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

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.

Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas

“…Some of these mechanisms include, the ability of cancer cells to repair the radiation-induced DNA damage; cell-cycle arrest; alterations in the expression of oncogenes and tumor suppressor genes; autophagy induction; variations in tumor microenvironment such as hypoxia, elevation in cytokine levels, and epithelial to mesenchymal transitions; generation of cancer stem cells (CSCs); and alterations in tumor metabolism [20]. Of these, the development of tumor hypoxia and the associated metabolic pathways is one of the most important contributors to clinical radioresistance [21]. Hypoxia, a state which deprives the tissue of adequate oxygen supply, is a common microenvironment feature of almost all solid tumors [22].…”

Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib

“…It would be of interest to employ a similar approach in OAC treatmentnaïve tumour tissue across the various stages of disease progression to further elucidate the role of altered energy metabolism in OAC and compare the findings to real-time metabolic analysis. Hypoxia promotes the transformation of tumour cell metabolism from oxidative metabolism to anaerobic glycolysis, which protects tumour cells, promotes tumour growth and the development of treatment resistance in tumour stem cells 26 . We sought to investigate if OAC treatment-naïve biopsies adapt their metabolic profile to conditions of hypoxia and if pyrazinib (P3) could inhibit mitochondrial respiration under hypoxic conditions of 0.5% O 2 .…”

“…In a study by Wang et al, in genetically modified macrophages overexpressing HIF-1α the OCR:ECAR ratio was dramatically decreased compared to non-HIF-1α overexpressing macrophages demonstrating a shift to glycolysis metabolism compared to mitochondrial oxidation in HIF-1α overexpressing macrophages 27 . Oxygen is a potent radiosensitiser and solid tumours with areas of hypoxia are the most aggressive and difficult tumours to treat 26 . A number of strategies which have attempted to increase oxygen delivery to the tumour have failed in the clinic largely due to the heterogenic nature of tumour vasculature 28 .…”

<p>Synergetic Influence of Bismuth Oxide Nanoparticles, Cisplatin and Baicalein-Rich Fraction on Reactive Oxygen Species Generation and Radiosensitization Effects for Clinical Radiotherapy Beams</p>

“…The ROS was induced due to the breakage of the chemical bonds of tissue molecules, especially water molecules after the irradiation, leading to DNA, RNA, and protein damages. 1,36 Following the induction of the high amount of ROS, it could initiate the cell apoptosis and cell cycle redistribution. 37,38 The presence of radiosensitizers could amplify the ROS production.…”