Gamma tocotrienol, a potent radioprotector, preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival.
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.
Department of Biochemistry and Molecular & Cell Biology, Georgetown University Medical Center and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Shubhankar
S
Suman
Kamal
K
Datta
Kushal
K
Chakraborty
Shilpa S
SS
Kulkarni
Kathryn
K
Doiron
Albert J
AJ
Fornace
K
K
Sree Kumar
Martin
M
Hauer-Jensen
Sanchita P
SP
Ghosh
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D002839:Chromans / Q000494:pharmacology*; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005720:Gamma Rays / Q000009:adverse effects; D020287:In Situ Nick-End Labeling; D007422:Intestines / Q000166:cytology / Q000187:drug effects*; D008297:Male; D051379:Mice; D011832:Radiation Injuries / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498806:Bag3 protein, mouse; C494773:Bak1 protein, mouse; D002839:Chromans; C498608:Dsip1 protein, mouse; D011837:Radiation-Protective Agents; D014157:Transcription Factors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D014810:Vitamin E; C013649:plastochromanol 8; D044767:Ubiquitin-Protein Ligases
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