Gamma tocotrienol, a potent radioprotector, preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival

Abstract

Gamma tocotrienol (GT3) has been reported as a potent ameliorator of radiation-induced gastrointestinal (GI) toxicity when administered prophylactically. This study aimed to evaluate the role of GT3 mediated pro- and anti-apoptotic gene regulation in protecting mice from radiation-induced GI damage. Male 10- to 12-weeks-old CD2F1 mice were administered with a single dose of 200 mg/kg of GT3 or equal volume of vehicle (5% Tween-80) 24 h before exposure to 11 Gy of whole-body γ-radiation. Mouse jejunum was surgically removed 4 and 24h after radiation exposure, and was used for PCR array, histology, immunohistochemistry, and immunoblot analysis. Results were compared among vehicle pre-treated no radiation, vehicle pre-treated irradiated, and GT3 pre-treated irradiated groups. GT3 pretreated irradiated groups, both 4h and 24h after radiation, showed greater upregulation of anti-apoptotic gene expression than vehicle pretreated irradiated groups. TUNEL staining and intestinal crypt analysis showed protection of jejunum after GT3 pre-treatment and immunoblot results were supportive of PCR data. Our study demonstrated that GT3-mediated protection of intestinal cells from a GI-toxic dose of radiation occurred via upregulation of antiapoptotic and downregulation of pro-apoptotic factors, both at the transcript as well as at the protein levels.

Keywords: ARS; ATM; Apoptosis; DNA-PK; DNA-dependent protein kinase; DRF; GI; GT3; Gamma tocotrienol; Gastrointestinal toxicity; PARP; ROS; Radiation; Radioprotection; TUNEL; acute radiation syndrome; ataxia-telangiectasia-mutated; dose reduction factor; gastrointestinal; poly-ADP-ribose polymerase; reactive oxygen species; terminal deoxynucleotidyl transferase dUTP nick end labeling; γ-tocotrienol.