Delta-Tocotrienol Protects Mouse and Human Hematopoietic Progenitors from Gamma-Irradiation Through Erk/mTOR Signaling
Abstract
Exposure to "-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 " -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 " -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 "- 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 "-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 resp
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2010
- Accession Number
- ADA529039
Entities
People
- Conor P. Mullaney
- Dadin Fu
- Mang Xiao
- Mark H. Whitnall
- Navil H. Latif
- Patrick H. New
- Steven R. Mog
- Venkataraman Srinivasan
- Xiang H. Li
Organizations
- Armed Forces Radiobiology Research Institute