Dr. Ron’s Research Review – September 12, 2012

This week’s research review focuses on Tocotrienols / Tocopherols and breast cancer

Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea, and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in gamma- and delta-tocopherols for 9 weeks. Mammary tumor growth was suppressed by 38%, 50%, or 80%, respectively. (Lee, Ju et al. 2009)

Epidemiological studies suggest that a low vitamin E status is associated with increased cancer risk. However, several recent large-scale human trials with high doses of alpha-tocopherol have produced disappointing results. Using a naturally occurring tocopherol mixture that is rich in gamma-T, we demonstrated the inhibition of chemically induced lung, colon, and mammary cancer formation as well as the growth of xenograft tumors derived from human lung and prostate cancer cells. (Yang and Suh 2012)

While tocopherols have failed to offer protection, tocotrienols, in particular, alpha-, delta-, and gamma-tocotrienols alone and in combination have demonstrated anticancer properties. Specific tocotrienols increase ERbeta translocation into the nucleus which, in turn, activates the expression of estrogen-responsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERbeta cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERbeta is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. (Nesaretnam, Meganathan et al. 2012)

Hypomethylated (gamma and delta) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. Hypomethylated "highly metabolized" T3 may result in cytoprotection and cancer prevention or even chemotherapeutic effects. (Viola, Pilolli et al. 2012)

Dr. Ron


Articles

Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma

            (Lee, Ju et al. 2009) Download

PURPOSE: Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of alpha-tocopherol (vitamin E) have been studied for decades, recent intervention studies with alpha-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of four isoforms, which are the alpha, beta, gamma, and delta 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 gamma- and delta-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 gamma- and delta-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-gamma, and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that gamma- and delta-tocopherols, but not alpha-tocopherol, activated peroxisome proliferator activated receptor-gamma and antagonized estrogen action in breast cancer. CONCLUSION: The results suggest that gamma- and delta-tocopherols may be effective agents for the prevention of breast cancer.

Tocotrienols and breast cancer: the evidence to date

            (Nesaretnam, Meganathan et al. 2012) Download

Breast cancer is the second most frequent cancer affecting women worldwide after lung cancer. The toxicity factor associated with synthetic drugs has turned the attention toward natural compounds as the primary focus of interest as anticancer agents. Vitamin E derivatives consisting of the well-established tocopherols and their analogs namely tocotrienols have been extensively studied due to their remarkable biological properties. While tocopherols have failed to offer protection, tocotrienols, in particular, alpha-, delta-, and gamma-tocotrienols alone and in combination have demonstrated anticancer properties. The discovery of the antiangiogenic, antiproliferative, and apoptotic effects of tocotrienols, as well as their role as an inducer of immunological functions, not only reveals a new horizon as a potent antitumor agent but also reinforces the notion that tocotrienols are indeed more than antioxidants. On the basis of a transcriptomic platform, we have recently demonstrated a novel mechanism for tocotrienol activity that involves estrogen receptor (ER) signaling. In silico simulations and in vitro binding analyses indicate a high affinity of specific forms of tocotrienols for ERbeta, but not for ERalpha. Moreover, we have demonstrated that specific tocotrienols increase ERbeta translocation into the nucleus which, in turn, activates the expression of estrogen-responsive genes (MIC-1, EGR-1 and Cathepsin D) in breast cancer cells only expressing ERbeta cells (MDA-MB-231) and in cells expressing both ER isoforms (MCF-7). The binding of specific tocotrienol forms to ERbeta is associated with the alteration of cell morphology, caspase-3 activation, DNA fragmentation, and apoptosis. Furthermore, a recently concluded clinical trial seems to suggest that tocotrienols in combination with tamoxifen may have the potential to extend breast cancer-specific survival.

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

            (Viola, Pilolli et al. 2012) Download

The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (gamma and delta) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated "highly metabolized" T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.


Cancer Prevention by Different Forms of Tocopherols

            (Yang and Suh 2012) Download

Many epidemiological studies have suggested that a low vitamin E nutritional status is associated with increased cancer risk. However, several recent large-scale human trials with high doses of alpha-tocopherol (alpha-T) have produced disappointing results. This points out the need for a better understanding of the biological activities of the different forms of tocopherols. Using a naturally occurring tocopherol mixture (gamma-TmT) that is rich in gamma-T, we demonstrated the inhibition of chemically induced lung, colon, and mammary cancer formation as well as the growth of xenograft tumors derived from human lung and prostate cancer cells. This broad anticancer activity of gamma-TmT has been attributed mainly to the trapping of reactive oxygen and nitrogen species and inhibition of arachidonic acid metabolism. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) and the inhibition of estrogen signaling have also been observed in the inhibition of mammary cancer development. delta-T has been shown to be more active than gamma-T in inhibiting the growth of human lung cancer cells in a xenograft tumor model and the development of aberrant crypt foci in azoxymethane-treated rats, whereas alpha-T is not effective in these models. The higher inhibitory activities of delta-T and gamma-T (than alpha-T) are proposed to be due to their trapping of reactive nitrogen species and their capacity to generate side-chain degradation products, which retain the intact chromanol ring structure and could have cancer preventive activities.

References

Lee, H. J., J. Ju, et al. (2009). "Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma." Clin Cancer Res 15(12): 4242-9.

Nesaretnam, K., P. Meganathan, et al. (2012). "Tocotrienols and breast cancer: the evidence to date." Genes Nutr 7(1): 3-9.

Viola, V., F. Pilolli, et al. (2012). "Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E." Genes Nutr 7(1): 29-41.

Yang, C. S. and N. Suh (2012). "Cancer Prevention by Different Forms of Tocopherols." Top Curr Chem.