Chemosensitization of B-Cell Lymphomas by Methylseleninic Acid Involves Nuclear Factor-κB Inhibition and the Rapid Generation of Other Selenium Species

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-B-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-KB (NF-KB) activity after an exposure of 5 h, similar to that obtained with the specific NF-KB 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-KB. 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-KB 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.

Methylseleninic acid inhibits HDAC activity in diffuse large B-cell lymphoma cell lines

“…HIF-1 expression is also regulated by NF-k itself subject to acetylation/deacetylation modifications of the p65, and possibly p52, subunits which affects DNA binding [2]. We have previously reported the NF-k inhibitory activity of MSA [14].…”

“…Regarding diffuse large B-cell lymphoma (DLBCL), our department has reported that serum Se at diagnosis is predictive of outcome in patients with B-cell non Hodgkin lymphoma, the majority of whom had DLBCL [18]. In addition, in vitro studies have demonstrated that high concentrations of Se are cytotoxic [17], whilst non-toxic concentrations can sensitise cells to the cytotoxic effects of chemotherapeutic agents [14]. The precise mechanism of Se action is not clear and differs based on the chemical form, dose/concentration and tumour type.…”

“…The precise mechanism of Se action is not clear and differs based on the chemical form, dose/concentration and tumour type. In DLBCL cell lines, Se has been shown to inhibit the activation of NF-κB [14]. These preclinical data have led to funding for a multi-centre clinical trial of high dose Se supplementation in the form of methylselenocysteine (MSC), in combination with immunochemotherapy, in patients with relapsed/refractory DLBCL.…”

The formulation for cancer prevention & therapy

“…This has been investigated using a panel of human B-cell lymphoma cell lines. Taken together, these results show that the NF-B pathway is one target for methylselenic acid (MSA) underlying the interaction between MSA and chemotherapy [201].…”

Effect of Selenite on T-Cell Mitogenesis: Contribution of ROS Production and Apoptosis Signal-Regulating Kinase 1

“…12) However, selenium has also been shown to inhibit cell growth, 13,14) induce cell death 15) or apoptosis, 16,17) and suppress NF-κB. 18,19) Although the essential roles of selenium in immune cell functions have already been reported, the functions and underlying mechanisms have yet to be elucidated due to these inconsistencies. Selenium has been shown to have anticancer effects at concentrations higher than nutritional requirements, 20,21) and these may be mediated through cell cycle arrest, apoptosis, and/ or the toxic effect.…”