Gamma Tocotrienol

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Wan Zurinah Wan Ngah - One of the best experts on this subject based on the ideXlab platform.

  • Gamma Tocotrienol acts as a bh3 mimetic to induce apoptosis in neuroblastoma sh sy5y cells
    Journal of Nutritional Biochemistry, 2016
    Co-Authors: Jen Kit Tan, Suemian Then, Musalmah Mazlan, Raja Noor Zaliha Raja Abdul Rahman, Rahman A A Jamal, Wan Zurinah Wan Ngah
    Abstract:

    Bcl-2 family proteins are crucial regulators of apoptosis. Both pro- and antiapoptotic members exist, and overexpression of the latter facilitates evasion of apoptosis in many cancer types. Bcl-2 homology domain 3 (BH3) mimetics are small molecule inhibitors of antiapoptotic Bcl-2 family members, and these inhibitors are promising anticancer agents. In this study, we report that Gamma-Tocotrienol (γT3), an isomer of vitamin E, can inhibit Bcl-2 to induce apoptosis. We demonstrate that γT3 induces cell death in human neuroblastoma SH-SY5Y cells by depolarising the mitochondrial membrane potential, enabling release of cytochrome c to the cytosol and increasing the activities of caspases-9 and -3. Treatment of cells with inhibitors of Bax or caspase-9 attenuated the cell death induced by γT3. Simulated docking analysis suggested that γT3 binds at the hydrophobic groove of Bcl-2, while a binding assay showed that γT3 competed with a fluorescent probe to bind at the hydrophobic groove. Our data suggest that γT3 mimics the action of BH3-only protein by binding to the hydrophobic groove of Bcl-2 and inducing apoptosis via the intrinsic pathway in a Bax- and caspase-9-dependent manner.

  • Gamma Tocotrienol treatment increased peroxiredoxin 4 expression in hepg2 liver cancer cell line
    BMC Complementary and Alternative Medicine, 2015
    Co-Authors: Farahani Abdul Rahman Sazli, Zakiah Jubri, Mariati Abdul Rahman, Saiful Anuar Karsani, Abdul Gapor Md Top, Wan Zurinah Wan Ngah
    Abstract:

    To determine the antiproliferative effect of Gamma-Tocotrienol (GTT) treatment on differential protein expression in HepG2 cells. HepG2 cells were treated with 70 μM GTT for 48 hours and differentially expressed protein spots were determined by two-dimensional electrophoresis (2DE), identified by MALDI-TOF mass spectrometer (MS) and validated by quantitative real-time polymerase chain reaction (qRT-PCR). GTT treatment on HepG2 cells showed a total of five differentially expressed proteins when compared to their respective untreated cells where three proteins were down-regulated and two proteins were up-regulated. One of these upregulated proteins was identified as peroxiredoxin-4 (Prx4). Validation by qRT-PCR however showed decreased expression of Prx4 mRNA in HepG2 cells following GTT treatment. GTT might directly influence the expression dynamics of peroxiredoxin-4 to control proliferation in liver cancer.

  • Gamma Tocotrienol treatment increased peroxiredoxin 4 expression in hepg2 liver cancer cell line
    BMC Complementary and Alternative Medicine, 2015
    Co-Authors: Farahani Abdul Rahman Sazli, Zakiah Jubri, Mariati Abdul Rahman, Saiful Anuar Karsani, Wan Zurinah Wan Ngah
    Abstract:

    Background To determine the antiproliferative effect of Gamma-Tocotrienol (GTT) treatment on differential protein expression in HepG2 cells.

  • Gamma Tocotrienol and hydroxy chavicol synergistically inhibits growth and induces apoptosis of human glioma cells
    BMC Complementary and Alternative Medicine, 2014
    Co-Authors: Wan Zurinah Wan Ngah, Norfilza Mohd Mokhtar, Rahman A A Jamal, Amirah Abdul Rahman, Roslan Harun
    Abstract:

    Gamma-Tocotrienol (GTT), an isomer of vitamin E and hydroxy-chavicol (HC), a major bioactive compound in Piper betle, has been reported to possess anti-carcinogenic properties by modulating different cellular signaling events. One possible strategy to overcome multi-drug resistance and high toxic doses of treatment is by applying combinational therapy especially using natural bioactives in cancer treatment. In this study, we investigated the interaction of GTT and HC and its mode of cell death on glioma cell lines. GTT or HC alone and in combination were tested for cytotoxicity on glioma cell lines 1321N1 (Grade II), SW1783 (Grade III) and LN18 (Grade IV) by [3-(4,5-dimethylthiazol-2- yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)- 2H- tetrazolium, inner salt] MTS assay. The interactions of each combination were evaluated by using the combination index (CI) obtained from an isobologram. Individually, GTT or HC displayed mild growth inhibitory effects against glioma cancer cell lines at concentration values ranging from 42–100 μg/ml and 75–119 μg/ml respectively. However, the combination of sub-lethal doses of GTT + HC dramatically enhanced the inhibition of glioma cancer cell proliferation and exhibited a strong synergistic effect on 1321N1 with CI of 0.55, and CI = 0.54 for SW1783. While in LN18 cells, moderate synergistic interaction of GTT + HC was observed with CI value of 0.73. Exposure of grade II, III and IV cells to combined treatments for 24 hours led to increased apoptosis as determined by annexin-V FITC/PI staining and caspase-3 apoptosis assay, showing caspase-3 activation of 27%, 7.1% and 79% respectively. In conclusion, combined treatments with sub-effective doses of GTT and HC resulted in synergistic inhibition of cell proliferation through the induction of apoptosis of human glioma cells in vitro.

  • Gamma Tocotrienol modulated gene expression in senescent human diploid fibroblasts as revealed by microarray analysis
    Oxidative Medicine and Cellular Longevity, 2013
    Co-Authors: Suzana Makpol, Azalina Zainuddin, Kien Hui Chua, Yasmin Anum Mohd Yusof, Wan Zurinah Wan Ngah
    Abstract:

    The effect of γ-Tocotrienol, a vitamin E isomer, in modulating gene expression in cellular aging of human diploid fibroblasts was studied. Senescent cells at passage 30 were incubated with 70 μM of γ-Tocotrienol for 24 h. Gene expression patterns were evaluated using Sentrix HumanRef-8 Expression BeadChip from Illumina, analysed using GeneSpring GX10 software, and validated using quantitative RT-PCR. A total of 100 genes were differentially expressed () by at least 1.5 fold in response to γ-Tocotrienol treatment. Amongst the genes were IRAK3, SelS, HSPA5, HERPUD1, DNAJB9, SEPR1, C18orf55, ARF4, RINT1, NXT1, CADPS2, COG6, and GLRX5. Significant gene list was further analysed by Gene Set Enrichment Analysis (GSEA), and the Normalized Enrichment Score (NES) showed that biological processes such as inflammation, protein transport, apoptosis, and cell redox homeostasis were modulated in senescent fibroblasts treated with γ-Tocotrienol. These findings revealed that γ-Tocotrienol may prevent cellular aging of human diploid fibroblasts by modulating gene expression.

Martin Hauerjensen - One of the best experts on this subject based on the ideXlab platform.

  • enhanced survival in mice exposed to ionizing radiation by combination of Gamma Tocotrienol and simvastatin
    Military Medicine, 2019
    Co-Authors: Rupak Pathak, Martin Hauerjensen, Vidya P Kumar, Sanchita P Ghosh
    Abstract:

    Ionizing radiation exposure is a major concern for active military service members, as well as civilian population. Considering that the exposure is not predictable, it is imperative that strategies to counteract radiation damage must be discovered. Recent in vitro studies performed in our laboratory demonstrated that the vitamin E analog Gamma-Tocotrienol (GT3) in combination with cholesterol-lowering drugs (Statins), synergistically induced endothelial thrombomodulin, an anticoagulant with radio-protective efficacy. It was hypothesized that the combination of treatment with both GT3 along with Statins would provide better radiation protection in vivo than each drug individually. CD2F1 mice were injected subcutaneously with either vehicle or single dose of GT3 (200 mg/kg body weight) 24 hours before irradiation followed by oral or subcutaneous administration of various doses of simvastatin (25, 50, and 100 mg/kg body weight) before exposure to lethal doses (11.5 and 12 Gy) of Cobalt-60 (60Co) Gamma-irradiation. The combined treatment group exhibited enhanced radiation lethality protection substantially, accelerated white blood cell recovery, and augmented restoration of bone marrow cellularity when compared to the animals treated with either drug exclusively. This information clearly suggests that combined treatment could be used as a safeguard for military personnel from exposure to harmful ionizing radiation.

  • proteomic changes in mouse spleen after radiation induced injury and its modulation by Gamma Tocotrienol
    Radiation Research, 2018
    Co-Authors: Amrita K Cheema, Martin Hauerjensen, Shukla Biswas, Vidya P Kumar, Neel Kamal Sharma, Stephanie D Byrum, Tatiana Altadill, Brian M Balgley, Alan J Tackett
    Abstract:

    Gamma-Tocotrienol (GT3), a naturally occurring vitamin E isomer, a promising radioprotector, has been shown to protect mice against radiation-induced hematopoietic and gastrointestinal injuries. We analyzed changes in protein expression profiles of spleen tissue after GT3 treatment in mice exposed to Gamma radiation to gain insights into the molecular mechanism of radioprotective efficacy. Male CD2F1 mice, 12-to-14 weeks old, were treated with either vehicle or GT3 at 24 h prior to 7 Gy total-body irradiation. Nonirradiated vehicle, nonirradiated GT3 and age-matched naive animals were used as controls. Blood and tissues were harvested on days 0, 1, 2, 4, 7, 10 and 14 postirradiation. High-resolution mass-spectrometry-based radioproteomics was used to identify differentially expressed proteins in spleen tissue with or without drug treatment. Subsequent bioinformatic analyses helped delineate molecular markers of biological pathways and networks regulating the cellular radiation responses in spleen. Our results show a robust alteration in spleen proteomic profiles including upregulation of the Wnt signaling pathway and actin-cytoskeleton linked proteins in mediating the radiation injury response in spleen. Furthermore, we show that 24 h pretreatment with GT3 attenuates radiation-induced hematopoietic injury in the spleen by modulating various cell signaling proteins. Taken together, our results show that the radioprotective effects of GT3 are mediated, via alleviation of radiation-induced alterations in biochemical pathways, with wide implications on overall hematopoietic injury.

  • cebpd is essential for Gamma Tocotrienol mediated protection against radiation induced hematopoietic and intestinal injury
    Antioxidants, 2018
    Co-Authors: Sudip Banerjee, Martin Hauerjensen, Rupak Pathak, Sumit K Shah, Stepan Melnyk, Snehalata A. Pawar
    Abstract:

    Gamma-Tocotrienol (GT3) confers protection against ionizing radiation (IR)-induced injury. However, the molecular targets that underlie the protective functions of GT3 are not yet known. We have reported that mice lacking CCAAT enhancer binding protein delta (Cebpd−/−) display increased mortality to IR due to injury to the hematopoietic and intestinal tissues and that Cebpd protects from IR-induced oxidative stress and cell death. The purpose of this study was to investigate whether Cebpd mediates the radio protective functions of GT3. We found that GT3-treated Cebpd−/− mice showed partial recovery of white blood cells compared to GT3-treated Cebpd+/+ mice at 2 weeks post-IR. GT3-treated Cebpd−/− mice showed an increased loss of intestinal crypt colonies, which correlated with increased expression of inflammatory cytokines and chemokines, increased levels of oxidized glutathione (GSSG), S-nitrosoglutathione (GSNO) and 3-nitrotyrosine (3-NT) after exposure to IR compared to GT3-treated Cebpd+/+ mice. Cebpd is induced by IR as well as a combination of IR and GT3 in the intestine. Studies have shown that granulocyte-colony stimulating factor (G-CSF), mediates the radioprotective functions of GT3. Interestingly, we found that IR alone as well as the combination of IR and GT3 caused robust augmentation of plasma G-CSF in both Cebpd+/+ and Cebpd−/− mice. These results identify a novel role for Cebpd in GT3-mediated protection against IR-induced injury, in part via modulation of IR-induced inflammation and oxidative/nitrosative stress, which is independent of G-CSF.

  • the vitamin e analog Gamma Tocotrienol gt3 and statins synergistically up regulate endothelial thrombomodulin tm
    International Journal of Molecular Sciences, 2016
    Co-Authors: Rupak Pathak, Sanchita P Ghosh, Daohong Zhou, Martin Hauerjensen
    Abstract:

    Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) and strongly induce endothelial thrombomodulin (TM); which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member Gamma-Tocotrienol (GT3) also suppresses HMGCR activity and induces TM expression without causing significant adverse side effects; even at high concentrations. To investigate the synergistic effect of statins and GT3 on TM; a low dose of atorvastatin and GT3 was used to treat human primary endothelial cells. Protein-level TM expression was measured by flow cytometry. TM functional activity was determined by activated protein C (APC) generation assay. Expression of Kruppel-like factor 2 (KLF2), one of the key transcription factors of TM, was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). TM expression increased in a dose-dependent manner after both atorvastatin and GT3 treatment. A combined treatment of a low-dose of atorvastatin and GT3 synergistically up-regulated TM expression and functional activity. Finally; atorvastatin and GT3 synergistically increased KLF2 expression. These findings suggest that combined treatment of statins with GT3 may provide significant health benefits in treating a number of pathophysiological conditions; including inflammatory and cardiovascular diseases.

  • the vitamin e analog Gamma Tocotrienol gt3 suppresses radiation induced cytogenetic damage
    Pharmaceutical Research, 2016
    Co-Authors: Rupak Pathak, Sanchita P Ghosh, Marjan Boerma, Abdel Bachri, Igor Koturbash, Regina K Binz, Jeffrey R Sawyer, Martin Hauerjensen
    Abstract:

    Purpose Ionizing radiation (IR) generates reactive oxygen species (ROS), which cause DNA double-strand breaks (DSBs) that are responsible for cytogenetic alterations. Because antioxidants are potent ROS scavengers, we determined whether the vitamin E isoform γ-Tocotrienol (GT3), a radio-protective multifunctional dietary antioxidant, can suppress IR-induced cytogenetic damage.

Soonkyu Chung - One of the best experts on this subject based on the ideXlab platform.

  • Gamma Tocotrienol attenuates the hepatic inflammation and fibrosis by suppressing endoplasmic reticulum stress in mice
    Molecular Nutrition & Food Research, 2018
    Co-Authors: Yongeun Kim, Sathish Kumar Natarajan, Soonkyu Chung
    Abstract:

    Scope Gamma-Tocotrienol (γT3), an unsaturated isoform of vitamin E, is implicated in the hepatoprotective effects. The aim is to determine the effectiveness of γT3 on nonalcoholic fatty liver disease (NAFLD). Methods and results C57BL/6 male mice are fed a diet containing high fat (45%) and cholesterol (0.2%) along with sucrose drink (HFCS) or HFCS diet supplemented with 0.1% γT3 (HFCS + γT3). The inclusion of γT3 robustly decreases the HFCS diet-induced de novo lipogenesis (DNL), ER stress, and inflammation leading to reduced hepatic steatosis and fibrosis. Next, mice are fed a methionine- and choline-deficient (MCD) diet or MCD diet with γT3 (MCD + γT3). The γT3 supplementation significantly reduces the MCD diet-induced hepatic ER stress and fibrosis despite the minimal impact on steatosis. To further investigate the role of ER stress, the mice with genetic ablation of CHOP are fed an MCD or MCD + γT3 diet. CHOP deletion abolishes the γT3-mediated suppression of hepatic fibrosis, suggesting that modulation of ER stress is a prerequisite to inhibit hepatic inflammation and fibrosis. Conclusion γT3 supplementation is effective in attenuating NAFLD and fibrosis through a synergistic mechanism of decreased DNL and hepatic ER stress. This work strongly supports the translational potential of γT3 supplementation against NAFLD.

  • Gamma Tocotrienol attenuates the aberrant lipid mediator production in nlrp3 inflammasome stimulated macrophages
    Journal of Nutritional Biochemistry, 2018
    Co-Authors: Yongeun Kim, Anthony D Gromovsky, Mark J Brown, Soonkyu Chung
    Abstract:

    The activation of NLRP3 inflammasome in innate immune cells is associated with enhanced production of pro-inflammatory lipid mediator eicosanoids that play a crucial role in propagating inflammation. Gamma-Tocotrienol (γT3) is an unsaturated vitamin E that has been demonstrated to attenuate NLRP3-inflammasome. However, the role of γT3 in regulating eicosanoid formation is unknown. We hypothesized that γT3 abolishes the eicosanoid production by modulating the macrophage lipidome. LPS-primed bone marrow-derived macrophages (BMDM) were stimulated with saturated fatty acids (SFA) along with γT3, and the effects of γT3 in modulating macrophage lipidome were quantified by using mass spectrometry based-shotgun lipidomic approaches. The SFA-mediated inflammasome activation induced robust changes in lipid species of glycerolipids (GL), glycerophospholipids (GPL), and sphingolipids in BMDM, which were distinctly different in the γT3-treated BMDM. The γT3 treatment caused substantial decreases of lysophospholipids (LysoPL), diacylglycerol (DAG), and free arachidonic acid (AA, C20:4), indicating that γT3 limits the availability of AA, the precursor for eicosanoids. This was confirmed by the pulse-chase experiment using [3H]-AA, and by diminished prostaglandin E2 (PGE2) secretion by ELISA. Concurrently, γT3 inhibited LPS-induced cyclooxygenases 2 (COX2) induction, further suppressing prostaglandin synthesis. In addition, γT3 attenuated ceramide synthesis by transcriptional downregulation of key enzymes for de novo synthesis. The altered lipid metabolism during inflammation is linked to reduced ATP production, which was partly rescued by γT3. Taken together, our work revealed that γT3 induces distinct modification of the macrophage lipidome to reduce AA release and corresponding lipid mediator synthesis, leading to attenuated cellular lipotoxicity.

  • Gamma Tocotrienol attenuates high fat diet induced obesity and insulin resistance by inhibiting adipose inflammation and m1 macrophage recruitment
    International Journal of Obesity, 2015
    Co-Authors: Lu Zhao, Inhae Kang, Xiefan Fang, W Wang, M A Lee, R R Hollins, Maurice R Marshall, Soonkyu Chung
    Abstract:

    Gamma-Tocotrienol attenuates high-fat diet-induced obesity and insulin resistance by inhibiting adipose inflammation and M1 macrophage recruitment

  • Gamma Tocotrienol improves high fat diet induced obesity and insulin resistance by inhibiting adipose inflammation and macrophage recruitment 383 4
    The FASEB Journal, 2014
    Co-Authors: Lu Zhao, Inhae Kang, Maurice R Marshall, Soonkyu Chung, Meshail Okla, Meeae Lee
    Abstract:

    Childhood obesity is associated with an abnormal increase of adipocyte hyperplasia. We have previously reported that Gamma Tocotrienol (γT3) potently inhibits adipocyte hyperplasia in human adipose...

  • activation of autophagy and ampk by Gamma Tocotrienol suppresses the adipogenesis in human adipose derived stem cells
    Molecular Nutrition & Food Research, 2014
    Co-Authors: Lu Zhao, Meshail Okla, Soonkyu Chung
    Abstract:

    Scope This study investigated the mechanistic details by which Gamma-Tocotrienol (γ-T3) manipulates adipocyte differentiation in human adipose derived stem cells (hASCs). Methods and results γ-T3 specifically inhibited the early stage of adipocyte differentiation by acting on downstream of C/EBP-β but upstream of C/EBP-α in hASCs. In searching a potential mechanism, we identified that γ-T3 promoted two catabolic signaling pathways: (i) AMP kinase (AMPK), and (ii) enhanced autophagy, as assessed by autophagic flux and cytosolic autophagosome (LC3II) accumulation. In addition, chronic exposure of γ-T3 induced caspase3-mediated apoptotic cell death. The blockage of AMPK by a dominant negative mutant of AMPK was insufficient to normalize γ-T3-mediated autophagy, suggesting that enhanced autophagic activity of γ-T3 is independent of AMPK activation. Intriguingly, AMPK inhibition significantly restored PPAR-γ activation, but marginally rescued lipid-loaded adipocyte morphology due to, at least partly, a lack of lipid droplet-coating protein. These data suggest that γ-T3 activates AMPK and autophagy signaling, which synergistically contributes to the suppression of adipogenic conversion of hASCs into adipocytes. Conclusion These results provide a novel insight into the molecular mechanism involved in anti-adipogenic action of γ-T3 in humans via AMPK and autophagy activation. Thus, γ-T3 may constitute a new dietary avenue to attenuate hyperplastic obesity in humans.

Yee Leng Yap - One of the best experts on this subject based on the ideXlab platform.

  • Gamma Tocotrienol as an effective agent in targeting prostate cancer stem cell like population
    International Journal of Cancer, 2011
    Co-Authors: Sze Ue Luk, Wei Ney Yap, Yc Wong, Davy T Lee, Terence Kin Wah Lee, Yungtuen Chiu, Raja S Vasireddy, Yickpang Ching, Colleen C Nelson, Yee Leng Yap
    Abstract:

    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.

  • Gamma Tocotrienol as an effective agent in targeting prostate cancer stem cell like population
    Faculty of Science and Technology; Institute of Health and Biomedical Innovation, 2010
    Co-Authors: Sze Ue Luk, Wei Ney Yap, Yc Wong, Davy T Lee, Terence Kin Wah Lee, Yungtuen Chiu, Raja S Vasireddy, Yickpang Ching, Colleen C Nelson, Yee Leng Yap
    Abstract:

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

  • id1 inhibitor of differentiation is a key protein mediating anti tumor responses of Gamma Tocotrienol in breast cancer cells
    Cancer Letters, 2010
    Co-Authors: Wei Ney Yap, Norazean Zaiden, Yee Ling Tan, Chang Piek Ngoh, Xue Wu Zhang, Y C Wong, Mingtat Ling, Yee Leng Yap
    Abstract:

    Gamma-Tocotrienol has demonstrated anti-proliferative effect on breast cancer (BCa) cells, but mechanisms involved are largely unknown. This study aimed at deciphering the molecular pathways responsible for its activity. Our results showed that treatment of BCa cells with Gamma-Tocotrienol resulted in induction of apoptosis as evidenced by activation of pro-caspases, accumulation of sub-G1 cells and DNA fragmentations. Examination of the pro-survival genes revealed that the Gamma-Tocotrienol-induced cell death was associated with suppression of Id1 and NF-κB through modulation of their upstream regulators (Src, Smad1/5/8, Fak and LOX). Meanwhile, Gamma-Tocotrienol treatment also resulted in the induction of JNK signaling pathway and inhibition of JNK activity by specific inhibitor partially blocked the effect of Gamma-Tocotrienol. Furthermore, synergistic effect was observed when cells were co-treated with Gamma-Tocotrienol and Docetaxel. Interestingly, in cells that treated with Gamma-Tocotrienol, alpha-tocopherol or β-aminoproprionitrile were found to partially restore Id1 expression. Meanwhile, this restoration of Id1 was found to protect the cells from Gamma-Tocotrienol induced apoptosis. Consistent outcome was observed in cells ectopically transfected with the Id-1 gene. Our results suggested that the anti-proliferative and chemosensitization effect of Gamma-Tocotrienol on BCa cells may be mediated through downregulation of Id1 protein.

  • abstract 1656 id1 inhibitor of differentiation is a key protein mediating anti tumor responses of Gamma Tocotrienol in breast cancer cells
    Cancer Research, 2010
    Co-Authors: Wei Ney Yap, Norazean Zaiden, Yee Ling Tan, Xue Wu Zhang, Y C Wong, Mingtat Ling, Piek Ngoh Chang, Yee Leng Yap
    Abstract:

    Background: Gamma-Tocotrienol has demonstrated anti-proliferative effect on breast cancer (BCa) cells, but mechanisms involved are largely unknown. This study aimed at deciphering the molecular pathways responsible for its activity. Methods: MTT cell proliferation, DNA fragmentation, TUNEL assay and flow cytometry were performed to investigate Gamma-Tocotrienol induced cell cytotoxicity and cell cycle arrest. Western blotting was used to characterize multiple signaling pathways associated with Gamma-Tocotrienol in BCa. Docetaxel, a chemotherapeutic drug that is able to provide significant survival advantage in metastatic BCa, was used in the chemosensitization studies. Results: Our results showed that treatment of BCa cells with Gamma-Tocotrienol resulted in induction of apoptosis as evidenced by activation of pro-caspases (cleaved caspase-3, −7, −8, −9 and cleaved PARP), accumulation of sub-G1 cells and DNA fragmentations. Examination of the pro-survival genes revealed that the Gamma-Tocotrienol-induced cell death was associated with suppression of Id1 and NF-κB through modulation of their upstream regulators (Src, Smad1/5/8, Fak and LOX). Meanwhile, Gamma-Tocotrienol treatment also resulted in the induction of JNK signaling pathway and inhibition of JNK activity by specific inhibitor partially blocked the effect of Gamma-Tocotrienol. Furthermore, synergistic effect was observed when cells were co-treated with Gamma-Tocotrienol and Docetaxel. Interestingly, in cells that treated with Gamma-Tocotrienol, alpha-tocopherol or s-aminoproprionitrile were found to partially restore Id1 expression. Meanwhile, this restoration of Id1 was found to protect the cells from Gamma-Tocotrienol induced apoptosis. Consistent outcome was observed in cells ectopically transfected with the Id-1 gene. Conclusion: Our results suggested that the anti-proliferative and chemosensitization effect of Gamma-Tocotrienol on BCa cells may be mediated through downregulation of Id1 protein. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1656.

Sanchita P Ghosh - One of the best experts on this subject based on the ideXlab platform.

  • Gamma Tocotrienol protects mice from targeted thoracic radiation injury
    Frontiers in Pharmacology, 2020
    Co-Authors: Vidya P Kumar, Shukla Biswas, Sasha Stone, Neel Kamal Sharma, Sanchita P Ghosh
    Abstract:

    Radiation injury will result in multiorgan dysfuntion leading to multiorgan failure. In addition to many factors such as radiation dose, dose rate, the severity of the injury will also depend on organ systems which are exposed. Here, we report the protective property of Gamma Tocotrienol (GT3) in total as well as partial body irradiation (PBI) model in C3H/HeN male mice. We have carried out PBI by targeting thoracic region (lung-PBI) using Small Animal Radiation Research Platform (SARRP), an X-ray irradiator with capabilities of an image guided irradiation with a variable collimator with minimized exposure to non-targeted tissues and organs. Precise and accurate irradiation of lungs was carried out at either 14 or 16 Gy at an approximate dose rate of 2.6 Gy/ min. Though a low throughput model, it is amenable to changes the field size on the spot. No damage to other non-targeted organs was observed in histopathological evaluation. There was no significant change in peripheral blood counts of irradiated mice in comparison to naive mice. Femoral bone marrow cells had no damage in irradiated mice. As expected, damage to the targeted tissue was observed in the histopathological evaluation and non-targeted tissue was found normal. Regeneration and increase of cellularity and megakaryocytes on GT3 treatment was compared to significant loss of cellularity in saline group. Peak alveolitis was observed on day 14 post-PBI and protection from alveolitis by GT3 was noted. In irradiated lung tissue, thirty proteins were found to be differentially expressed but modulated by GT3 to reverse the effects of irradiation. We propose that possible mode of action of GT3 could be Angiopoietin 2-Tie2 pathway leading to AKT/ERK pathways resulting in disruption in cell survival/ angiogenesis.

  • enhanced survival in mice exposed to ionizing radiation by combination of Gamma Tocotrienol and simvastatin
    Military Medicine, 2019
    Co-Authors: Rupak Pathak, Martin Hauerjensen, Vidya P Kumar, Sanchita P Ghosh
    Abstract:

    Ionizing radiation exposure is a major concern for active military service members, as well as civilian population. Considering that the exposure is not predictable, it is imperative that strategies to counteract radiation damage must be discovered. Recent in vitro studies performed in our laboratory demonstrated that the vitamin E analog Gamma-Tocotrienol (GT3) in combination with cholesterol-lowering drugs (Statins), synergistically induced endothelial thrombomodulin, an anticoagulant with radio-protective efficacy. It was hypothesized that the combination of treatment with both GT3 along with Statins would provide better radiation protection in vivo than each drug individually. CD2F1 mice were injected subcutaneously with either vehicle or single dose of GT3 (200 mg/kg body weight) 24 hours before irradiation followed by oral or subcutaneous administration of various doses of simvastatin (25, 50, and 100 mg/kg body weight) before exposure to lethal doses (11.5 and 12 Gy) of Cobalt-60 (60Co) Gamma-irradiation. The combined treatment group exhibited enhanced radiation lethality protection substantially, accelerated white blood cell recovery, and augmented restoration of bone marrow cellularity when compared to the animals treated with either drug exclusively. This information clearly suggests that combined treatment could be used as a safeguard for military personnel from exposure to harmful ionizing radiation.

  • Gamma-Tocotrienol Protects the Intestine from Radiation Potentially by Accelerating Mesenchymal Immune Cell Recovery
    MDPI AG, 2019
    Co-Authors: Sarita Garg, Sanchita P Ghosh, Ratan Sadhukhan, Sudip Banerjee, Alena V. Savenka, Alexei G. Basnakian, Victoria Mchargue, Junru Wang, Snehalata A. Pawar, Jerry Ware
    Abstract:

    Natural antioxidant Gamma-Tocotrienol (GT3), a vitamin E family member, provides intestinal radiation protection. We seek to understand whether this protection is mediated via mucosal epithelial stem cells or sub-mucosal mesenchymal immune cells. Vehicle- or GT3-treated male CD2F1 mice were exposed to total body irradiation (TBI). Cell death was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Villus height and crypt depth were measured with computer-assisted software in tissue sections. Functional activity was determined with an intestinal permeability assay. Immune cell recovery was measured with immunohistochemistry and Western blot, and the regeneration of intestinal crypts was assessed with ex vivo organoid culture. A single dose of GT3 (200 mg/kg body weight (bwt)) administered 24 h before TBI suppressed cell death, prevented a decrease in villus height, increased crypt depth, attenuated intestinal permeability, and upregulated occludin level in the intestine compared to the vehicle treated group. GT3 accelerated mesenchymal immune cell recovery after irradiation, but it did not promote ex vivo organoid formation and failed to enhance the expression of stem cell markers. Finally, GT3 significantly upregulated protein kinase B or AKT phosphorylation after TBI. Pretreatment with GT3 attenuates TBI-induced structural and functional damage to the intestine, potentially by facilitating intestinal immune cell recovery. Thus, GT3 could be used as an intestinal radioprotector

  • the vitamin e analog Gamma Tocotrienol gt3 and statins synergistically up regulate endothelial thrombomodulin tm
    International Journal of Molecular Sciences, 2016
    Co-Authors: Rupak Pathak, Sanchita P Ghosh, Daohong Zhou, Martin Hauerjensen
    Abstract:

    Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) and strongly induce endothelial thrombomodulin (TM); which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member Gamma-Tocotrienol (GT3) also suppresses HMGCR activity and induces TM expression without causing significant adverse side effects; even at high concentrations. To investigate the synergistic effect of statins and GT3 on TM; a low dose of atorvastatin and GT3 was used to treat human primary endothelial cells. Protein-level TM expression was measured by flow cytometry. TM functional activity was determined by activated protein C (APC) generation assay. Expression of Kruppel-like factor 2 (KLF2), one of the key transcription factors of TM, was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). TM expression increased in a dose-dependent manner after both atorvastatin and GT3 treatment. A combined treatment of a low-dose of atorvastatin and GT3 synergistically up-regulated TM expression and functional activity. Finally; atorvastatin and GT3 synergistically increased KLF2 expression. These findings suggest that combined treatment of statins with GT3 may provide significant health benefits in treating a number of pathophysiological conditions; including inflammatory and cardiovascular diseases.

  • Research Article Synergistic Radioprotection by Gamma-Tocotrienol and Pentoxifylline: Role of cAMP Signaling
    2016
    Co-Authors: Martin Hauer-jensen, Sanchita P Ghosh
    Abstract:

    Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. This study was designed to determine the efficacy and mechanisms of radioprotection by the combination of Gamma-Tocotrienol (GT3) and pentoxifylline (PTX) against acute radiation injury. Materials and Methods. Post-irradiation survival was monitored to determine the most efficacious dose and time of administration of PTX. Dose reduction factor (DRF) was calculated to compare the radioprotective efficacy of the combination. To determine the mechanism of synergistic radioprotection by the combination, mevalonate or calmodulin were coadministered with the GT3-PTX combination. Mevalonate was used to reverse the inhibitory effect of GT3 on 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), and calmodulin was used to reverse the inhibition of phosphodiesterase (PDE) by PTX. Results. The combination was most effective when 200mg/kg of PTX was administered 15min before irradiation along with 200mg/kg of GT3 (−24 h) and resulted in a DRF of 1.5. White blood cells and neutrophil counts showed accelerated recovery in GT3-PTX-treated groups compared to GT3. Mevalonate had no effect on the radioprotection of GT3-PTX; calmodulin abrogated the synergistic radioprotection by GT3-PTX. Conclusion. The mechanism of radioprotection by GT3-PTX may involve PDE inhibition. 1

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