Author Affiliations

  1. Xiang Hong Li,
  2. Dadin Fu,
  3. Nabil H. Latif,
  4. Conor P. Mullaney,
  5. Patrick H. Ney,
  6. Steven R. Mog,
  7. Mark H. Whitnall,
  8. Venkataraman Srinivasan and
  9. Mang Xiao*
  1. Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences
  1. * Corresponding author; email: xiao{at}afrri.usuhs.mil

Abstract

Background and Objectives. 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 report, we demonstrate that natural delta-tocotrienol, one of the isomers of vitamin E, significantly enhanced survival in total body lethally irradiated mice. We explored the effects and mechanisms of delta-tocotrienol on hematopoietic progenitor cell survival after γ-irradiation in both in vivo and in vitro experiments.

Design and Methods. CD2F1 mice and human hematopoietic progenitor CD34+ cells were treated with delta-tocotrienol or vehicle control 24 h before or 6 h after γ-irradiation. Effects of delta-tocotrienol on hematopoietic progenitor cell survival and regeneration were evaluated by clonogenicity, flow cytometry, and bone marrow histochemical staining. Delta-tocotrienol and γ-irradiation-induced signal regulatory activities were assessed by immunofluorescence staining, immunoblotting and siRNA assay.

Results. Delta-tocotrienol displayed significant radioprotective effects. A single injection of delta-tocotrienol protected 100% of CD2F1 mice from total body irradiation-induced death as measured by 30-day post-irradiation survival. Delta-tocotrienol increased cell survival, and regeneration of hematopoietic microfoci and lineage-negative/Sca-1-positive/ckit-positive stem and progenitor cells in irradiated mouse bone marrow, and protected human CD34+ cells from radiation-induced damage. Delta-tocotrienol activated Erk1/2 phosphorylation and significantly inhibited formation of DNA-damage marker γ-H2AX foci. In addition, delta-tocotrienol upregulated mTOR 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 Erk1/2 expression by siRNA abrogated delta-tocotrienol-induced mTOR phosphorylation and clonogenicity, and increased γ-H2AX foci formation in irradiated CD34+ cells.

Interpretation and Conclusions. Our data indicate that DT3 protects mouse bone marrow and human CD34+ cells from radiation-induced damage through Erk activation-associated mTOR survival pathways.

  • Received April 20, 2010.
  • Accepted August 27, 2010.