δ-tocotrienol protects mouse and human hematopoietic progenitors from γ-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling

• Published in: Haematologica (Roma) Vol. 95; no. 12; pp. 1996 - 2004
• Main Authors: XIANG HONG LI, DADIN FU, LATIF, Nabil H, MULLANEY, Conor P, NEY, Patrick H, MOG, Steven R, WHITNALL, Mark H, SRINIVASAN, Venkataraman, MANG XIAO
• Format: Journal Article
• Language: English
• Published: Pavia Ferrata Storti Foundation 01-12-2010
• Subjects: Animals; Antigens, CD34 - metabolism; Biological and medical sciences; Blotting, Western; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Cells - radiation effects; Cell Survival - drug effects; Cell Survival - radiation effects; Cells, Cultured; Dose-Response Relationship, Radiation; Enzyme Activation - drug effects; Enzyme Activation - radiation effects; Eukaryotic Initiation Factor-4E - metabolism; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gamma Rays; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - radiation effects; Histones - metabolism; Humans; Male; Medical sciences; Mice; Microscopy, Fluorescence; Original; Phosphorylation - drug effects; Phosphorylation - radiation effects; Ribosomal Protein S6 - metabolism; RNA Interference; Signal Transduction - drug effects; Signal Transduction - radiation effects; Survival Analysis; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Vitamin E - analogs & derivatives; Vitamin E - pharmacology; Human; γ-tocotrienol; Extracellular signal-regulated protein kinase; Hematology; Enzyme; Transferases; Stem cell; Rodentia; Hematopoietic cell; Mitogen-activated protein kinase; Extracellular; Radioprotection; Signal transduction; Vertebrata; Mammalia; Mouse; Kinase; Animal; Mammalian target of rapamycin; Irradiation; mTOR; Erk
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2010.026492

Exposure to γ-radiation causes rapid hematopoietic cell apoptosis and bone marrow suppression. However, there are no approved radiation countermeasures for the acute radiation syndrome. In this study, we demonstrated that natural δ-tocotrienol, one of the isomers of vitamin E, significantly enhanced survival in total body lethally irradiated mice. We explored the effects and mechanisms of δ-tocotrienol on hematopoietic progenitor cell survival after γ-irradiation in both in vivo and in vitro experiments.
CD2F1 mice and human hematopoietic progenitor CD34(+) cells were treated with δ-tocotrienol or vehicle control 24 h before or 6 h after γ-irradiation. Effects of δ-tocotrienol on hematopoietic progenitor cell survival and regeneration were evaluated by clonogenicity studies, flow cytometry, and bone marrow histochemical staining. δ-tocotrienol and γ-irradiation-induced signal regulatory activities were assessed by immunofluorescence staining, immunoblotting and short-interfering RNA assay.
δ-tocotrienol displayed significant radioprotective effects. A single injection of δ-tocotrienol protected 100% of CD2F1 mice from total body irradiation-induced death as measured by 30-day post-irradiation survival. δ-tocotrienol increased cell survival, and regeneration of hematopoietic microfoci and lineage(-)/Sca-1(+)/ckit(+) stem and progenitor cells in irradiated mouse bone marrow, and protected human CD34(+) cells from radiation-induced damage. δ-tocotrienol activated extracellular signal-related kinase 1/2 phosphorylation and significantly inhibited formation of DNA-damage marker γ-H2AX foci. In addition, δ-tocotrienol up-regulated mammalian target of rapamycin and phosphorylation of its downstream effector 4EBP-1. These alterations were associated with activation of mRNA translation regulator eIF4E and ribosomal protein S6, which is responsible for cell survival and growth. Inhibition of extracellular signal-related kinase 1/2 expression by short interfering RNA abrogated δ-tocotrienol-induced mammalian target of rapamycin phosphorylation and clonogenicity, and increased γ-H2AX foci formation in irradiated CD34(+) cells.
Our data indicate that δ-tocotrienol protects mouse bone marrow and human CD34(+) cells from radiation-induced damage through extracellular signal-related kinase activation-associated mammalian target of rapamycin survival pathways.