Suppression of Tumor Growth by Palm Tocotrienols Via the Attenuation of Angiogenesis

Wong, Weng-Yew; Selvaduray, Kanga Rani; Cheng, Minghui; Nesaretnam, Kalanithi

doi:10.1080/01635580802582736

Cited by 61 publications

(44 citation statements)

References 30 publications

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“…We have also demonstrated selective induction of apoptosis by VEDT of pancreatic transformed and malignant epithelial cells but not normal immortalized human pancreatic ductal epithelial cells (12, 32). Other anticancer effects of tocotrienol include the inhibition of cell migration and invasion and the inhibition of angiogenesis (21, 24, 34). Our present data also confirm that VEDT decreased VEGF expression in the tumors and inhibited angiogenesis in KPC mice.…”

Section: Discussionmentioning

confidence: 99%

Vitamin E δ-Tocotrienol Prolongs Survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) Transgenic Mouse Model of Pancreatic Cancer

Husain

Centeno

Chen

et al. 2013

Cancer Prevention Research

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Previous work has shown that vitamin E δ-tocotrienol (VEDT) prolongs survival and delays progression of pancreatic cancer in the LSL-KrasG12D/+;Pdx-1-Cre mouse model of pancreatic cancer. However, the effect of VEDT alone or in combination with gemcitabine in the more aggressive LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model is unknown. Here, we studied the effects of VEDT and the combination of VEDT and gemcitabine in the KPC mice. KPC mice were randomized into 4 groups: 1) vehicle (olive oil, 1.0 mL/kg PO twice/day and PBS 1.0 mL/kg IP twice/week), 2) gemcitabine (100 mg/kg IP twice/week), 3) VEDT (200 mg/kg PO twice/day), and 4) gemcitabine + VEDT. Mice received treatment until they displayed symptoms of impending death from pancreatic cancer, at which point animals were euthanized. At 16 weeks, survival was 10% in the vehicle group, 30% in the gemcitabine group, 70% in the VEDT group (P<0.01), and 90% in the VEDT combined with gemcitabine group (P<0.05). VEDT alone and combined with gemcitabine resulted in reversal of epithelial-to-mesenchymal transition in tumors. Biomarkers of apoptosis (plasma CK18), PARP1 cleavage, and Bax expression were more greatly induced in tumors subjected to combined treatment versus individual treatment. Combined treatment induced cell cycle inhibitors (p27Kip1 and p21Cip1) and inhibited VEGF, vascularity (CD31), and oncogenic signaling (pAKT, pMEK, and pERK) greater than individual drugs. No significant differences in body weight gain between drug treatment and control mice were observed. These results strongly support further investigation of VEDT alone and in combination with gemcitabine for pancreatic cancer prevention and treatment.

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Section: Discussionmentioning

confidence: 99%

Vitamin E δ-Tocotrienol Prolongs Survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) Transgenic Mouse Model of Pancreatic Cancer

Husain

Centeno

Chen

et al. 2013

Cancer Prevention Research

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“…35 The anticancer effect of T3 was found to be mediated through antiproliferation, 16,36,37 induction of apoptosis, 38,39 cell cycle arrest, 13,40 antiangiogenesis 41 and antiinvasion. 18 More recently, c-T3, one of the four isoforms of T3, was reported to possess chemosensitizing effects, 17,18 which led us to speculate that c-T3 may be able to target the chemoresistant cancer stem-like cells.…”

Section: Discussionmentioning

confidence: 99%

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

Luk

Yap²,

Chiu

et al. 2011

Intl Journal of Cancer

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Emerging evidence supports that prostate cancer originates from a rare subpopulation 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 (γ‐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 γ‐T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel‐induced apoptosis, suggesting that γ‐T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that γ‐T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen‐independent prostate cancer cell lines (PC‐3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by γ‐T3 treatment. In addition, pretreatment of PC‐3 cells with γ‐T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133‐enriched PC‐3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to γ‐T3 treatment as the CD133‐depleted population. Our data suggest that γ‐T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.

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“…In vivo studies so far performed in immunocompromised animals after ectopic implantation of breast cancer cells (Nesaretnam et al 2004) as well as other studies that investigated tumor mass growth and vascularization in other models of ectopic implants (Nakagawa et al 2007;Shibata et al 2009;Weng-Yew et al 2009), have not provided an affordable model system to clarify this point. These studies were based on the supplementation of high dosages (between 1 and 10 mg/day) of T3 under the form of palm oil derived T3-rich fraction (TRF) that provided different contributions to the observed anti-cancer effects by the individual forms of T3 contained in this type formulation.…”

Section: Metabolite Formation and Activitymentioning

confidence: 99%

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

et al. 2011

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The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (c and d) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated ''highly metabolized'' T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.Keywords Tocotrienols Á Vitamin E Á Breast cancer Á Antioxidants Á Apoptosis Á Cell signaling Á Inflammation Á Metabolism Á Gene expression Á Cell redox T3 structure-function and specificity of actionIn the vitamin E family of molecules, tocotrienols (T3) are often considered of minor importance since these are less abundant than a and c tocopherol (TOH) in the circulation and in solid tissues. This has contributed to hinder our knowledge on the biological functions of this group of vitamers that is now regaining great interest, thanks to a number of recent studies that suggested health-promoting functions related with the cholesterol-lowering, cytoprotective, and anticarcinogenic effects of T3 [reviewed in (Aggarwal et al. (2010)].Structure-function studies demonstrate that many of these functions are more potent when the unsaturated (isoprenyl) side chain of T3 is combined with a hypomethylated (HM) chroman ring. The unsaturated chain characteristic of all the T3 forms confers well-defined physical and chemical characteristics that appear to include vitamer-specific interactions with other lipids and cell proteins (Atkinson

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Suppression of Tumor Growth by Palm Tocotrienols Via the Attenuation of Angiogenesis

Cited by 61 publications

References 30 publications

Vitamin E δ-Tocotrienol Prolongs Survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) Transgenic Mouse Model of Pancreatic Cancer

Vitamin E δ-Tocotrienol Prolongs Survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) Transgenic Mouse Model of Pancreatic Cancer

Gamma‐tocotrienol as an effective agent in targeting prostate cancer stem cell‐like population

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

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