Abstract
Although recent reports suggest that selenium can modulate the activity of cytotoxic drugs, the mechanism underlying this activity remains unclear. This has been investigated using a panel of human B-cell lymphoma cell lines. The cytotoxic effects of chemotherapeutic agents (e.g., doxorubicin, etoposide, 4-hydroperoxycyclophosphamide, melphalan, and 1-beta-d-arabinofuranosylcytosine) were increased by up to 2.5-fold when combined with minimally toxic concentrations (EC(5-10)) of the organic selenium compound, methylseleninic acid (MSA). DNA strand breaks were identified using comet assays, but the measured genotoxic activity of the combinations did not explain the observed synergistic effects in cell death. However, minimally toxic (EC(10)) concentrations of MSA induced a 50% decrease in nuclear factor-kappaB (NF-kappaB) activity after an exposure of 5 h, similar to that obtained with the specific NF-kappaB inhibitor, BAY 11-7082. Combinations of BAY 11-7082 with these cytotoxic drugs also resulted in synergism, suggesting that the chemosensitizing activity of MSA is mediated, at least in part, by its effects on NF-kappaB. Basal intracellular selenium concentration was higher in a MSA-sensitive cell line. After exposure to MSA, methylselenocysteine and selenomethionine were identified as the main intracellular species generated. Volatile selenium species, trapped using solid-phase microextraction fibers, were identified as dimethylselenide and dimethyldiselenide. These volatile species are thought to be the most biologically active forms of selenium. Taken together, these results show that the NF-kappaB pathway is one target for MSA underlying the interaction between MSA and chemotherapy. These data encourage the further clinical development of selenium as a potential modulator of cytotoxic drug activity in B-cell lymphomas.
Highlights
Selenium is an essential trace element that has immunomodulatory activity [1, 2], and has several functions relevant to cancer medicine
The emerging role of selenium as a potential chemomodulatory agent led us to explore the supplementation effect of methylseleninic acid (MSA) when combined with established cytotoxic drugs, with the aim of improving the treatment of lymphoid malignancies
First attempts have been made to increase the therapeutic efficacy of standard cytotoxic drugs using selenium compounds [20, 21]
Summary
Selenium is an essential trace element that has immunomodulatory activity [1, 2], and has several functions relevant to cancer medicine. Several studies have reported that selenium, at supranutritional concentrations, may modulate the activity of cytotoxic chemotherapy. In a study from our own research group, serum selenium concentration at diagnosis was predictive of dose delivery, treatment response, and long-term survival in a group of 99 patients with aggressive non–Hodgkin’s lymphoma. Serum selenium remained predictive of outcome in a multivariate analysis that included clinical variables as cofactors, as reported by Deffuant et al [7] in cutaneous T-cell lymphoma patients. Selenium compounds are cytotoxic to tumor cells in vitro [10] and at high doses (15 mg/kg) are lethally toxic in nude mice [11].3
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