(helpful but can block drugs and other supplements, against ER+ or ER- cells, NOT w/TAM, NOT with punicic acid/Pomegranate, yes w/Paclitaxel, w/ERB inhibs, PI3k/Akt ERB3, tocotrienols important, anti CSC in PCa, Tocomin brand, w/statins, w/chemo)
Chin J Cancer. 2009 Oct;28(10):1114-8. Anticancer mechanisms of vitamin E succinate.
Dong YH, Guo YH, Gu XB.
Beijing Oriental TenGen Technological Development Co. Ltd., Beijing 100078, P. R. China. guoyinhan@163.com. Vitamin E succinate (RRR-alpha-tocopheryl succinate, VES) is an ester derivative of vitamin E. Roles of vitamin E (alpha-tocopherol) family in cancer prevention and therapy have been investigated since 1960s'. Experimental evidences indicated that VES is one of the most effective anticancer compounds of the vitamin E family. VES can effectively inhibit many kinds of tumors without toxic effects on normal cells and tissues. This article reviewed the anticancer mechanisms of VES in the following four aspects: 1) the molecular structure, chemical property and carrier of VES. 2) the mechanisms of VES in inhibiting cancer cell proliferation. 3) the mechanisms of VES-induced apoptosis of cancer cells. 4) the mechanisms of VES in preventing tumor metastasis. Investigation on the anticancer mechanisms of VES would help find new targets and develop new effective and safe drugs for cancer prevention and treatment.
PMID: 19799824 [PubMed - in process]
Anticancer Res. 2010 Jul;30(7):2869-74. gamma-Tocotrienol controls proliferation, modulates expression of cell cycle regulatory proteins and up-regulates quinone reductase NQO2 in MCF-7 breast cancer cells.
Hsieh TC, Elangovan S, Wu JM.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
BACKGROUND: Tocotrienols, a subgroup of the vitamin E family, have demonstrated antioxidant and anticancer properties. Differential growth responses among different types of tocotrienols have been observed in breast cancer cells; however, specific bioactivity of each individual tocotrienol remains to be elucidated.
MATERIALS AND METHODS: In this study, the effects of gamma-tocotrienol were examined with regard to its ability to suppress cell proliferation via modulation of cell cycle regulatory protein expression, and also from the perspective of control of cellular oxidoreductive status through regulation of detoxification enzymes, e.g., quinone reductase NQO2, using estrogen receptor-positive MCF-7 human breast cancer cells.
RESULTS: It was shown that treatment by gamma-tocotrienol suppressed MCF-7 cell proliferation in a dose- and time-dependent manner. Growth suppression by gamma-tocotrienol was accompanied by changes in the levels of cell cycle regulatory proteins, notably, Rb/E2F complex, cyclin D1/cdk4 and cyclin B1/cdk1, as exemplified by loss of cyclin D1, inhibition of specific Rb phosphorylation (pRb-p at Thr821), and by the time- and dose-dependent increase in the expression of NQO2.
CONCLUSION: By exerting control on expression of specific cell cycle regulatory proteins in concomitance with suppression of cell proliferation, as well as the induction of NQO2, gamma-tocotrienol offers promise as an added chemopreventive and/or chemotherapeutic agent against breast cancer carcinogenesis.
PMID: 20683025 [PubMed - indexed for MEDLINE]
Cell Prolif. 2010 Feb;43(1):77-83. Epub 2009 Nov 17. Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression.
Samant GV, Wali VB, Sylvester PW.
College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA. Abstract
OBJECTIVES: Previous studies have shown that gamma-tocotrienol induces potent anti-proliferative effects on +SA mammary tumour cells in culture; here, investigations have been conducted to determine its effects on intracellular signalling proteins involved in regulating cell cycle progression.
MATERIALS AND METHODS: +SA cells were maintained in mitogen-free defined media containing 0 or 4 micromgamma-tocotrienol, for 48 h to synchronize cell cycle in G(0) phase, and then they were exposed to 100 ng/ml EGF to initiate cell cycle progression. Whole cell lysates were collected at various time points from each treatment group and were prepared for Western blot analysis.
RESULTS AND CONCLUSIONS: Treatment with 4 micromgamma-tocotrienol significantly inhibited +SA cell proliferation over a 4-day culture period. Moreover, this treatment resulted in a relatively large reduction in cyclin D1, cyclin dependent kinase (CDK)4, CDK2 and CDK6 levels, between 4 and 24 h after EGF exposure. Tocotrienol treatment also resulted in a relatively large increase in CDK inhibitor (CKI) p27, prior to and after EGF exposure, but had little effect on levels of CKIs, p21 and p15. Tocotrienol treatment also induced a large relative reduction in retinoblastoma (Rb) protein phosphorylation at ser780 and ser807/811. These findings strongly suggest that anti-proliferative effects of gamma-tocotrienol are associated with reduction in cell cycle progression from G(1) to S, as evidenced by increased p27 levels, and a corresponding decrease in cyclin D1, CDK2, CDK4, CDK6 and phosphorylated Rb levels.
PMID: 19922488 [PubMed - indexed for MEDLINE]
Anticancer Res. 2008 Sep-Oct;28(5A):2641-7. Growth inhibition of human MDA-mB-231 breast cancer cells by delta-tocotrienol is associated with loss of cyclin D1/CDK4 expression and accompanying changes in the state of phosphorylation of the retinoblastoma tumor suppressor gene product.
Elangovan S, Hsieh TC, Wu JM.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Tocotrienols, a subgroup within the vitamin E family of compounds, have shown antiproliferative and anticancer properties, however, the molecular basis of these effects remains to be elucidated. In this study, the effect of 3-tocotrienol on cell cycle arrest was assessed by studying the retinoblastoma protein (Rb) levels and phosphorylation status, levels of E2F (a transcription factor critically involved in the G1/S-phase transition of the mammalian cell cycle; originally identified as a DNA-binding protein essential for early region 1A-dependent activation of the adenovirus promoter designated E2), and other cell cycle controlling proteins in estrogen receptor-negative MDA-MB-231 breast cancer cells. The cell growth assay demonstrated that exposure of the MDA-MB-231 cells to 6-tocotrienol (1-20 microM) resulted in a dose- and time-dependent inhibition of cell growth as compared with vehicle treated cells and the magnitude of growth inhibition was higher at 10 and 20 microM treatment for 48 and 72 h. The phosphorylation status of Rb plays a central role in the control of the cell cycle at the G0/G1-phase. delta-Tocotrienol treatment reduced the total Rb and its phosphorylation at the Ser780, Ser795, Ser 807/811 and Thr826 positions in a dose- and time-dependent fashion. The site-specific inhibition of the phosphorylation of Rb by delta-tocotrienol was tightly associated with a marked reduction in the expression of cyclin D1 and its regulatory partner cyclin-dependant kinase 4 (CDK4), which is responsible for the phosphorylation of Rb at Ser780, Ser795, Ser 807/811 and Thr826. In addition, delta-tocotrienol also reduced the expression of E2F that occurred simultaneously with the loss of Rb phosphorylation and inhibition of cell cycle progression. Interestingly, delta-tocotrienol also caused a marked reduction in the expression of G2/M regulatory proteins including cyclin B1 and CDK1. To the best of our knowledge, this study was the first to reveal that the target of cell proliferative inhibitory action of delta-tocotrienol in a model estrogen receptor-negative human breast cancer cell line MDA-MB-231 is mediated by the loss of cyclin D1 and associated suppression of site-specific Rb phosphorylation, suggesting its future development and use as an anticancer agent.
PMID: 19035289 [PubMed - indexed for MEDLINE]
Biomed Pharmacother. 2009 Nov 14. [Epub ahead of print] Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling.
Shirode AB, Sylvester PW.
College of Pharmacy, University of Louisiana, 700, University Avenue, Monroe, LA 71209-0470, United States. The selective cyclooxygenase (COX)-2 inhibitor, celecoxib, and the vitamin E isoform, gamma-tocotrienol, both display potent anticancer activity. However, high dose clinical use of selective COX-2 inhibitors has been limited by gastrointestinal and cardiovascular toxicity, whereas limited absorption and transport of gamma-tocotrienol by the body has made it difficult to obtain and sustain therapeutic levels in the blood and target tissues. Studies were conducted to characterize the synergistic anticancer antiproliferative effects of combined low dose celecoxib and gamma-tocotrienol treatment on mammary tumor cells in culture. The highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined control or treatment media. Treatment effects on COX-1, COX-2, Akt, NFkappaB and prostaglandin E(2) (PGE(2)) synthesis were assessed following a 3- or 4-day culture period. Treatment with 3-4muM gamma-tocotrienol or 7.5-10muM celecoxib alone significantly inhibited +SA cell growth in a dose-responsive manner. However, combined treatment with subeffective doses of gamma-tocotrienol (0.25muM) and celecoxib (2.5muM) resulted in a synergistic antiproliferative effect, as determined by isobologram analysis, and this growth inhibitory effect was associated with a reduction in PGE(2) synthesis, and decrease in COX-2, phospho-Akt (active), and phospho-NFkappaB (active) levels. These results demonstrate that the synergistic anticancer effects of combined celecoxib and gamma-tocotrienol therapy are mediated by COX-2 dependent and independent mechanisms. These findings also suggest that combination therapy with these agents may provide enhanced therapeutic response in breast cancer patients, while avoiding the toxicity associated with high-dose COX-2 inhibitor monotherapy.
PMID: 19954924 [PubMed - as supplied by publisher]
Int J Cancer. 2010 Jul 8. [Epub ahead of print] Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population.
Emerging evidence supports that prostate cancer originates from a rare sub-population of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (gamma-T3) is one of the vitamin-E constituents which have been shown to have anticancer effects against a wide-range of human cancers. Recently, we have reported that gamma-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that gamma-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that gamma-T3 can down-regulate the expression of prostate CSC markers (CD133/CD44) in androgen independent (AI) prostate cancer cell lines (PC-3 & DU145), as evident from western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by gamma-T3 treatment. In addition, pre-treatment of PC-3 cells with gamma-T3 was found to suppress tumor initiation ability of the cells. More importantly, while CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to gamma-T3 treatment as the CD133-depleted population. Our data suggest that gamma-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.
PMID: 20617516 [PubMed - as supplied by publisher]
immuno-compromised mice with human-grafted prostate tumours were given two weeks' dosing of gamma-tocotrienol. Researchers saw that gamma-tocotrienol was selectively deposited in solid tumours, and this led to over 50% tumour shrinkage. Linked to this tumour shrinkage ability, gamma-tocotrienol showed two effects associated with the killing of cancer cells. Firstly, there was a decrease in the expression of two cell proteins (PCNA and Ki67) associated with cell proliferation. Secondly, there was the activation of cellular processes called caspase cascades that are associated with programmed cell death. These inhibitive properties have been previously reported in studies investigating the effect of gamma-tocotrienol on breast cancer and melanoma. Together, these data suggest a common mechanism by which gamma-tocotrienol is able to reverse the growth of cancer cells.
J Surg Res. 2009 May 1;153(1):143-7. Epub 2008 Apr 22. Vitamin E increases biomarkers of estrogen stimulation when taken with tamoxifen.
Peralta EA, Brewer AT, Louis S, Dunnington GL.
Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL 62794-9638, USA. eperalta@siumed.edu
BACKGROUND: Vitamin E (alpha-tocopherol acetate, AT) diminishes the antiproliferative effect of tamoxifen on breast cancer cells in vitro. METHODS: A prospective study of seven women taking tamoxifen for adjuvant therapy of breast cancer. Four who were already taking AT supplements had random core biopsies of the normal breast and again 30 days after discontinuing AT. Three who were not on AT had biopsies before and after adding AT 400 mg for 30 days. Biopsies were stained for estrogen receptor (ER) and the mitogen-activated protein kinase p-ERK. Tissue extracts were assayed for p-ERK by enzyme-linked immunosorbent assay. Serum levels of alpha-tocopherol and tamoxifen were measured. RESULTS: Five out of seven patients had lower tamoxifen levels while taking AT, four of these went to subtherapeutic levels. Biopsies showed 23% of ductal cells were ER positive when patients were off AT and 70% on AT (P = 0.02). P-ERK staining was 21% off AT and 82% on AT. Five of seven patients had significantly higher tissue p-ERK when on AT. CONCLUSIONS: Biomarkers of estrogen-stimulation (ER, progesterone receptor, and p-ERK) were higher in breast biopsies of women taking vitamin E supplements while taking tamoxifen. Findings suggest that vitamin E supplements may interfere with the therapeutic effects of tamoxifen.
PMID: 18468636 [PubMed - indexed for MEDLINE]
Int J Oncol. 2010 Feb;36(2):421-6. Punicic acid is an omega-5 fatty acid capable of inhibiting breast cancer proliferation.
Grossmann ME, Mizuno NK, Schuster T, Cleary MP.
University of Minnesota, Hormel Institute, Austin, MN 55912-3679, USA.
Pomegranate extracts have been used as anticancer agents and they contain a large number of potentially bioactive substances. Punicic acid is an omega-5 long chain polyunsaturated fatty acid found in Punica granatum (pomegranate) seed oil. A number of long chain fatty acids have been reported to have cancer preventive actions. Here we investigated the potential ability of punicic acid to affect growth of both an estrogen insensitive breast cancer cell line (MDA-MB-231) and an estrogen sensitive cell line developed from the MDA-MB-231 cells (MDA-ERalpha7). Proliferation was inhibited 92 and 96% for MDA-MB-231 and MDA-ERalpha7 cells, respectively compared to untreated cells by 40 microM punicic acid. Furthermore, punicic acid induced apoptosis in the MDA-MB-231 and MDA-ERalpha7 cells by 86 and 91%, respectively compared to untreated control cells and disrupted cellular mitochondrial membrane potential. We also investigated whether lipid oxidation was required for the function of punicic acid by adding 20 microM of the antioxidant tocotrienol to the assays. This resulted in reversal of the effects of punicic acid on proliferation inhibition, apoptosis and disruption of the mitochondrial membrane potential. Finally, we evaluated the role of PKC signaling in the anti-cancer effects of punicic acid by performing proliferation assays in the presence of the PKC inhibitor bisindolymaleimide I. Proliferation inhibition by punicic acid was partially blocked in both the MDA-MB-231 and MDA-ERalpha7 cells. These results suggest that punicic acid has breast cancer inhibitor properties that are dependent on lipid peroxidation and the PKC pathway.
PMID: 20043077 [PubMed - in process]
Cancer Sci. 2009 Sep 14. [Epub ahead of print] Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo.
Kanai K, Kikuchi E, Mikami S, Suzuki E, Uchida Y, Kodaira K, Miyajima A, Ohigashi T, Nakashima J, Oya M.
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
There have been several studies on the antitumor activities of vitamin E succinate (alpha-TOS) as complementary and alternative medicine. In the present study, we investigated the cytotoxic effect of alpha-TOS and the enhancement of chemosensitivity to paclitaxel by alpha-TOS in bladder cancer. KU-19-19 and 5637 bladder cancer cell lines were cultured in alpha-TOS and/or paclitaxel in vitro. Cell viability, flow cytometric analysis, and nuclear factor-kappa B (NF-kappaB) activity were analyzed. For in vivo therapeutic experiments, pre-established KU-19-19 tumors were treated with alpha-TOS and/or paclitaxel. In KU-19-19 and 5637 cells, the combination treatment resulted in a significantly higher level of growth inhibition, and apoptosis was significantly induced by the combination treatment. NF-kappaB was activated by paclitaxel; however, the activation of NF-kappaB was inhibited by alpha-TOS. Also, the combination treatment significantly inhibited tumor growth in mice. In the immunostaining of the tumors, apoptosis was induced and proliferation was inhibited by the combination treatment. Combination treatment of alpha-TOS and paclitaxel showed promising anticancer effects in terms of inhibiting bladder cancer cell growth and viability in vitro and in vivo. One of the potential mechanisms by which the combination therapy has synergistic cytotoxic effects against bladder cancer may be that alpha-TOS inhibits NF-kappaB induced by chemotherapeutic agents. (Cancer Sci 2009).
PMID: 19824995 [PubMed - as supplied by publisher]
Clin Cancer Res. 2009 Jan 1;15(1):190-200.
RRR-alpha-vitamin E succinate potentiates the antitumor effect of calcitriol in prostate cancer without overt side effects.
Yin Y, Ni J, Chen M, Guo Y, Yeh S.
Department of Urology and Pathology, University of Rochester Medical Center, Rochester, New York, USA.
Shuyuan Yeh, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642. Phone: 585-273-2750; Fax: 585-756-4133; E-mail: shuyuan_yeh@urmc.rochester.edu.
Abstract
PURPOSE: To determine the antitumor efficacy of using calcitriol combined with RRR-alpha-vitamin E succinate (VES) on prostate cancer. EXPERIMENTAL DESIGN: The effects of VES or VES in combination with calcitriol on the calcitriol target genes were evaluated by Western blot and real-time PCR. The antiproliferation effect of the combination in prostate cancer cells was evaluated by the combination index method. The role of the vitamin D(3) receptor (VDR) in the enhanced antitumor effects of the combination was confirmed by small interfering RNA knockdown strategy. Xenograft-bearing mice were used to reaffirm the antitumor efficacy of this combination. Pathohistology analyses and expressions of VDR and its target genes were analyzed in untreated and treated tumors. RESULTS: VES selectively increased VDR protein in different prostate cancer cells. Low doses of calcitriol combined with VES were significantly superior to the additive effect of individual treatments against prostate cancer cell proliferation. The expression of VDR target genes involved in antiproliferation were further sensitized in the presence of VES. Knockdown of VDR expression abolished the combination benefits in LNCaP and PC3 cells. Consistently, in prostate cancer xenograft models, VES enhanced the therapeutic efficacy of a tolerated dose of calcitriol yet without overt evidence of systemic toxicity and hypercalcemia. This notable in vivo effect was also accompanied by up-regulation of VDR target genes. CONCLUSIONS: Low-dose calcitriol combined with vitamin E analogue could be a solution to the calcemic side effect. The demonstration of superior antitumor activity of low-dose calcitriol plus VES provides the preclinical basis for developing a useful therapeutic strategy for prostate cancer.
PMID: 19118046 [PubMed - indexed for MEDLINE]Free Article
Quote:
Translational Relevance
Because vitamin E succinate and calcitriol have been applied in different clinical trials in combination with other agents for prostate cancer therapy, it is a relatively small and close step to initiate clinical trials of vitamin E succinate plus calcitriol to treat prostate cancer. What is important is showing persuasive evidence to prove that combined vitamin E succinate and calcitriol to treat prostate cancer is effective. Our data indeed provide solid and supportive evidence both in prostate cancer cells and in preclinical animal cancer models. Thus, the potential impact of this study could be profound for developing an alternative and improved strategy to treat prostate cancer.
Nutr Cancer. 2008;60(3):401-11. Vitamin E analog alpha-TEA, methylseleninic acid, and trans-resveratrol in combination synergistically inhibit human breast cancer cell growth.
Snyder RM, Yu W, Jia L, Sanders BG, Kline K.
Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, Texas 78712-1097, USA.
Alpha-tocopherol ether-linked acetic acid analog [2,5,7,8-tetramethyl-2R-(4R, 8R-12-trimethyltridecyl) chroman-6-yloxyacetic acid (alpha-TEA)] is a novel form of vitamin E effective at killing cancer cells but not normal cells. alpha -TEA alone and together with methylseleninic acid (MSA) and trans-resveratrol (t-RES) were investigated for ability to induce apoptosis, DNA synthesis arrest, and cellular differentiation and inhibit colony formation in human MDA-MB-435-F-L breast cancer cells in culture. The 3 agents alone were effective in inhibiting cell growth by each of the 4 different assays, and 3-way combination treatments synergistically inhibited cell proliferation in each assay in comparison to individual treatments. Furthermore, combinations of alpha -TEA, t-RES, and MSA significantly enhanced levels of apoptosis in human breast (MDA-MB-231, MCF7, and T47D) and prostate (LnCaP, PC-3, and DU-145) cancer cell lines as well as in immortalized but nontumorigenic MCF10A cells but not primary cultures of human mammary epithelial cells. Western immunoblotting confirmed the induction of apoptosis in that the 3 agents induced poly(adenosine diphosphate-ribose) polymerase cleavage, with earlier detection and more complete cleavage seen in the combination treatment. Mechanistic studies showed combination treatments to inhibit cell proliferation via downregulation of cyclin D1 and induce apoptosis via activation of caspases 8 and 9 and downregulation of prosurvival proteins FLIP and survivin. In summary, the combination of alpha-TEA, MSA, and t-RES is more effective than single treatments for inhibiting cell proliferation, inducing cellular differentiation, and inducing cell death by apoptosis in human cancer cells in culture.
PMID: 18444175 [PubMed - indexed for MEDLINE]
Lipids. 1998 May;33(5):461-9. Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status.
Nesaretnam K, Stephen R, Dils R, Darbre P.
Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, England. sarnesar@porim.gov.my Potential antiproliferative effects of tocotrienols, the major vitamin E component in palm oil, were investigated on the growth of both estrogen-responsive (ER+) MCF7 human breast cancer cells and estrogen-unresponsive (ER-) MDA-MB-231 human breast cancer cells, and effects were compared with those of alpha-tocopherol (alphaT). The tocotrienol-rich fraction (TRF) of palm oil inhibited growth of MCF7 cells in both the presence and absence of estradiol with a nonlinear dose-response but such that complete suppression of growth was achieved at 8 microg/mL. MDA-MB-231 cells were also inhibited by TRF but with a linear dose-response such that 20 microg/mL TRF was needed for complete growth suppression. Separation of the TRF into individual tocotrienols revealed that all fractions could inhibit growth of both ER+ and ER- cells and of ER+ cells in both the presence and absence of estradiol. However, the gamma- and delta-fractions were the most inhibitory. Complete inhibition of MCF7 cell growth was achieved at 6 microg/mL of gamma-tocotrienol/delta-tocotrienol (gammaT3/deltaT3) in the absence of estradiol and 10 microg/mL of deltaT3 in the presence of estradiol, whereas complete suppression of MDA-MB-231 cell growth was not achieved even at concentrations of 10 microg/mL of deltaT3. By contrast to these inhibitory effects of tocotrienols, alphaT had no inhibitory effect on MCF7 cell growth in either the presence or the absence of estradiol, nor on MDA-MB-231 cell growth. These results confirm studies using other sublines of human breast cancer cells and demonstrate that tocotrienols can exert direct inhibitory effects on the growth of breast cancer cells. In searching for the mechanism of inhibition, studies of the effects of TRF on estrogen-regulated pS2 gene expression in MCF7 cells showed that tocotrienols do not act via an estrogen receptor-mediated pathway and must therefore act differently from estrogen antagonists. Furthermore, tocotrienols did not increase levels of growth-inhibitory insulin-like growth factor binding proteins (IGFBP) in MCF7 cells, implying also a different mechanism from that proposed for retinoic acid inhibition of estrogen-responsive breast cancer cell growth. Inhibition of the growth of breast cancer cells by tocotrienols could have important clinical implications not only because tocotrienols are able to inhibit the growth of both ER+ and ER- phenotypes but also because ER+ cells could be growth-inhibited in the presence as well as in the absence of estradiol. Future clinical applications of TRF could come from potential growth suppression of ER+ breast cancer cells otherwise resistant to growth inhibition by antiestrogens and retinoic acid.
Samant GV, Sylvester PW.
College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209-0470, USA. The antiproliferative effects of gamma-tocotrienol are associated with suppression in epidermal growth factor (EGF)-dependent phosphatidylinositol-3-kinase (PI3K)/PI3K-dependent kinase-1 (PDK-1)/Akt mitogenic signalling in neoplastic mammary epithelial cells. Studies were conducted to investigate the direct effects of gamma-tocotrienol treatment on specific components within the PI3K/PDK-1/Akt mitogenic pathway. +SA cells were grown in culture and maintained in serum-free media containing 10 ng/ml EGF as a mitogen. Treatment with 0-8 microm gamma-tocotrienol resulted in a dose-responsive decrease in the +SA cell growth and a corresponding decrease in phospho-Akt (active) levels. However, gamma-tocotrienol treatment had no direct inhibitory effect on Akt or PI3K enzymatic activity, suggesting that the inhibitory effects of gamma-tocotrienol occur upstream of PI3K, possibly at the level of the EGF-receptor (ErbB1). Additional studies were conducted to determine the effects of gamma-tocotrienol on ErbB receptor activation. Results showed that gamma-tocotrienol treatment had little or no effect on ErbB1 or ErbB2 receptor tyrosine phosphorylation, a prerequisite for substrate interaction and signal transduction, but did cause a significant and progressive decrease in the ErbB3 tyrosine phosphorylation. Because ErbB1 or ErbB2 receptors form heterodimers with the ErbB3 receptor, and ErbB3 heterodimers have been shown to be the most potent activators of PI3K, these findings strongly suggest that the antiproliferative effects of gamma-tocotrienol in neoplastic +SA mouse mammary epithelial cells are mediated by a suppression in ErbB3-receptor tyrosine phosphorylation and subsequent reduction in PI3K/PDK-1/Akt mitogenic signalling.
PMID: 17109639 [PubMed - indexed for MEDLINE]
BMC Cancer. 2010 Mar 8;10(1):84. [Epub ahead of print] Enhanced antiproliferative and apoptotic response to combined treatment of gamma-tocotrienol with erlotinib or gefitinib in mammary tumor cells.
Bachawal SV, Wali VB, Sylvester PW.
ABSTRACT: BACKGROUND: Aberrant ErbB receptor signaling is associated with various types of malignancies. gamma-Tocotrienol is a member of the vitamin E family of compounds that displays potent anticancer activity that is associated with suppression in ErbB receptor phosphorylation and mitogenic signaling. Erlotinib and gefitinib are tyrosine kinase inhibitors that block ErbB1 receptor activation, whereas trastuzumab is a monoclonal antibody that has been designed to specifically inhibit ErbB2 receptor activation. However, the clinical effectiveness of these agents have been disappointing because of cooperation between different ErbB family members that can rescue cancer cells from agents directed against a single ErbB receptor subtype. It was hypothesized that targeting multiple ErbB receptor subtypes with combined treatment of gamma-tocotrienol and ErbB receptor inhibitors would provide greater anticancer effects than monotherapy targeting only a single ErbB receptor subtype. METHODS: Highly malignant mouse +SA mammary epithelial cells were maintained in culture on serum-free defined media containing 10ng/ml EGF as a mitogen. Cell viability wase determined by MTT assay, whereas Western blot and immunofluorescent staining was used to determine treatment effects on ErbB receptor subtype level and activation. Treatment-induced apoptosis was determined using annexin V staining and Western blot analysis of cleaved caspase-3 and PARP levels. RESULTS: Treatment with 3.5 uM gamma-tocotrienol, 0.5 uM erlotinib or 1.0 uM gefitinib alone, significantly inhibited +SA tumor cell growth. Combined treatment with subeffective doses of erlotinib (0.25 uM) or gefitinib (0.5 uM) with subeffective doses of gamma-tocotrienol (0.5-3.0 uM) significantly inhibited the growth and induced apoptosis in a dose-responsive manner. Trastuzumab treatment alone or in combination had no effect on +SA cell growth and viability. Combined treatment of gamma-tocotrienol with erlotinib or gefitinib also cause a large decrease in ErbB3, ErbB4, and to a lesser extent ErbB2 receptor levels, and EGF-dependent ErbB2-4 tyrosine phosphorylation (activation), but had no effect on ErbB1 receptor levels or activation. CONCLUSION: Combination treatment of gamma-tocotrienol with specific ErbB receptor inhibitors is more effective in reducing mammary tumor cell growth and viability than high dose monotherapy, suggesting that targeting multiple ErbB receptors with combination therapy may significantly improve the therapeutic response in breast cancer patients.
PMID: 20211018 [PubMed - as supplied by publisher]
Suggesting tocotrienols (TTs) element of "Vitamin E" are the therapeutic component:
Mol Nutr Food Res. 2010 Mar 19. [Epub ahead of print] Tocotrienols activity in MCF-7 breast cancer cells: Involvement of ERbeta signal transduction.
Comitato R, Leoni G, Canali R, Ambra R, Nesaretnam K, Virgili F.
National Research Institute for Food and Nutrition, Rome, Italy.
The term Vitamin E is utilized to describe eight molecules, subdivided into two groups, tocopherols and tocotrienols (TTs). It has been shown that specific TTs affect the growth of several lines of tumour cells, and that this activity is not shared by tocopherols. In agreement with these observations, a TTs-rich fraction from palm oil (PTRF) was reported to inhibit proliferation and induce apoptosis in several cancer cells. However, the molecular mechanism involved in TTs activity is still unclear. We have recently proposed that TTs pro-apoptotic activity involves estrogen receptor beta (ERbeta) signalling. In this study, we report that, in MCF-7 breast cancer cell, expressing both ERalpha and ERbeta, PTRF treatment increases ERbeta nuclear translocation, as demonstrated by immunofluorescence experiments and significantly inhibits ERalpha expression (-458.91-fold of change) and complete disappearing of the protein from the nucleus. Moreover, PTRF treatment induces ER-dependent genes expression (macrophage inhibitory cytokine-1, early growth response-1 and Cathepsin D) which is inhibited by the ER inhibitor, ICI 182.780, and induces DNA fragmentation. Finally, cDNA-array experiments suggest that the activation of specific pathways in cells treated with gamma-TT with respect to alpha-TT. Our data suggest a novel potential molecular mechanism for TTs activity.
PMID: 20306477 [PubMed - as supplied by publisher]
Mol Nutr Food Res. 2010 May;54(5):669-78. Tocotrienols activity in MCF-7 breast cancer cells: involvement of ERbeta signal transduction.
The term Vitamin E is utilized to describe eight molecules, subdivided into two groups, tocopherols and tocotrienols (TTs). It has been shown that specific TTs affect the growth of several lines of tumour cells, and that this activity is not shared by tocopherols. In agreement with these observations, a TTs-rich fraction from palm oil (PTRF) was reported to inhibit proliferation and induce apoptosis in several cancer cells. However, the molecular mechanism involved in TTs activity is still unclear. We have recently proposed that TTs pro-apoptotic activity involves estrogen receptor beta (ERbeta) signalling. In this study, we report that, in MCF-7 breast cancer cell, expressing both ERalpha and ERbeta, PTRF treatment increases ERbeta nuclear translocation, as demonstrated by immunofluorescence experiments and significantly inhibits ERalpha expression (-458.91-fold of change) and complete disappearing of the protein from the nucleus. Moreover, PTRF treatment induces ER-dependent genes expression (macrophage inhibitory cytokine-1, early growth response-1 and Cathepsin D) which is inhibited by the ER inhibitor, ICI 182.780, and induces DNA fragmentation. Finally, cDNA-array experiments suggest that the activation of specific pathways in cells treated with gamma-TT with respect to alpha-TT. Our data suggest a novel potential molecular mechanism for TTs activity.
PISCATAWAY, N.J.—Supplemental mixed tocotrienols may suppress prostate cancer formation and progression, according to a new study (Nutr Cancer. 2010;62(6):789-94. DOI: 10.1080/01635581003605896). Researchers from Rutgers University examined the impact of a mixed-tocotrienol diet against prostate tumorigenesis in the transgenic adenocarcinoma mouse prostate (TRAMP) mouse model, which bears close resemblance to the stages of human prostate cancer progression. Animals were fed 0.1, 0.3 or 1 percent mixed tocotrienols (as Tocomin®, from Carotech) in the diet from eight weeks to 24 weeks; the effects were compared to positive and negative control animals. The animals fed mixed tocotrienols had a lower incidence of tumor formation; while 73 percent of animals in the control group developed palpable tumors, only 38, 33 and 22 percent of mice in the 0.1, 0.3 and 1 percent, respective, Tocomin diets developed such tumors. Added tocotrienols also significantly reduced the levels of high-grade neoplastic lesions as compared to positive results, which was found to be associated with increased expression of proapoptotic proteins and modulation of other cell cycle regulatory proteins.
WH Leong, vice president of Edison, N.J.-based Carotech, commented the study outcome poses great potential “Prostate cancer is the second most common male cancer in most developed nations," he said. “The American Cancer Society estimated that for this year, about 217,000 new prostate cancer cases will be identified in the United States and 32,000 men will die of prostate cancer. … This study further supports the potential use of Tocomin full spectrum tocotrienol complex as a prostate cancer chemopreventive agent in humans."
Exp Biol Med (Maywood). 2009 Jun;234(6):639-50. Epub 2009 Apr 9. Combined treatment of gamma-tocotrienol with statins induce mammary tumor cell cycle arrest in G1.
Wali VB, Bachawal SV, Sylvester PW.
College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209-0470, USA.
Statins and gamma-tocotrienol (a rare isoform of vitamin E) both inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase activity and display anticancer activity. However, clinical application of statins has been limited by high dose toxicity. Previous studies showed that combined statin and gamma-tocotrienol treatment synergistically inhibits growth of highly malignant +SA mammary epithelial cells in culture. To investigate the mechanism mediating this growth inhibition, studies were conducted to determine the effect of combination low dose gamma-tocotrienol and statin treatment on +SA mammary tumor cell cycle progression. Treatment with 0.25 microM simvastatin, lovastatin, mevastatin, 10 microM pravastatin or 2.0 microM gamma-tocotrienol alone had no effect, while combined treatment of individual statins with gamma-tocotrienol significantly inhibited +SA cell proliferation during the 4-day culture period. Flow cytometric analysis demonstrated that combined treatment induced cell cycle arrest in G1. Additional studies showed that treatment with 0.25 microM simvastatin or 2 microM gamma-tocotrienol alone had no effect on the relative intracellular levels of cyclin D1, CDK2, CDK4 and CDK6, but combined treatment caused a large reduction in cyclin D1 and CDK2 levels. Combined treatments also caused a relatively large increase in p27, but had no effect on p21 and p15 levels, and resulted in a large reduction in retinoblastoma (Rb) protein phosphorylation at ser780 and ser807/811. Similar effects were observed following combined treatment of gamma-tocotrienol with low doses of lovastatin, mevastatin and pravastatin. These findings demonstrate that combination low dose statin and gamma-tocotrienol treatment induced mammary tumor cell cycle arrest at G1, resulting from an increase in p27 expression, and a corresponding decrease in cyclin D1, CDK2, and hypophosphorylation of Rb protein. These findings suggest that combined treatment of statins with gamma-tocotrienol may provide significant health benefits in the treatment of breast cancer in women, while avoiding myotoxicity associated with high dose statin monotherapy.
PMID: 19359655 [PubMed - indexed for MEDLINE]Free Article
J Biol Chem. 2010 Aug 18. [Epub ahead of print] {gamma}-Tocotrienol but not {gamma}-tocopherol blocks STAT3 cell signaling pathway through induction of protein tyrosine phosphatase SHP-1 and sensitizes tumor cells to chemotherapeutic agents.
Although gamma-tocotrienol (T3), a vitamin E isolated primarily from palm and rice bran oil, has been linked with anticancer activities, the mechanism of this action is poorly understood. In the present report, we investigated whether gamma-T3 can modulate STAT3 cell signaling pathway, closely linked to inflammation and tumorigenesis. We found that gamma-T3 but not gamma-tocopherol, the most common saturated form of Vitamin E, inhibited constitutive activation of STAT3 in a dose- and time-dependent manner and this inhibition was not cell type specific. gamma-T3 also inhibited STAT3 DNA binding. This correlated with inhibition of Src kinase and JAK1 and JAK2 kinases. Pervanadate reversed the gamma-T3-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. When examined further, we found that gamma-T3 induced the expression of the tyrosine phosphatase SHP-1, and gene-silencing of the SHP-1 by small interfering RNA abolished the ability of gamma-T3 to inhibit STAT3 activation, suggesting a vital role for SHP-1 in the action of this T3. Also gamma-T3 down modulated activation of STAT3 and induced SHP-1 in in vivo. Eventually, gamma-T3 down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G(1) phase of the cell cycle, and induction of apoptosis. This vitamin also sensitized the tumor cells to the apoptotic effects of thalidomide and bortezomib. Overall, our results suggest that gamma-T3 is a novel blocker of STAT3 activation pathway in both in vitro and in vivo and thus may have potential in prevention and treatment of cancers.
PMID: 20720018 [PubMed - as supplied by publisher]Free Article
Ah now, Rich, there ya go again! How will they patent Vit E?
BTW, those of us who take Vit E should always get the "Mixed tocopherols" Vit E. You want the natural form, so stay away from those products that begin with "d,l' as in d, l-alpha-tocopherol. Most Vit E is just d-alpha-tocopherol which is not balanced. The synthetic stuff will have the "d,l". You want the beta-, gamma-, and delta-tocopherols along with the alpha.
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Smile On!
Laurel
Dx'd w/multifocal DCIS/IDS 3/08
7mm invasive component
Partial mast. 5/08
Stage 1b, ER 80%, PR 90%, HER-2 6.9 on FISH
0/5 nodes
4 AC, 4 TH finished 9/08
Herceptin every 3 weeks. Finished 7/09
Tamoxifen 10/08. Switched to Femara 8/09
Bilat SPM w/reconstruction 10/08
Clinical Trial w/Clondronate 12/08
Stopped Clondronate--too hard on my gizzard!
Switched back to Tamoxifen due to tendon pain from Femara
15 Years NED
I think I just might hang around awhile....
Linear Mode
