Radioprotective efficacy of delta-tocotrienol, a vitamin E isoform, is mediated through granulocyte colony-stimulating factor

Abstract

Newman, Victoria L.; and Fatanmi, Oluseyi O., "Radioprotective efficacy of delta-tocotrienol, a vitamin E isoform, is mediated through granulocyte colony-stimulating factor" (2014 Aims: The objectives of this study were to determine the cytokine induction by delta tocotrienol (DT3, a promising radiation countermeasure) and to investigate the role of granulocyte colony-stimulating factor (G-CSF) in its radioprotective efficacy against ionizing radiation in mice. Main methods:Multiplex Luminex was used to analyze cytokines induced by DT3 and other tocols (gammatocotrienol and tocopherol succinate) in CD2F1 mice. Mice were injected with an optimal dose of DT3 and a G-CSF antibody, and their 30-day survival against cobalt-60 gamma-irradiation was monitored. The neutralization of G-CSF by the administration of a G-CSF-specific antibody in DT3-injected mice was investigated by multiplex Luminex. Key findings: Our data demonstrate that DT3 induced high levels of various cytokines comparable to other tocols being developed as radiation countermeasures. DT3 significantly protected mice against ionizing radiation, and the administration of a G-CSF neutralizing antibody to DT3-treated animals resulted in the complete abrogation of DT3's radioprotective efficacy and neutralization of G-CSF in peripheral blood. Significance: Our study findings suggest that G-CSF induced by DT3 mediates its radioprotective efficacy against ionizing radiation in mice.Published by Elsevier Inc.

The Potentiation of the Radioprotective Efficacy of Two Medical Countermeasures, Gamma-Tocotrienol and Amifostine, by a Combination Prophylactic Modality

“…Earlier we have demonstrated that a number of radiation countermeasures currently under investigation stimulate G-CSF production in mice, including CBLB502 in nonhuman primates in addition to mice and canines (15, 16, 40–43) . Further, the radioprotective efficacy of several of these agents was abrogated by administration of G-CSF antibody (15, 16, 41–44) , suggesting that radioprotective efficacy of these agents is mediated through G-CSF.…”

“…The serum was collected and stored at –70°C until used. Luminex 200 (Luminex Corp., Austin, TX, USA) was used to detect cytokines, chemokines, and growth factors in mouse serum samples supernatants as described earlier using multiplex kits (Bio-Rad Inc., Hercules, CA, USA) (15) . Mice administered amifostine were treated with 50, 100 or 150 mg/kg dose.…”

Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS): A review

“…These new countermeasures include agents such as 5-androstenediol (5-AED/Neumune Ò ) [24,25], CBLB502 (truncated flagellin: Entolimod™) [26], CBLB612 and CBLB613 (both lipopeptides of mycoplasma origin) [27,28], vitamin E isomers and their derivatives (d-tocotrienol [29,30], c-tocotrienol [31], and a-tocopherol succinate [32,33]). Further, we have demonstrated in mice, that the administration of a G-CSF antibody completely abrogates the radioprotective efficacy of some radiation countermeasures (e.g., Fig.…”

“…(STAT -signal transducer and activator of transcription, STAT5 -transcription factor of 5B, STAT3 -transcription factor of 3, P indicates phosphorylated or activated signal, RAS -Rat Sarcoma, RAF -rapid accelerated fibrosarcoma -extracellular-signal-regulated kinase 5, P13K -phosphatidylinositol-4,5-bisphosphate 3-kinase (phophatidylinositide 3-kinases), BAD -Bcl-2 associated death promoter, BCLxL -B-cell lymphoma-extra-large, CASPASES -cysteine-aspartic proteases AKA cysteine-dependent aspartate-directed proteases, PDK -pyruvate dehydrogenase kinase, AKT -protein kinase B, a serine/threonine-specific protein kinase, BcL-2 -an anti-apoptotic protein, CiAP2 -Baculoviral IAP repeatcontaining protein 3). [34], CBLB502 [26], d-tocotrienol [29], c-tocotrienol [31], and a-tocopherol succinate [33,35]), clearly suggesting that G-CSF, plays an important role in the radioprotective efficacy of these countermeasures. Recently, G-CSF and interleukin-6 (IL-6) have been identified as candidate biomarkers for the radioprotective and radiomitigative efficacy of CBLB502.…”

Addressing the Symptoms or Fixing the Problem? Developing Countermeasures against Normal Tissue Radiation Injury

“…While many of the potential countermeasures in this category are partly or wholly antioxidant in nature, such as the vitamin-derived tocopherols and tocotrienols (59), it has been suggested that the free radical scavenging mechanisms associated with such compounds will unlikely be sufficiently reactive to enable efficient removal of the primary and secondary radicals associated with high doses of radiation (60). Therefore, any observed success more likely comes from alternative or additional modes of action, such as effects on cytokine expression (61). However, it is worth noting that in scenarios where protection strategies are needed against relatively low, albeit chronic, exposures, such as the space environment, the low toxicity risk associated with purely antioxidant approaches could prove to be of considerable benefit.…”