Abstract
Selenium, a trace element with anticancer properties, can reduce harmful toxicities of chemotherapy and radiotherapy without compromising efficacy. However, the dose-response relationship in normal versus malignant human cells is unclear. We evaluated how methylseleninic acid (MSA) modulates the toxicity and efficacy of chemotherapy and radiation on malignant and non-malignant human mononuclear blood cells in vitro. We specifically investigated its effects on endoplasmic reticulum stress induction, intracellular glutathione concentration, DNA damage and viability of peripheral blood mononuclear cells and THP1 monocytic leukaemia cells in response to radiation, cytosine arabinoside or doxorubicin chemotherapy. MSA, at lower concentrations, induced protective responses in normal cells but cytotoxic effects in malignant cells, alone and in conjunction with chemotherapy or radiation. However, in normal cells higher concentrations of MSA were directly toxic and increased the cytotoxicity of radiation but not chemotherapy. In malignant cells higher MSA concentrations were generally more effective in combination with cancer treatments. Thus, optimal MSA concentrations differed between normal and malignant cells and treatments. This work supports clinical reports that selenium can significantly reduce dose-limiting toxicities of anticancer therapies and potentially improve efficacy of anticancer treatments. The optimal selenium compound and dose is not yet determined.
Highlights
Selenium (Se) is an essential trace element that is extensively studied in the prevention of numerous malignancies [1], the majority of research on Se has focused on providing adequate nutritional intake in populations that have inherently low Se intake [2]
Given that endoplasmic reticulum (ER) stress signalling can be induced in response to oxidative triggers, we investigated the impact of Se on intracellular glutathione levels [30,31,32], a key component in maintaining redox homeostasis in the cell, and how this influences DNA damage and viability of normal and malignant cells to cytotoxic chemotherapy or radiation [33,34,35]
While we demonstrated that methylseleninic acid (MSA) reduced chemotherapy-induced DNA damage in normal cells, it was ineffective in protecting them against radiation-induced DNA damage and cytotoxicity
Summary
Selenium (Se) is an essential trace element that is extensively studied in the prevention of numerous malignancies [1], the majority of research on Se has focused on providing adequate nutritional intake in populations that have inherently low Se intake [2]. The 40-fold higher initial concentration of GSH present in THP-1 cells compared to PBMCs would protect the malignant cells against cytotoxic therapies, whereas the MSA-induced severe depletion of GSH in malignant cells shown in this study may contribute to the increased sensitivity to these treatments with MSA These results are consistent with work showing that Se compounds inhibit the cisplatin-induced increase in GSH in ovarian cancer cells, thereby preventing chemoresistance [32]. It is encouraging in this study that MSA generally protected normal cells while sensitising malignant cells to cytotoxic therapies, and that it informs about mechanisms that plausibly contribute to the reduction of clinically-significant toxicities seen in clinical trials with Se supplementation during cancer treatments [10,11,12,14]. The highest MSA concentration, was most effective at inducing DNA damage with radiation and at augmenting the cytotoxicity of radiation or chemotherapy
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