Specific accumulation of γ- and δ-tocotrienols in tumor and their antitumor effect in vivo

Hiura, Yuhei; Tachibana, Hirofumi; Arakawa, Ryo; Aoyama, Natsuki; Okabe, Masaru; Sakai, Miyo; Yamada, Koji

doi:10.1016/j.jnutbio.2008.06.004

Cited by 54 publications

(33 citation statements)

References 35 publications

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“…Consistent with recent studies indicating high T3 deposition in hepatoma cells [22] , pancreatic cells [16] and adipose breast tissues [23] , we determined in our study that ␥ T3 also accumulated in AIPCa tumors following intraperitoneal administration. Compared to the ␥ T3 concentration determined in AIPCa tumors, the ␥ T3 deposition in 5 vital organs (heart, liver, spleen, lungs and kidneys) was approximately half ( fig.…”

Section: Discussionsupporting

confidence: 92%

In vivo Evidence of γ-Tocotrienol as a Chemosensitizer in the Treatment of Hormone-Refractory Prostate Cancer

Yap¹,

Zaiden²,

Luk

et al. 2010

Pharmacology

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γ-Tocotrienol (γT3) is known to selectively kill prostate cancer (PCa) cells and to sensitize the cells to docetaxel (DTX)-induced apoptosis. In the present study, the pharmacokinetics of γT3 and the in vivo cytotoxic response of androgen-independent prostate cancer (AIPCa) tumor following γT3 treatment were investigated. Here, we investigated these antitumor effects for PCa tumors in vivo. The pharmacokinetic and tissue distribution of γT3 after exogenous γT3 supplementation were examined. Meanwhile, the response of the tumor to γT3 alone or in combination with DTX were studied by real-time in vivo bioluminescent imaging and by examination of biomarkers associated with cell proliferation and apoptosis. After intraperitoneal injection, γT3 rapidly disappeared from the serum and was selectively deposited in the AIPCa tumor cells. Administration of γT3 alone for 2 weeks resulted in a significant shrinkage of the AIPCa tumors. Meanwhile, further inhibition of the AIPCa tumor growth was achieved by combined treatment of γT3 and DTX (p < 0.002). The in vivo cytotoxic antitumor effects induced by γT3 seem to be associated with a decrease in expression of cell proliferation markers (proliferating cell nuclear antigen, Ki-67 and Id1) and an increase in the rate of cancer cell apoptosis [cleaved caspase 3 and poly(ADP-ribose) polymerase]. Additionally, the combined agents may be more effective at suppressing the invasiveness of AIPCa. Overall, our results indicate that γT3, either alone or in combination with DTX, may provide a treatment strategy that can improve therapeutic efficacy against AIPCa while reducing the toxicity often seen in patients treated with DTX.

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Section: Discussionsupporting

confidence: 92%

In vivo Evidence of γ-Tocotrienol as a Chemosensitizer in the Treatment of Hormone-Refractory Prostate Cancer

Yap¹,

Zaiden²,

Luk

et al. 2010

Pharmacology

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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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“…Although g-tocotrienol has been found to suppress proliferation, to inhibit invasion/migration, and induce apoptosis in human gastric cancer SGC-7901 cells (28)(29)(30)(31), but its potential to act as a chemosensitizing agent in gastric cancer cell lines and xenograft models has never been explored before (16)(17)(18)(19). Thus, in the present study, we investigated whether g-tocotrienol could sensitize human gastric cancer to capecitabine in vitro and in a xenograft mouse model.…”

Section: Introductionmentioning

confidence: 94%

“…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

135

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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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Specific accumulation of γ- and δ-tocotrienols in tumor and their antitumor effect in vivo

Cited by 54 publications

References 35 publications

In vivo Evidence of γ-Tocotrienol as a Chemosensitizer in the Treatment of Hormone-Refractory Prostate Cancer

In vivo Evidence of γ-Tocotrienol as a Chemosensitizer in the Treatment of Hormone-Refractory Prostate Cancer

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

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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