Vitamin E is a generic term that refers to a family of compounds that is further divided into two subgroups called tocopherols and tocotrienols. Although all natural forms of vitamin E display potent antioxidant activity, tocotrienols are significantly more potent than tocopherols in inhibiting tumor cell growth and viability, and anticancer activity of tocotrienols is mediated independently of their antioxidant activity. In addition, the anticancer effects of tocotrienols are observed using treatment doses that have little or no effect on normal cell function or viability. This review will summarize experimental studies that have identified the intracellular mechanism mediating the anticancer effects of tocotrienols. Evidence is also provided showing that combined treatment of tocotrienol with other cancer chemotherapies can result in a synergistic inhibition in cancer cell growth and viability. Taken together, these findings strongly indicate that tocotrienols may provide significant health benefits in the prevention and/or treatment of cancer when used either alone as monotherapy or in combination with other anticancer agents.
γ-Tocotrienol is a natural vitamin E that displays potent anticancer activity, and previous studies suggest that these effects involve alterations in PPARγ activity. Treatment with 0.5–6 μM γ-tocotrienol, 0.4–50 μM PPARγ agonists (rosiglitazone or troglitazone), or 0.4–25 μM PPARγ antagonists (GW9662 or T0070907) alone resulted in a dose-responsive inhibition of MCF-7 and MDA-MB-231 breast cancer proliferation. However, combined treatment of 1–4 μM γ-tocotrienol with PPARγ agonists reversed the growth inhibitory effects of γ-tocotrienol, whereas combined treatment of 1–4 μM γ-tocotrienol with PPARγ antagonists synergistically inhibited MCF-7 and MDA-MB-231 cell growth. Combined treatment of γ-tocotrienol and PPARγ agonists caused an increase in transcription activity of PPARγ along with increased expression of PPARγ and RXR, and decrease in PPARγ coactivators, CBP p/300, CBP C-20, and SRC-1, in both breast cancer cell lines. In contrast, combined treatment of γ-tocotrienol with PPARγ antagonists resulted in a decrease in transcription activity of PPARγ, along with decreased expression of PPARγ and RXR, increase in PPARγ coactivators, and corresponding decrease in PI3K/Akt mitogenic signaling in these cells. These findings suggest that elevations in PPARγ are correlated with increased breast cancer growth and survival, and treatment that decreases PPARγ expression may provide benefit in the treatment of breast cancer.
Previous findings showed that the anticancer effects of combined γ-tocotrienol and peroxisome proliferator activated receptor γ (PPARγ) antagonist treatment caused a large reduction in PPARγ expression. However, other studies suggest that the antiproliferative effects of γ-tocotrienol and/or PPARγ antagonists are mediated, at least in part, through PPARγ-independent mechanism(s). Studies were conducted to characterize the role of PPARγ in mediating the effects of combined treatment of γ-tocotrienol with PPARγ agonists or antagonists on the growth of PPARγ negative +SA mammary cells and PPARγ-positive and PPARγ-silenced MCF-7 and MDA-MB-231 breast cancer cells. Combined treatment of γ-tocotrienol with PPARγ antagonist decreased, while combined treatment of γ-tocotrienol with PPARγ agonist increased, growth of all cancer cells. However, treatment with high doses of 15d-PGJ2, an endogenous natural ligand for PPARγ, had no effect on cancer cell growth. Western blot and qRT-PCR studies showed that the growth inhibitory effects of combined γ-tocotrienol and PPARγ antagonist treatment decreased cyclooxygenase (COX-2), prostaglandin synthase (PGDS), and prostaglandin D2 (PGD2) synthesis. In conclusion, the anticancer effects of combined γ-tocotrienol and PPARγ antagonists treatment in PPARγ negative/silenced breast cancer cells are mediated through PPARγ-independent mechanisms that are associated with a downregulation in COX-2, PGDS, and PGD2 synthesis.
The highly malignant +SA mouse mammary epithelial cells were used as the model cell line over the years to establish the anticancer activity of tocotrienols. Tocotrienols, however, have poor oral bioavailability and were therefore entrapped into parenteral nanoemulsions for parenteral administration. The objective of this work was to test whether the activity of tocotrienols in lipid nanoemulsions against the +SA cells was retained. A secondary objective was to test whether stabilizing the nanoemulsions with poloxamer or sodium oleate would affect their activity. Nanoemulsions were found to be significantly more potent than tocotrienol/albumin conjugate. The IC50 values of the poloxamer and sodium oleate nanoemulsions were 3 and 6 microM, respectively, whereas the IC50 value of the conjugate was 10 microM. The antiproliferative activity of the nanoemulsions was also found to inversely correlate with particle size. No activity was observed with nanoemulsions loaded with alpha-tocopherol or vehicle, which confirmed the cytotoxic activity of tocotrienols and the potential use of nanoemulsions in cancer therapy.
γ-Tocotrienol (γT3) is a member of the vitamin E family of compounds that displays potent antiproliferative effects against breast cancer cells. Recent studies have shown that combined treatment of subeffective doses of γ-T3 with subeffective doses of statins, cyclooxygenase-2 inhibitors, or EGF receptor inhibitors caused a synergistic inhibition in the highly malignant +SA mammary epithelial cell growth. Peroxisome proliferator-activated receptor gamma (PPARγ), a member of the nuclear receptor family is a ligand activated transcription factor that directly regulates transcription of target genes. The present study investigated the effects of γT3 used in combination with PPARγ agonists and antagonists on breast cancer cell growth in culture. Treatment with 0.5-6μM γT3, 0.4-50μM PPARγ agonist (rosiglitazone or troglitazone) or 0.4-25 PPARγ antagonist (GW9662 or T0070907) alone resulted in a dose-responsive inhibition of MCF-7 and MDA-MB-231 breast cancer cell growth. However, combined treatment with subeffective doses (2-3μM) of γT3 with subeffective doses (3-5μM) or PPARγ agonists was found to increase MCF-7 and MDA-MB-231 cell growth, whereas combined treatment with similar subeffective doses of γT3 with subeffective doses (4-6μM) of PPARγ antagonists was found to significantly inhibited growth of both breast cancer cell lines. Western blot analysis showed that combined treatment with similar subeffective doses of γT3 and PPARγ antagonists resulted in a relatively large decrease in the levels of phosphorylated PPARγ and its heterodimer partner, retinoid X receptor (RXR), in a time-dependent manner. In addition, combined treatment with these agents caused an overexpression of specific PPARγ transcriptional co-activators including, CREB-binding protein H-300 (CBP H-300), CBP C-20, and steroid receptor co-activator-1 (SRC-1). These results indicate that the anti-proliferative effects induced by combined treatment of γT3 with PPARγ antagonists are mediated through a PPARγ-dependent mechanism in these breast cancer cell lines. Additional studies showed that the antiproliferative effects induced by combined treatment with γT3 and PPARγ antagonists was also associated with a reduction in phosphatidylinositol-3-kinase (PI3K)/PI3-K-dependent kinase (PDK)/Akt mitogenic signaling in MCF-7 and MDA-MB-231 human breast cancer cell lines. In summary, these findings strongly suggest that the antiproliferative effects of combined treatment of γT3 and PPARγ antagonists in breast cancer cells are mediated by suppression in PPARγ-RXR phosphorylation and subsequent reduction in PI3K/PDK/Akt mitogenic signaling. This study was supported by a grant from First Tech International Ltd., and the Malaysian Palm Oil Council. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 150. doi:1538-7445.AM2012-150
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