A comparison of tocopherol and tocotrienol for the chemoprevention of chemically induced rat mammary tumors

Gould, Michael N.; Haag, Jill D.; Kennan, Wendy S.; Tanner, Martin A.; Elson, Charles E.

doi:10.1093/ajcn/53.4.1068s

Cited by 89 publications

(32 citation statements)

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“…T3 has been shown to mediate its activity against a variety of chronic diseases, including cardiovascular diseases, neurologic diseases, diabetes, and cancer (9)(10)(11)(12)(13)(14). T3s have shown anticancer activity against cancers such as colon, breast, liver, lung, kidney, prostate, skin, and other cancers both in vitro (15)(16)(17)(18)(19)(20) and in vivo (21)(22)(23)(24)(25). T3 has the potency to induce apoptosis in a variety of cancer cell types (types 1-5).…”

Section: Introductionmentioning

confidence: 99%

γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors

Kannappan

Ravindran

Prasad

et al. 2010

Molecular Cancer Therapeutics

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G 1 cell cycle arrest revealed that γ-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that γ-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that γ-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by γ-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by γ-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by γ-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that γ-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ ERK/p53 pathway and by downregulating cell survival proteins. Mol Cancer Ther; 9(8); 2196-207. ©2010 AACR.

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Section: Introductionmentioning

confidence: 99%

γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors

Kannappan

Ravindran

Prasad

et al. 2010

Molecular Cancer Therapeutics

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“…Tocotrienols from palm oil have been shown to inhibit proliferation and growth of various cancer cells including the breast, prostate and colon cancer cells both in vitro and in vivo (Nesaretnam et al 1992(Nesaretnam et al , 1995(Nesaretnam et al , 1998(Nesaretnam et al , 2004Guthrie et al 1997;Agarwal et al 2004;Srivastava and Gupta 2006;Gould et al 1991).…”

Section: Discussionmentioning

confidence: 99%

Palm tocotrienols decrease levels of pro-angiogenic markers in human umbilical vein endothelial cells (HUVEC) and murine mammary cancer cells

Selvaduray

Radhakrishnan

Kutty³

et al. 2011

Genes Nutr

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Anti-angiogenic therapy is widely being used to halt tumour angiogenesis. In this study, the antiangiogenic activity of palm tocotrienol-rich fraction (TRF) and its individual components (c-and d-tocotrienol) were first investigated in vitro in human umbilical vein endothelial cells (HUVEC) and 4T1 mouse mammary cancer cells. Results showed reduced levels of Interkeukin (IL)-8 and IL-6, two pro-angiogenic cytokines in HUVEC treated with palm tocotrienols compared with a-tocopherol (a-T) and control cells (P \ 0.05). The production of IL-8 and IL-6 was lowest in d-tocotrienol (d-T3)-treated cells followed by c-tocotrienol (c-T3) and TRF. There was significant (P \ 0.05) reduction in IL-8 and vascular endothelial growth factor (VEGF) production in 4T1 cells treated with TRF or d-T3. There was decreased expression of VEGF and its receptors; VEGF-R1 (fms-like tyrosine kinase, Flt-1) and VEGF-R2 (Kinase-insert-domain-containing receptor, KDR/Flk-2) in tumour tissues excised from mice supplemented with TRF were observed. There was also decreased expression of VEGF-R2 in lung tissues of mice supplemented with TRF. These observations correlate with the smaller tumour size recorded in the tocotrienol-treated mice. This study confirms previous observations that palm tocotrienols exhibit anti-angiogenic properties that may inhibit tumour progression.

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“…For instance, g-tocotrienol has been reported to suppress the proliferation of a wide variety of tumor cells (15), including gastric (16)(17)(18)(19), hepatocellular carcinoma (20), melanoma (21), breast (22), colorectal (23), and prostate (24). In vivo mice studies have shown that g-tocotrienol can suppress the growth of breast tumor (25), prostate (26), lung cancer and melanoma (27) and also inhibit the growth of liver and pancreatic cancer either alone or in combination with chemotherapeutic drugs and radiation (28,29). How g-tocotrienol mediates its anticancer effects is not completely understood, but the roles of various signaling cascades/kinases/transcription factors such as mitogen-activated protein kinases (17), phosphoinositide 3-kinase (PI3K)/Akt (30), NF-kB (13), STAT3 (20), telomerase (31), PPAR-g (32), hypoxiainducible factor-1a (33), b-catenin (23), EGF (24), and inhibitor of differentiation family proteins (34) have been implicated.…”

Section: Introductionmentioning

confidence: 99%

First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway

Manu

Shanmugam

Ramachandran

et al. 2012

Clinical Cancer Research

133

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Purpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether g-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.Experimental Design: The effect of g-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-kB activation by DNAbinding assay, and gene expression by Western blotting. The effect of g-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.Results: g-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-kB, and suppressed the NF-kBregulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of g-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and g-tocotrienol. As compared with vehicle control, g-tocotrienol also suppressed the NF-kB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.Conclusions: Overall our results show that g-tocotrienol can potentiate the effects of capecitabine through suppression of NF-kB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

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A comparison of tocopherol and tocotrienol for the chemoprevention of chemically induced rat mammary tumors

Cited by 89 publications

References 1 publication

γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors

γ-Tocotrienol Promotes TRAIL-Induced Apoptosis through Reactive Oxygen Species/Extracellular Signal-Regulated Kinase/p53–Mediated Upregulation of Death Receptors

Palm tocotrienols decrease levels of pro-angiogenic markers in human umbilical vein endothelial cells (HUVEC) and murine mammary cancer cells

First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway

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