Ebselen Analogues Reduce 2-chloroethyl Ethyl Sulphide Toxicity in A-431 Cells

Abstract

Vesicants are potent blistering agents. The prototype vesicant is sulphur mustard gas, fi rst used in World War I, which still has no effective antidote. We used a mustard gas surrogate 2-chloroethyl ethyl sulphide (CEES) to study the ability of resveratrol (RES) and pterostilbene (PTS), two well-established stilbene antioxidants, ebselen (EB-1), an organoselenium compound, and three EB-1 analogues (EB-2, EB-3, and EB-4) to reduce CEES toxicity in human epidermoid carcinoma cells (A-431). Following a 24-hour incubation of a toxic concentration of CEES (1000 μmol L ) did not decrease cell viability. Treatment with CEES and test antioxidants for 24 h showed that only EB-1 and its analogues EB-2, EB-3, and EB-4 but not the stilbene compounds could rescue the cells from death. EB-1 and EB-4 were the most effective at reducing CEES cytotoxicity and did so in a concentration-dependent manner, while EB-2 and EB-3 demonstrated the least protective effect. In summary, the data described herein indicate that organoselenium antioxidants, especially EB-4, may prove useful as countermeasures to blistering agents.

Combination of ebselen and hydrocortisone substantially reduces nitrogen mustard-induced cutaneous injury

“…EB-1 is an anti-inflammatory antioxidant compound that is under investigation for reperfusion injury ( Aras et al, 2014 ), stroke ( Yamaguchi et al, 1998 ), hearing loss ( Kil et al, 2021 ) and bipolar disorder ( Singh et al, 2013 ). Previous research in our lab has shown the edema-reducing and anti-vesicant ( Lulla et al, 2014 ), anti-bacterial ( Chan et al, 2007 ), anti-fungal ( Billack et al, 2010 , Orie et al, 2017 ) and cyto-protective ( Hardej and Billack, 2007 , Pino and Billack, 2008 , Pino et al, 2013 ) properties of EB-1. The second compound tested here was HC, a corticosteroid with immunosuppressant activity (Issekutz, 1983, Coutinho and Chapman, 2011 ), is used topically in the treatment of various inflammatory skin conditions such as allergic rashes, eczema and psoriasis.…”

“…Indeed, HN2 exhibits a very complex mechanism of toxicity that involves many macromolecules and cell signaling pathways ( Korkmaz et al, 2006 , McManus and Huebner, 2005 , Tewari-Singh and Agarwal, 2016 ). Our group previously reported that HN2 triggers numerous responses in cultured skin cells in vitro , including damaged nuclear DNA, increased lipid peroxidation and apoptosis via activation of caspases 3 and 9 ( Lulla et al, 2013 , Pino and Billack, 2008 , Pino et al, 2014 ), and that the organoselenium compound ebselen (EB-1) reduces the toxicity of both HN2 ( Hardej and Billack, 2007 , Lulla et al, 2014 ) and the sulfur half mustard CEES in vitro ( Pino et al, 2013 ).…”

Topical Delivery of Ebselen Encapsulated in Biopolymeric Nanocapsules: Drug Repurposing Enhanced Antifungal Activity

“…Based on the determined values of logP for Eb -calculated (2.92) [33] and experimentally estimated (2.8) [34] we could conclude that is a hydrophobic molecule. Therefore, predominantly should be present in the oily core of formed nanocapsules.…”

Mustard Gas Inhalation Injury

“…31 Use of ebselen (2-phenyl-1, 2-benzisoselenazol-3(2H)-one), a peroxynitrite scavenger, and 3 analogs have been shown to reduce CEES toxicity in vitro. 54 Also, an NM exposure model has been shown to reduce histopathology but not NM-induced elevation in lung iNOS levels. 55 Melatonin, a scavenger of both reactive nitrogen and oxygen species, when given to NM-exposed rats, was able to reduce NM-induced increase in iNOS, glutathione peroxidase activity, and reduced inflammation in the lung.…”