The Vitamin E Analog Gamma-Tocotrienol (GT3) Suppresses Radiation-Induced Cytogenetic Damage.

Rupak Pathak,Regina K Binz,Igor Koturbash,Marjan Boerma,Sanchita P Ghosh,Jeffrey R Sawyer,Martin Hauer-Jensen,Abdel Bachri

doi:10.1007/s11095-016-1950-0

Abstract

PurposeIonizing radiation (IR) generates reactive oxygen species (ROS), which cause DNA double-strand breaks (DSBs) that are responsible for cytogenetic alterations. Because antioxidants are potent ROS scavengers, we determined whether the vitamin E isoform γ-tocotrienol (GT3), a radio-protective multifunctional dietary antioxidant, can suppress IR-induced cytogenetic damage.MethodsWe measured DSB formation in irradiated primary human umbilical vein endothelial cells (HUVECs) by quantifying the formation of γ-H2AX foci. Chromosomal aberrations (CAs) were analyzed in irradiated HUVECs and in the bone marrow cells of irradiated mice by conventional and fluorescence-based chromosome painting techniques. Gene expression was measured in HUVECs with quantitative reverse transcriptase polymerase chain reaction (qRT-PCR).ResultsGT3 pretreatment reduced DSB formation in HUVECS, and also decreased CAs in HUVECs and mouse bone marrow cells after irradiation. Moreover, GT3 increased expression of the DNA-repair gene RAD50 and attenuated radiation-induced RAD50 suppression.ConclusionsGT3 attenuates radiation-induced cytogenetic damage, possibly by affecting RAD50 expression. GT3 should be explored as a therapeutic to reduce the risk of developing genetic diseases after radiation exposure.

Highlights

Ionizing radiation (IR) compromises the redox state of cells and generates reactive oxygen species (ROS) in excess
Because GT3 has strong antioxidant properties and protects endothelial cells from radiation damage [15,17], we proposed that GT3 pretreatment would suppress radiation-induced double-strand breaks (DSBs) in human umbilical vein endothelial cells (HUVECs)
To determine whether GT3 was able to suppress DSBs in HUVECs, we assayed the formation of γH2AX foci as an indicator of DSBs after irradiation

Summary

Introduction

Ionizing radiation (IR) compromises the redox state of cells and generates reactive oxygen species (ROS) in excess. DSBs are serious lesions that can cause numerous structural chromosomal aberrations (CAs) such as sister chromatid unions, chromatid- or chromosome-type breaks, and dicentric or ring chromosomes [2]. Such CAs are deleterious and are associated with the progression and development of several diseases, including cancer [3]. CAs have been found in all major tumor types and are associated with mental illness, congenital heart disease, and respiratory problems [4,5,6] This suggests that CAs are a hallmark of cancer and a cytogenetic signature of various pathophysiological conditions. While CAs can arise spontaneously, radiation is a major factor that induces CAs

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