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Review
. 2019 Jan 18;11(1):112.
doi: 10.3390/cancers11010112.

Hypoxic Radioresistance: Can ROS Be the Key to Overcome It?

Hui Wang  1 , Heng Jiang  2 , Melissa Van De Gucht  3 , Mark De Ridder  4
Affiliations
Review

Hypoxic Radioresistance: Can ROS Be the Key to Overcome It?

Hui Wang et al. Cancers (Basel). .

Abstract

Radiotherapy is a mainstay treatment for many types of cancer and kills cancer cells via generation of reactive oxygen species (ROS). Incorporating radiation with pharmacological ROS inducers, therefore, has been widely investigated as an approach to enhance aerobic radiosensitization. However, this strategy was overlooked in hypoxic counterpart, one of the most important causes of radiotherapy failure, due to the notion that hypoxic cells are immune to ROS insults because of the shortage of ROS substrate oxygen. Paradoxically, evidence reveals that ROS are produced more in hypoxic than normoxic cells and serve as signaling molecules that render cells adaptive to hypoxia. As a result, hypoxic tumor cells heavily rely on antioxidant systems to sustain the ROS homeostasis. Thereby, they become sensitive to insults that impair the ROS detoxification network, which has been verified in diverse models with or without radiation. Of note, hypoxic radioresistance has been overviewed in different contexts. To the best of our knowledge, this review is the first to systemically summarize the interplay among radiation, hypoxia, and ROS, and to discuss whether perturbation of ROS homeostasis could provide a new avenue to tackle hypoxic radioresistance.

Keywords: hypoxia; radiation; radiosensitization; reactive oxygen species.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Direct and indirect actions of radiation. In direct reaction, radiation directly interacts with DNA resulting in DNA damage. In indirect reaction, radiation interacts with other molecules in the cells, particularly water, to produce free radicals such as hydrogen atoms (H+), hydroxyl radicals (HO), and superoxide radical anion (O2−), which in turn induce the damage to the DNA.
Figure 2
Figure 2
The oxygen fixation hypothesis. Under aerobic condition, radiation induced DNA radicals are able to react with oxygen, resulting in permanent DNA damage and strand breaks. Under hypoxic condition, the lack of oxygen enables the DNA radicals to be reduced to the original form that hampers the generation of strand breaks. Hypoxia-induced radioresistance can be estimated by survival curves. Briefly, the oxygen enhancement ratio (OER) or hypoxic radioresistance can be represented by a ratio, which is calculated by dividing doses administered under hypoxic to aerobic conditions needed to achieve a same survival fractions.
Figure 3
Figure 3
The interplay among hypoxia, ROS and radiation, and strategies to overcome hypoxic radioresistance. Radiotherapy kills cancer cells by causing DNA damage via generation of reactive oxygen species (ROS). However, under hypoxic condition, hypoxia induces HIF-1α accumulation by (1) prevention of protein degradation, or (2) upregulation of gene expression via ROS mediated pathways. As a result of increased HIF-1α, HIF-1 is activated and regulates more than a hundred of genes, conferring radioresistance by acting upon multiple mechanisms at different levels. For example, HIF-1 enhances expression of genes implicated in antioxidant defense systems, resulting in increased capacity to buffer ROS and radioresistance. In addition, hypoxia and radiation induced ROS could trigger a feedback loop that is in favor of generation of antioxidant. To counteract hypoxic radioresistance, historically, hyperbaric oxygen, and oxygen mimetic radiosensitizers have been explored, but failed in implementing in clinical practice due to their inconvenient application or side effects. Given ROS are the primary effector molecules of radiation, and hypoxic tumor cells strongly dependent on antioxidant defense systems to sustain ROS homeostasis, exposure of ROS insults to hypoxic tumor cells or perturbation of ROS adaptation pathway may lead to selective cytotoxicity and radiosensitization. In respect of this, approaches such as inhibition of HIF-1, suppression of antioxidant enzymes, and NO donors are under active investigation. The radiosensitizing approaches are indicated in red frames.
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