstract

Tocotrienols, a subgroup within the vitamin E family of compounds, have been shown to display potent anticancer activity and inhibit preneoplastic and neoplastic mammary epithelial cell proliferation at treatment doses that have little or no effect on normal cell growth and function. However, the specific intracellular mechanisms mediating the antiproliferative effects of tocotrienols are presently unknown. Because Akt and nuclear factor kappaB (NFkappaB) are intimately involved in mammary tumor cell proliferation and survival, studies were conducted to determine the effects of gamma-tocotrienol on Akt and NFkappaB activity in neoplastic +SA mammary epithelial cells in vitro. Treatment with 0-8 microM gamma-tocotrienol for 0-3 days caused a dose-responsive inhibition in +SA cell growth and mitotic activity, as determined by MTT colorimetric assay and proliferating cell nuclear antigen immunocytochemical staining, respectively. Studies also showed that treatment with 4 microM gamma-tocotrienol, a dose that inhibited +SA cell growth by more than 50% compared with that of untreated control cells, decreased intracellular levels of activated phosphotidylinositol 3-kinase-dependent kinase (PI3K)-dependent kinase 1 (phospho-PDK-1) and Akt, and reduced phospho-Akt kinase activity. Furthermore, these effects were not found to be associated with an increase in either phosphatase and tensin homologue deleted from chromosome 10 (PTEN) or protein phosphatase type 2A phosphatase activity. In addition, gamma-tocotrienol treatment was shown to decrease NFkappaB transcriptional activity, apparently by suppressing the activation of IkappaB-kinase-alpha/beta, an enzyme associated with inducing NFkappaB activation. In summary, these findings demonstrate that the antiproliferative effects of gamma-tocotrienol result, at least in part, from a reduction in Akt and NFkappaB activity in neoplastic +SA mammary epithelial cells.

γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors

“…T3 has the potency to induce apoptosis in a variety of cancer cell types (types 1-5). It has also been shown to downregulate the phosphatidylinositol 3-kinase/phosphoinositide-dependent kinase-1, AKT pathway (26,27) and c-myc expression (28) and to activate caspase-3, caspase-8, and caspase-9 (16,28,29). Despite this evidence, although more than 15,000 reports have been published on TPs, only 600 reports have been published on T3s, indicating a big gap in information available on the two types of vitamin E. Failure of recent clinical trials with TP against prostate cancer, costing more than US$143 million, further questions the usefulness of this vitamin.…”

γ-Tocotrienol Inhibits Nuclear Factor-κB Signaling Pathway through Inhibition of Receptor-interacting Protein and TAK1 Leading to Suppression of Antiapoptotic Gene Products and Potentiation of Apoptosis

“…Constitutively active NF-B has been found in a wide variety of leukemic and tumor epithelial cells (44), and it is needed for the proliferation of those cells (43,82). The inhibition of the proliferation of neoplastic mammary epithelial cells by tocotrienols has been suggested to correlate with inhibition of NF-B activity (83). Why tumor cells express constitutively active NF-B is not fully understood, but the role of IKK has been implicated (43,82).…”

Tocotrienols fight cancer by targeting multiple cell signaling pathways

“…A number of PI3K pathway inhibitors have been developed and are being evaluated in preclinical studies and early clinical trials (Courtney et al 2010). Tocotrienol has been shown to inhibit PI3K/Pl3K-dependent kinase 1 (Pdk-1)/Akt signaling in a phosphatase and tensin homologue deleted from chromosome 10 (PTEN) and in protein phosphatase type 2A independent manner in neoplastic mammary epithelial cells (Sylvester et al 2005;Shah and Sylvester 2005a). Samant and Sylvester (2006) found that the effect of tocotrienol on PI3K/Pdk-1/Akt signaling is mediated through the suppression of ErbB3-receptor tyrosine phosphorylation in neoplastic mammary epithelial cells.…”