Harnessing epigenetics and metabolism to modulate tissue response to radiotherapy

Radiotherapy (RT), since its first utilization, remains among the primary modalities to treat cancer with about 50% of cancer patients receiving RT nowadays. Despite the overall significant curative potential, two obstacles remain that substantially affect the success of RT. These are the normal tissue toxicity that often is the major dose-limiting factor for a number of human cancers and tumor radioresistance.

Epigenetic and metabolic processes play important roles in normal biological processes, as well as in response to exogenous stressors. Recent studies demonstrate that ionizing radiation is a potent epigenotoxic stressor and is capable of causing alterations in the metabolome. In parallel with these new findings, understanding that epigenetics and metabolomics may be used in order to modulate the tissue response to radiation has been increasingly demonstrated; for instance, treatment of cancer cells with the DNA demethylation agent 5-aza results in their radiosensitization (Dote et al. 2005). On the other hand, modulation of amino acid balance after radiotherapy allows normalization of metabolic profiles in normal cells and results in an increase in the normal tissue tolerance to radiation, besides other effects.

In this Special Issue, the current knowledge of normal and cancerous tissue epigenetic and metabolic responses was connected to the response to ionizing radiation therapy. This Special Issue covered the following aspects: basic science, normal tissue toxicity, radiosensitization of cancer, and associated stromal cells as well as an important aspect of chemoprevention.

Koukourakis and Giatromanolaki provide a comprehensive review of the Warburg effect with particular emphasis given to the role of lactate dehydrogenase 5 (LDH5). The latter is a major enzyme involved in the anaerobic transformation of pyruvate to lactate. The authors provide supporting evidence of LDH5 as a predictor of response to RT and a major target for cancer cell radiosensitization (Koukourakis and Giatromanolaki 2018).

Lung cancer remains one of the leading causes of cancer-related deaths in the US and worldwide, and is regularly treated with a variety of radiotherapy regimens. The work from Boysen et al. demonstrates the potential of glutaminase inhibitor CB-839 to increase radiation sensitivity of lung tumor cells and the response of human lung tumor xenografts in mice. Previously this agent has been used on its own in an attempt to reduce the metabolic activity in malignant cells and slow tumor progression. However, this required high dosing and long treatment durations. The study presented here brings to light a compelling possibility of using the inhibition of glutaminase for a short time before and during radiation exposure to inhibit the cells’ ability to counteract both metabolic and radiation-induced radical stress. In the studied model, there was a significant increase in cellular and tumor radiosensitivity with a single short course of treatment suggesting a clinically feasible combined modality approach (Boysen et al. 2018).

The role of diet in the success of cancer therapy is becoming increasingly recognized. For instance, depriving cancer cells of just one amino acid (methionine) results in tumor radiosensitization both in vitro and in vivo (Miousse et al. 2018). Klement (2017), in a comprehensive review, discusses the role of a ketogenic diet as a complementary treatment in both normal and cancerous tissue toxicity. Accumulating evidence suggests that ketogenic therapy causes metabolic shifts from glycolysis toward mitochondrial metabolism that can selectively increase production of ROS and cause impairment of ATP production in tumor cells. On the other hand, the differential stress resistance characterized by disbalance between the glucose and growth factors on one side and ketone bodies on the other triggers normal but not cancerous cell reprogramming towards maintenance and stress resistance. The ketone body ß-hydroxybutyrate is of particular interest; it is an endogenous class-I histone deacetylase inhibitor that holds a tremendous potential to be utilized as both radioprotector for normal cells and a potent radiosensitizer for cancerous cells (Klement 2017).

Another important aspect of dietary intervention that can potentiate the effects of radiotherapy while preventing or decreasing the normal tissue toxicity is discussed by Maqsudur Rashid et al. (2018). Polyunsaturated fatty acids (PUFA) are essential fatty acids that are found in fish, vegetable oil, and flaxseeds. Accumulating evidence indicates that n-3 PUFA demonstrates radiosensitizing properties in vitro, in vivo, and in clinical trials. A number of studies where PUFA revealed radioprotective properties have also been reported. Among those of particular importance are studies demonstrating protection of radiation-induced gastrointestinal (GI) syndrome in mice (Maqsudur Rashid et al. 2018).

Radiation-induced GI injury, or radiation enteropathy, and potential strategies for its prevention are further discussed in the manuscript by Pathak et al. (2018). Despite remarkable technological advances in RT, the risk of radiation enteropathy still remains to be imminent with the lack of successful approaches for its mitigation. To prevent RT-induced undesirable alterations in the GI tract, the authors propose utilization of natural plant products. Indeed, accumulating evidence suggests that the number of phytochemicals, such as vitamin E analogs α-tocopherol, as well as γ- and δ-tocotrienols, together with genistein, lycopene and ascorbic acid to name a few, have the potential to suppress intestinal radiation toxicity (Pathak et al. 2018).

Advancement of cancer leads to alterations in the host’s metabolism, which is often further associated with an ongoing, progressive loss of muscle mass, and fat tissue. Therefore, balanced nutrition in cancer patients is one of the pillars of successful cancer therapy. van der Meij et al. (2018) in their review article discuss the importance of amino acid supplements, the building blocks of proteins and polypeptides, and regulators of the key metabolic pathways during and after cancer therapy. A high protein intake or amino acid supplementation may improve muscle protein synthesis and lead to more favorable clinical outcomes.

Another drawback of RT is the radiation-induced brain injury in patients surviving more than 6 months following cranial irradiation. Stem cell therapy shows considerable effectiveness in treating various forms of cognitive dysfunction after RT. At the same time, safety concerns arise that are associated with grafting foreign stem cells into the brain. To overcome these limitations, the membrane-bound extracellular vesicles (EV) were recently proposed. In this issue, Leavitt et al. (2018) discuss the potential of microRNAs, the most important bioactive cargo within EV, for amelioration of RT-induced cognitive deficits.

The original article from Haritwal et al. (2018) reports Trichostatin A (TSA), a histone deacetylase inhibitor (HDAC), to mitigate radiation-induced androphysiological anomalies and metabolic alterations in the mouse model. Specifically, the authors reported that administration of TSA 1 and 24 h after irradiation resulted in significant reduction of abnormal sperm counts compared to irradiated mice with TSA. Mitigation of radiation-induced testicular damage with TSA was associated with normalization of metabolomic profiles.

The review by Karabulutoglou et al. (2018) summarizes the current knowledge on how alterations in dietary and metabolic factors may affect the risk of development of radiation-induced leukemia by inhibiting or reversing the leukemic progression. The role of dietary interventions and factors such as dietary restriction, amino acids, vitamins, antibiotics, and microbiota are being discussed extensively. Furthermore, the authors provide a comprehensive review of epigenetic regulation of hematopoiesis and how epigenetic reprogramming may influence the process of leukemogenesis.

DNA double-strand breaks are the most lethal type of DNA damage and changes in chromatin structure in the vicinity of the damage sites facilitate the efficient initiation of the DNA damage signaling cascade. The review manuscript by Sharma and Hendzel (2018) provides a state-of-the-art knowledge on the relationship between histone posttranslational modifications – the key epigenetic regulators of chromatic structure – and the radiation-induced DNA damage signaling and repair.

The contribution of mitochondrial dysfunction to the post-irradiation epigenetic reprogramming and further genomic instability is the subject of the review article by Baulch (2018). This paradigm-shifting theory, the solid foundations for which were laid by the author and her mentor and then colleague Bill Morgan, considers involvement of mitochondrial alterations in the synthesis of the methyl, acetyl, and phosphate donors. As all three are needed for covalent DNA and histone modifications, these will lead to altered epigenetic status of the cell, leading further to the development of genomic instability (Baulch 2018).

Additional information

Funding

The authors would like to acknowledge the support provided by the National Institutes of Health [1P20GM109005], Arkansas Biosciences Institute and the Winthrop P. Rockefeller Cancer Institute.