Apoptotic Mechanisms of Tocotrienols in Mammary Cancer

Summary

Principal Investigator: P W Sylvester
Abstract: Tocopherols and tocotrienols represent the two subgroups in the vitamin E family of compounds. However, only tocotrienols display potent antiproliferative and apoptotic activity on mammary cancer cells using treatment doses that have no effect on normal mammary epithelial cell growth or viability. Determining the mechanism(s) mediating the anticancer effects of tocotrienols would provide essential information necessary for understanding the potential health benefits of these compounds in reducing the risk of breast cancer in women. Several signaling pathways have been identified that may be involved in mediating the inhibitory effects of tocotrienols. The specific aims of this proposal are: 1) to determine the role of vehicle fatty acid composition in modulating tocotrienol absorption and tissue distribution in vivo. Although the in vitro anticancer activity of tocotrienols are firmly established, and dietary intake of palm oil, the richest natural source of tocotrienols, inhibits carcinogen-induced mammary tumorigenesis, while palm oil diets stripped of tocotrienols have no protective effect, dietary supplementation of isolated tocotrienols has produced conflicting results in vivo. Since fat-soluble vitamins (tocotrienols) must be first emulsified by bile before absorption in the gut, and bile excretion is dependent upon the fatty acid composition in the diet, consumption of isolated tocotrienols alone is not sufficient to stimulate adequate bile excretion and is associated with the poor absorption of tocotrienols. It is believed that optimizing tocotrienol absorption and tissue distribution will enhance anticancer potency in vivo. 2) To determine the intracellular signaling mechanism(s) mediating the antiproliferative effects of tocotrienols in preneoplastic and neoplastic mammary epithelial cells in vitro. The antiproliferative effects of tocotrienols are associated with decreased signaling in multiple mitogenic pathways. However, the exact site(s) of action where tocotrienols act to inhibitory mitogenic signaling has not been determined; 3) To determine the intracellular signaling mechanism(s) mediating tocotrienol-induced caspase-8 activation and apoptosis in preneoplastic, neoplastic and malignant mammary epithelial cells in vitro. Although caspase-8 activation is associated with death receptor signaling, the exact receptor/ligand signaling mechanism(s) mediating tocotrienol-induced caspase-8 activation has not been determined.
Funding Period: 2000-07-01 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Tocotrienols target PI3K/Akt signaling in anti-breast cancer therapy
    Paul W Sylvester
    College of Pharmacy, University of Louisiana at Monroe, 700 University Ave, Monroe, LA 71209 0470, USA
    Anticancer Agents Med Chem 13:1039-47. 2013
  2. pmc Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling
    Amit B Shirode
    College of Pharmacy, University of Louisiana, 700 University Avenue, Monroe, LA 71209 0470, USA
    Biomed Pharmacother 64:327-32. 2010
  3. pmc Enhanced antiproliferative and apoptotic response to combined treatment of gamma-tocotrienol with erlotinib or gefitinib in mammary tumor cells
    Sunitha V Bachawal
    College of Pharmacy, University of Louisiana at Monroe, 700 University Ave, Monroe, Louisiana 71209, USA
    BMC Cancer 10:84. 2010
  4. ncbi Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells
    Sunitha V Bachawal
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA
    Anticancer Res 30:429-37. 2010
  5. ncbi The value of tocotrienols in the prevention and treatment of cancer
    Paul W Sylvester
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA
    J Am Coll Nutr 29:324S-333S. 2010
  6. ncbi Optimization of the tetrazolium dye (MTT) colorimetric assay for cellular growth and viability
    Paul W Sylvester
    Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA
    Methods Mol Biol 716:157-68. 2011
  7. ncbi Tocotrienol combination therapy results in synergistic anticancer response
    Paul W Sylvester
    College of Pharmacy, 700 University Avenue, University of Louisiana at Monroe, Monroe, LA 71209 0470, USA
    Front Biosci (Landmark Ed) 16:3183-95. 2011
  8. ncbi Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression
    G V Samant
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA
    Cell Prolif 43:77-83. 2010
  9. ncbi Suppression in mevalonate synthesis mediates antitumor effects of combined statin and gamma-tocotrienol treatment
    Vikram B Wali
    College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209 470, USA
    Lipids 44:925-34. 2009
  10. ncbi Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells
    Vikram B Wali
    University of Louisiana at Monroe, LA 71209, USA
    Apoptosis 14:1366-77. 2009

Scientific Experts

Detail Information

Publications20

  1. ncbi Tocotrienols target PI3K/Akt signaling in anti-breast cancer therapy
    Paul W Sylvester
    College of Pharmacy, University of Louisiana at Monroe, 700 University Ave, Monroe, LA 71209 0470, USA
    Anticancer Agents Med Chem 13:1039-47. 2013
    ....
  2. pmc Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling
    Amit B Shirode
    College of Pharmacy, University of Louisiana, 700 University Avenue, Monroe, LA 71209 0470, USA
    Biomed Pharmacother 64:327-32. 2010
    ..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...
  3. pmc Enhanced antiproliferative and apoptotic response to combined treatment of gamma-tocotrienol with erlotinib or gefitinib in mammary tumor cells
    Sunitha V Bachawal
    College of Pharmacy, University of Louisiana at Monroe, 700 University Ave, Monroe, Louisiana 71209, USA
    BMC Cancer 10:84. 2010
    ....
  4. ncbi Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells
    Sunitha V Bachawal
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA
    Anticancer Res 30:429-37. 2010
    ..However, combination treatment of TKIs with gamma-tocotrienol targets multiple ErbB receptors and significantly inhibit +SA murine mammary tumor cell growth...
  5. ncbi The value of tocotrienols in the prevention and treatment of cancer
    Paul W Sylvester
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA
    J Am Coll Nutr 29:324S-333S. 2010
    ....
  6. ncbi Optimization of the tetrazolium dye (MTT) colorimetric assay for cellular growth and viability
    Paul W Sylvester
    Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA
    Methods Mol Biol 716:157-68. 2011
    ..By controlling these important parameters, the MTT colorimetric assay provides accurate and reliable quantification of viable cell number...
  7. ncbi Tocotrienol combination therapy results in synergistic anticancer response
    Paul W Sylvester
    College of Pharmacy, 700 University Avenue, University of Louisiana at Monroe, Monroe, LA 71209 0470, USA
    Front Biosci (Landmark Ed) 16:3183-95. 2011
    ....
  8. ncbi Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression
    G V Samant
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA
    Cell Prolif 43:77-83. 2010
    ....
  9. ncbi Suppression in mevalonate synthesis mediates antitumor effects of combined statin and gamma-tocotrienol treatment
    Vikram B Wali
    College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209 470, USA
    Lipids 44:925-34. 2009
    ....
  10. ncbi Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells
    Vikram B Wali
    University of Louisiana at Monroe, LA 71209, USA
    Apoptosis 14:1366-77. 2009
    ..These results demonstrate that ER stress apoptotic signaling is associated with gamma-tocotrienol-induced apoptosis in +SA mammary tumor cells...
  11. ncbi Tocotrienol-induced cytotoxicity is unrelated to mitochondrial stress apoptotic signaling in neoplastic mammary epithelial cells
    Sumit J Shah
    School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209 0470, USA
    Biochem Cell Biol 83:86-95. 2005
    ..In summary, these findings clearly demonstrate that tocotrienol-induced apoptosis occurs independently of mitochondrial stress apoptotic signaling in neoplastic +SA mammary epithelial cells...
  12. ncbi Gamma-tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor kappaB activity
    Sumit J Shah
    School of Pharmacy, 700 University Avenue, University of Louisiana at Monroe, Monroe, LA 71209 0470, USA
    Exp Biol Med (Maywood) 230:235-41. 2005
    ..In summary, these findings demonstrate that the antiproliferative effects of gamma-tocotrienol result, at least in part, from a reduction in Akt and NFkappaB activity in neoplastic +SA mammary epithelial cells...
  13. ncbi Intracellular signaling mechanisms mediating the antiproliferative and apoptotic effects of gamma-tocotrienol in neoplastic mammary epithelial cells
    Paul W Sylvester
    School of Pharmacy, 700 University Avenue, University of Louisiana at Monroe, Monroe, LA 71209 0497, USA
    J Plant Physiol 162:803-10. 2005
    ....
  14. ncbi Intracellular mechanisms mediating tocotrienol-induced apoptosis in neoplastic mammary epithelial cells
    Paul W Sylvester
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA
    Asia Pac J Clin Nutr 14:366-73. 2005
    ....
  15. ncbi gamma-Tocotrienol inhibits ErbB3-dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells
    G V Samant
    College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209 0470, USA
    Cell Prolif 39:563-74. 2006
    ....
  16. ncbi Biocatalytic and semisynthetic studies of the anticancer tobacco cembranoids
    Khalid A El Sayed
    University of Louisiana at Monroe, Department of Basic Pharmaceutical Sciences, College of Pharmacy, Monroe, Louisiana 71209, USA
    Expert Opin Investig Drugs 16:877-87. 2007
    ..This review focuses on the biocatalytic and semisynthetic studies of tobacco cembanoids and their anticancer activity...
  17. ncbi Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells
    Vikram B Wali
    College of Pharmacy, University of Louisiana at Monroe, 700 University Ave, Monroe, LA 71209 0470, USA
    Lipids 42:1113-23. 2007
    ....
  18. ncbi Combined treatment of gamma-tocotrienol with statins induce mammary tumor cell cycle arrest in G1
    Vikram B Wali
    College of Pharmacy, University of Louisiana at Monroe, 700 University Avenue, Monroe, LA 71209 0470, USA
    Exp Biol Med (Maywood) 234:639-50. 2009
    ..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...
  19. ncbi Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells
    Paul W Sylvester
    School of Pharmacy, 700 University Avenue, University of Louisiana at Monroe, Monroe, LA 71209 0470, USA
    Front Biosci 10:699-709. 2005
    ....