Mechanisms underlying the radioprotective properties of γ-tocotrienol: comparative gene expression profiling in tocol-treated endothelial cells

Berbée, Maaike; Fu, Qiang; Boerma, Marjan; Kumar, Krishna B.; Loose, David S.; Hauer‐Jensen, Martin

doi:10.1007/s12263-011-0228-8

Cited by 32 publications

(31 citation statements)

References 29 publications

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“…GT3 protects endothelial cells from radiation-induced injury not only by virtue of its antioxidant properties, but also by inhibition of HMG-CoA reductase and improving the availability of the nitric oxide synthase cofactor tetrahydrobiopterin (44). GT3 induces multiple changes in functional genetic pathways known to be of critical importance in the cellular responses to radiation exposure, such as oxidative stress, DNA damage, cell cycle phase, regulation of cell death, cell proliferation, hematopoiesis and blood vessel development (45). Recently, it has been reported that GT3-mediated protection of intestinal cells occurs via up-regulation of anti-apoptotic and downregulation of pro-apoptotic factors (46).…”

Section: Discussionmentioning

confidence: 99%

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

Singh

Kulkarni²,

Fatanmi³

et al. 2016

Radiation Research

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105

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The search for treatments to counter potentially lethal radiation-induced injury over the past several decades has led to the development of multiple classes of radiation countermeasures. However, to date only granulocyte colony-stimulating factor (G-CSF; filgrastim, Neupogen)and pegylated G-CSF (pegfilgrastim, Neulasta) have been approved by the United States Food and Drug Administration (FDA) for the treatment of hematopoietic acute radiation syndrome (ARS). Gamma-tocotrienol (GT3) has demonstrated strong radioprotective efficacy in the mouse model, indicating the need for further evaluation in a large animal model. In this study, we evaluated GT3 pharmacokinetics (PK) and efficacy at different doses of cobalt-60 gamma radiation (0.6 Gy/min) using the nonhuman primate (NHP) model. The PK results demonstrated increased area under the curve with increasing drug dose and half-life of GT3. GT3 treatment resulted in reduced group mean neutropenia by 3-5 days and thrombocytopenia by 1-5 days. At 5.8 and 6.5 Gy total-body irradiation, GT3 treatment completely prevented thrombocytopenia. The capability of GT3 to reduce severity and duration of neutropenia and thrombocytopenia was dose dependent; 75 mg/kg treatment was more effective than 37.5 mg/kg treatment after a 5.8 Gy dose. However, the higher GT3 dose (75 mg/kg) was associated with higher frequency of adverse skin effects (small abscess) at the injection site. GT3 treatment of irradiated NHPs caused no significant difference in animal survival at 60 days postirradiation, however, low mortality was observed in irradiated, vehicle-treated groups as well. The data from this pilot study further elucidate the role and pharmacokinetics of GT3 in hematopoietic recovery after irradiation in a NHP model, and demonstrate the potential of GT3 as a promising radioprotector.

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Section: Discussionmentioning

confidence: 99%

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

Singh

Kulkarni²,

Fatanmi³

et al. 2016

Radiation Research

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105

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“…2 Moreover, tocotrienols have particular properties that may make them effective against cardiovascular disease. While tocotrienols have antioxidant properties as strong as α-tocopherol (8), they accumulate in endothelial cells to at least 30-fold higher levels than α-tocopherol and modulate at least 20-fold larger numbers of genes in endothelial cells (9, 10). Moreover, γ- and δ-tocotrienols reduce the intracellular levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis (11, 12).…”

Section: Introductionmentioning

confidence: 99%

A Tocotrienol-Enriched Formulation Protects against Radiation-Induced Changes in Cardiac Mitochondria without Modifying Late Cardiac Function or Structure

et al. 2015

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Radiation-induced heart disease (RIHD) is a common and sometimes severe late side effect of radiation therapy for intrathoracic and chest wall tumors. We have previously shown that local heart irradiation in a rat model caused prolonged changes in mitochondrial respiration and increased susceptibility to mitochondrial permeability transition pore (mPTP) opening. Because tocotrienols are known to protect against oxidative stress-induced mitochondrial dysfunction, in this study, we examined the effects of tocotrienols on radiation-induced alterations in mitochondria, and structural and functional manifestations of RIHD. Male Sprague-Dawley rats received image-guided localized X irradiation to the heart to a total dose of 21 Gy. Twenty-four hours before irradiation, rats received a tocotrienol-enriched formulation or vehicle by oral gavage. Mitochondrial function and mitochondrial membrane parameters were studied at 2 weeks and 28 weeks after irradiation. In addition, cardiac function and histology were examined at 28 weeks. A single oral dose of the tocotrienol-enriched formulation preserved Bax/Bcl2 ratios and prevented mPTP opening and radiation-induced alterations in succinate-driven mitochondrial respiration. Nevertheless, the late effects of local heart irradiation pertaining to myocardial function and structure were not modified. Our studies suggest that a single dose of tocotrienols protects against radiation-induced mitochondrial changes, but these effects are not sufficient against long-term alterations in cardiac function or remodeling.

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“…These effects led to enhancement of hematopoietic recovery and improvement of 30-day survival after total body irradiation (TBI) [21-23]. These results suggested that administration of emulsified GT3 by subcutaneous injection has long-term biological effects; however, whether the biological effects are due to the increase of GT3 level in the early phase or the persistent functions as the accumulation in tissues is unknown.…”

Section: Introductionmentioning

confidence: 99%

Tissue distribution of emulsified γ-tocotrienol and its long-term biological effects after subcutaneous administration

Deng¹,

Peng²,

Wu³

et al. 2014

Lipids Health Dis

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Backgroundγ-tocotrienol (GT3), an analogue of vitamin E, has gained increasing scientific interest recently as it provides significant health benefits. It has been shown that emulsified GT3, after subcutaneous administration, has long-term biological effects. However, whether the effects are due to the increase of GT3 level in the early phase following administration or the persistent functions after accumulation in tissues is unknown. This study was conducted to determine the levels of GT3 in different tissues by high performance liquid chromatography (HPLC) with a fluorescence detector after a single-dose of GT3 with polyethylene glycol (PEG-400) emulsion via subcutaneous injection. Previous studies have explored that GT3 has favorable effects on bone and can inhibit osteoclast formation. To confirm the persistent biological activity of accumulated GT3 in tissues, receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) gene expressions, which have an important role in regulating osteoclast formation, were also evaluated in bone tissue on day 1, 3, 7 and 14 after a signal subcutaneous injection of GT3.MethodsC57BL/6 female mice were administrated GT3 (100 mg/kg body weight) with PEG-400 emulsion by subcutaneous injection. GT3 levels in different tissues were determined by HPLC with a fluorescence detector. Gene expressions were measured by real-time PCR.ResultsGT3 predominantly accumulated in adipose and heart tissue, and was maintained at a relatively stable level in bone tissues after a single-dose administration. Accumulated GT3 in bone tissues significantly inhibited the increase in RANKL expression and the decrease in OPG expression induced by db-cAMP.ConclusionsWe investigated the tissue distribution of GT3 with PEG emulsion by subcutaneous administration, which has never been reported so far. Our results suggest that GT3 with PEG emulsion accumulated in tissues is able to carry out a long-term biological effect and has therapeutic value for treating and preventing osteoporosis.

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Mechanisms underlying the radioprotective properties of γ-tocotrienol: comparative gene expression profiling in tocol-treated endothelial cells

Cited by 32 publications

References 29 publications

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

Radioprotective Efficacy of Gamma-Tocotrienol in Nonhuman Primates

A Tocotrienol-Enriched Formulation Protects against Radiation-Induced Changes in Cardiac Mitochondria without Modifying Late Cardiac Function or Structure

Tissue distribution of emulsified γ-tocotrienol and its long-term biological effects after subcutaneous administration

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