Mixed Tocopherols Prevent Mammary Tumorigenesis by Inhibiting Estrogen Action and Activating PPAR-γ

Abstract

Purpose: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of a-tocopherol (vitamin E) have been studied for decades, recent intervention studies with a-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the a, h, g, and y variants, and recent attention is being given to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in g-and y-tocopherols against mammary tumorigenesis. Experimental Design: Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in g-and y-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation, and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. Results: Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3, and peroxisome proliferator activated receptor-g, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that g-and y-tocopherols, but not a-tocopherol, activated peroxisome proliferator activated receptor-g and antagonized estrogen action in breast cancer. Conclusion:The results suggest that g-and y-tocopherols may be effective agents for the prevention of breast cancer.

Vitamin E supplementation and mammalian lifespan

“…However, P21 also shows ''antagonistic duality'' as it has pro-cancer properties under certain conditions [69]. In agreement with our findings, vitamin E deficiency decreased p21 expression in the liver of rats [70] and mixed tocopherol diets suppressed mammary tumour growth in female rats while increasing p21 expression levels [71]. In addition, vitamin E-induced apoptosis in colorectal cancer cell lines appears to be mediated through P21 via a mechanism involving a CCAAT/enhancer binding protein transcription factor C/EBPb, independent of P53 [72].…”

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

“…Hypomethylated forms, and particularly the gamma form of TOH, have been observed to activate cell cycle regulators such as p27/Rb both in vitro (Betti et al 2006) and in vivo (Lee et al 2009). Therefore, p21 and other genes directly or indirectly involved in cell cycle control, such as p27 and p53, may represent the real effectors in the anti-cancer signaling of T3, influencing the balance between signals that drive the cell into senescence pathways and cell cycle arrest or alternatively toward apoptotic cell death.…”

α‐Tocopheryl phosphate – An active lipid mediator?

“…In a rat ischemia/reperfusion model, aTP normalizes reduced phosphorylation of Akt, p44/42 mitogen activated kinase b (MAPK), p38 MAPK b, and NF-kB binding, but decreased phosphorylation of Src and MAPKa and increased survival by decreasing apoptosis [111]. In response to aT, both induction [127,133,134] and inhibition [125,135,136] of the PI3K/Akt pathway have been observed, and the cellular response may depend on the degree of conversion of aT to aTP in a given tissue and cell type.…”