Mitochondrial stress controls the radiosensitivity of the oxygen effect: Implications for radiotherapy.

Richard B. Richardson,Mary-Ellen Harper

doi:10.18632/oncotarget.7412

Richard B. Richardson, Mary-Ellen Harper

Open Access

https://doi.org/10.18632/oncotarget.7412

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Journal: Oncotarget	Publication Date: Feb 15, 2016
Citations: 64	License type: cc-by

Affiliation: Canadian Nuclear Laboratories, University of Ottawa

Abstract

It has been more than 60 years since the discovery of the oxygen effect that empirically demonstrates the direct association between cell radiosensitivity and oxygen tension, important parameters in radiotherapy. Yet the mechanisms underlying this principal tenet of radiobiology are poorly understood. Better understanding of the oxygen effect may explain difficulty in eliminating hypoxic tumor cells, a major cause of regrowth after therapy. Our analysis utilizes the Howard-Flanders and Alper formula, which describes the relationship of radiosensitivity with oxygen tension. Here, we assign and qualitatively assess the relative contributions of two important mechanisms. The first mechanism involves the emission of reactive oxygen species from the mitochondrial electron transport chain, which increases with oxygen tension. The second mechanism is related to an energy and repair deficit, which increases with hypoxia. Following a radiation exposure, the uncoupling of the oxidative phosphorylation system (proton leak) in mitochondria lowers the emission of reactive oxygen species which has implications for fractionated radiotherapy, particularly of hypoxic tumors. Our analysis shows that, in oxygenated tumor and normal cells, mitochondria, rather than the nucleus, are the primary loci of radiotherapy effects, especially for low linear energy transfer radiation. Therefore, the oxygen effect can be explained by radiation-induced effects in mitochondria that generate reactive oxygen species, which in turn indirectly target nuclear DNA.

Highlights

Many web sites of hospital radiology or radiotherapy departments state that nuclear DNA is the most important radiosensitive target within cells, as it is involved in cell death, the initiation and therapy of cancer, and other biological effects
We demonstrate that damage by both low-linear energy transfer (LET) (e.g., β, X- or γ-ray exposures) and high-LET (e.g., α-particle) radiations to cells in well-oxygenated tissues is related to the mitochondrial O2 consumption and production of reactive oxygen species (ROS), and that repair in hypoxic tissues is limited by deficiencies in adenosine triphosphate (ATP)
Our explanation of the oxygen effect is based on the Howard-Flanders and Alper formula [14] for oxygen enhancement ratio (OER), which can be rearranged as two components (Fig. 2A) for nominal cell parameter values

Summary

Introduction

Many web sites of hospital radiology or radiotherapy departments state that nuclear DNA (nucDNA) is the most important radiosensitive target within cells, as it is involved in cell death, the initiation and therapy of cancer, and other biological effects. Supportive of the nucleuscentric view is the widely accepted premise that radiationinduced reproductive death of mammalian cells is principally due to lesions in nucDNA, doublestrand breaks (DSBs) [1]. These lesions are thought to lead to enhanced cell death in the presence of oxygen — the oxygen effect [2]. The best known explanation of the oxygen effect is the oxygen fixation hypothesis developed in the 1950s, which posited that radiation-induced non-restorable nucDNA lesions are lethal to cells in the presence of diatomic oxygen (O2) [3]. Doubts have since emerged concerning the oxygen fixation hypothesis [3], not the least because the hypothesis fails to take into account nitric oxide (NO) as a radiosensitizer with similar effects as O2 (see Discussion)

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