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Planta Med 2012; 78(16): 1731-1739
DOI: 10.1055/s-0032-1315302
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Mechanisms Mediating the Synergistic Anticancer Effects of Combined γ-Tocotrienol and Sesamin Treatment

Mohamed R. Akl
1   College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, USA
,
Nehad M. Ayoub
1   College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, USA
,
Paul W. Sylvester
1   College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana, USA
› Author Affiliations
Further Information

Publication History

received 05 June 2012
revised 25 July 2012

accepted 07 August 2012

Publication Date:
17 September 2012 (online)

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Abstract

Epidemiological studies have highlighted the ability of phytochemicals to reduce the risk of breast cancer by attenuating specific intracellular signaling pathways that regulate cell proliferation and survival. γ-Tocotrienol is a natural form of vitamin E that displays potent anticancer activity at doses that have no discernible toxicity toward normal cells. Sesamin is an abundant phytochemical found in sesame seed oil that also shows antiproliferative and antiangiogenic activity against human breast cancer cells. In this study, the combined treatment of subeffective doses of γ-tocotrienol and sesamin caused a synergistic inhibition of murine +SA mammary epithelial cell growth, as determined by the MTT assay and immunofluorescent Ki-67 staining. Western blot studies revealed that combined low-dose treatment of γ-tocotrienol and sesamin caused a marked reduction in EGF-induced ErbB3 and ErbB4 receptors phosphorylation (activation) and a relatively large decrease in intracellular levels of total and/or phosphorylated c-Raf, MEK1/2, ERK1/2, PI3K, PDK1, Akt, p-NFκB, Jak1, Jak2, and Stat1, as compared to cells treated with only one compound or in the vehicle-treated control group. These findings demonstrate that the synergistic growth inhibitory effects of γ-tocotrienol and sesamin treatment are associated with suppression of EGF-dependent mitogenic signaling in mammary tumor cells and suggest that dietary supplementation with these phytochemicals may provide some benefits in the prevention and/or treatment of breast cancer.

Key words

γ-tocotrienol - sesamin - ErbB receptors - phytochemicals - breast cancer
 

  • References

  • 1 Amin A, Gali-Muhtasib H, Ocker M, Schneider-Stock R. Overview of major classes of plant-derived anticancer drugs. Int J Biomed Sci 2009; 5: 1-11
    Google Scholar
  • 2 Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992; 18: 1-29
    CrossrefPubMedGoogle Scholar
  • 3 Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996; 96: 1027-1039
    CrossrefPubMedGoogle Scholar
  • 4 Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, Griel AE, Etherton TD. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. Am J Med 2002; 113 (Suppl. 09) 71S-88S
    CrossrefPubMedGoogle Scholar
  • 5 Sylvester PW, Theriault A. Role of tocotrienols in the prevention of cardiovascular disease and breast cancer. Curr Top Nutraceut Res 2003; 1: 121-136
    PubMedGoogle Scholar
  • 6 Sylvester PW. Synergistic anticancer effects of combined gamma-tocotrienol with statin or receptor tyrosine kinase inhibitor treatment. Genes Nutr 2012; 7: 63-74
    CrossrefPubMedGoogle Scholar
  • 7 Shah S, Gapor A, Sylvester PW. Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. Nutr Cancer 2003; 45: 236-246
    CrossrefPubMedGoogle Scholar
  • 8 Samant GV, Sylvester PW. gamma-Tocotrienol inhibits ErbB3-dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells. Cell Prolif 2006; 39: 563-574
    CrossrefPubMedGoogle Scholar
  • 9 Shirode AB, Sylvester PW. Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling. Biomed Pharmacother 2010; 64: 327-332
    CrossrefPubMedGoogle Scholar
  • 10 Bachawal SV, Wali VB, Sylvester PW. Enhanced antiproliferative and apoptotic response to combined treatment of gamma-tocotrienol with erlotinib or gefitinib in mammary tumor cells. BMC Cancer 2010; 10: 84
    CrossrefPubMedGoogle Scholar
  • 11 Wali VB, Sylvester PW. Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells. Lipids 2007; 42: 1113-1123
    CrossrefPubMedGoogle Scholar
  • 12 Hirose N, Doi F, Ueki T, Akazawa K, Chijiiwa K, Sugano M, Akimoto K, Shimizu S, Yamada H. Suppressive effect of sesamin against 7,12-dimethylbenz[a]-anthracene induced rat mammary carcinogenesis. Anticancer Res 1992; 12: 1259-1265
    PubMedGoogle Scholar
  • 13 Yokota T, Matsuzaki Y, Koyama M, Hitomi T, Kawanaka M, Enoki-Konishi M, Okuyama Y, Takayasu J, Nishino H, Nishikawa A, Osawa T, Sakai T. Sesamin, a lignan of sesame, down-regulates cyclin D1 protein expression in human tumor cells. Cancer Sci 2007; 98: 1447-1453
    CrossrefPubMedGoogle Scholar
  • 14 Lee CC, Liu KJ, Wu YC, Lin SJ, Chang CC, Huang TS. Sesamin inhibits macrophage-induced vascular endothelial growth factor and matrix metalloproteinase-9 expression and proangiogenic activity in breast cancer cells. Inflammation 2011; 34: 209-221
    CrossrefPubMedGoogle Scholar
  • 15 Ikeda S, Toyoshima K, Yamashita K. Dietary sesame seeds elevate alpha- and gamma-tocotrienol concentrations in skin and adipose tissue of rats fed the tocotrienol-rich fraction extracted from palm oil. J Nutr 2001; 131: 2892-2897
    PubMedGoogle Scholar
  • 16 Yamada Y, Obayashi M, Ishikawa T, Kiso Y, Ono Y, Yamashita K. Dietary tocotrienol reduces UVB-induced skin damage and sesamin enhances tocotrienol effects in hairless mice. J Nutr Sci Vitaminol (Tokyo) 2008; 54: 117-123
    CrossrefPubMedGoogle Scholar
  • 17 Hardy KM, Booth BW, Hendrix MJ, Salomon DS, Strizzi L. ErbB/EGF signaling and EMT in mammary development and breast cancer. J Mammary Gland Biol Neoplasia 2010; 15: 191-199
    CrossrefPubMedGoogle Scholar
  • 18 Favoni RE, de Cupis A. The role of polypeptide growth factors in human carcinomas: new targets for a novel pharmacological approach. Pharmacol Rev 2000; 52: 179-206
    PubMedGoogle Scholar
  • 19 Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem 2000; 275: 8806-8811
    CrossrefPubMedGoogle Scholar
  • 20 Samant GV, Wali VB, Sylvester PW. Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif 2009; 43: 77-83
    PubMedGoogle Scholar
  • 21 Bachawal SV, Wali VB, Sylvester PW. Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells. Anticancer Res 2010; 30: 429-437
    PubMedGoogle Scholar
  • 22 Anderson LW, Danielson KG, Hosick HL. New cell line. Epithelial cell line and subline established from premalignant mouse mammary tissue. In Vitro 1979; 15: 841-843
    CrossrefPubMedGoogle Scholar
  • 23 Anderson LW, Danielson KG, Hosick HL. Metastatic potential of hyperplastic alveolar nodule derived mouse mammary tumor cells following intravenous inoculation. Eur J Cancer Clin Oncol 1981; 17: 1001-1008
    CrossrefPubMedGoogle Scholar
  • 24 Danielson KG, Anderson LW, Hosick HL. Selection and characterization in culture of mammary tumor cells with distinctive growth properties in vivo . Cancer Res 1980; 40: 1812-1819
    PubMedGoogle Scholar
  • 25 McIntyre BS, Briski KP, Gapor A, Sylvester PW. Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells. Proc Soc Exp Biol Med 2000; 224: 292-301
    CrossrefPubMedGoogle Scholar
  • 26 Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA 2004; 7: 13306-13311
    PubMedGoogle Scholar
  • 27 Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 1979; 76: 4350-4354
    CrossrefPubMedGoogle Scholar
  • 28 Urruticoechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 2005; 23: 7212-7220
    CrossrefPubMedGoogle Scholar
  • 29 Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res 2008; 68: 5878-5887
    CrossrefPubMedGoogle Scholar
  • 30 Monsey J, Shen W, Schlesinger P, Bose R. Her4 and Her2/neu tyrosine kinase domains dimerize and activate in a reconstituted in vitro system. J Biol Chem 2010; 285: 7035-7044
    CrossrefPubMedGoogle Scholar
  • 31 Furth PA, Nakles RE, Millman S, Diaz-Cruz ES, Cabrera MC. Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer. Breast Cancer Res 2011; 13: 220
    CrossrefPubMedGoogle Scholar