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.
- Copyright © 2010, Ferrata Storti Foundation