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Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2) and sulfur mustard, are potent vesicants that modify and disrupt cellular macromolecules, including DNA leading to cytotoxicity and tissue injury. In many cell types, HN2 upregulates DNA damage signaling pathways including ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3-related (ATR), as well as DNA-dependent protein kinase (DNA-PK). In the present studies, we investigated crosstalk between HN2-induced DNA damage response and cell cycle progression using human A549 lung epithelial cells. HN2 (1-20 µM; 24 h) caused a concentration-dependent arrest of cells in the S and G2/M phases of the cell cycle. This was associated with inhibition of DNA synthesis, as measured by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into S phase cells. Cell cycle arrest was correlated with activation of DNA damage and cell cycle checkpoint signaling. Thus, HN2 treatment resulted in time- and concentration-dependent increases in expression of phosphorylated ATM (S1981), Chk2 (T68), H2AX (Ser139), and p53 (ser15). Activation of DNA damage signaling was most pronounced in S-phase cells followed by G2/M-phase cells. HN2-induced cell cycle arrest was suppressed by the ATM and DNA-PK inhibitors, KU55933 and NU7441, respectively, and to a lesser extent by VE-821, an ATR inhibitor. This was correlated with abrogation of DNA damage checkpoints signaling. These data indicate that activation of ATM, ATR, and DNA-PK signaling pathways by HN2 are important in the mechanism of vesicant-induced cell cycle arrest and cytotoxicity. Drugs that inhibit activation of DNA damage signaling may be effective countermeasures for vesicant-induced tissue injury.
This article was published in the following journal.
Name: Chemical research in toxicology
Sulfur mustard gas, also called HD, is one of the main chemical warfare agents and has claimed thousands of lives and left many more contaminated. The development of functional materials to promptly c...
Sulfur mustard (SM) as a cytotoxic and blistering agent can alkylate a variety of cellular components, causing the incidence of ongoing oxidative stress.
Mechlorethamine (HN2) is an alkylating agent and sulfur mustard mimetic. Topical exposure to HN2 is associated with tissue blistering. Previous work in our laboratory has shown that ebselen (EB-1) pos...
A new metal-free catalytic reaction system is developed to selectively oxidize 2-chloroethyl ethyl sulfide (CEES), a surrogate of sulfur mustard. The combination of two catalytic precursors, tribromid...
to assess the effect of Heliox with Noninvasive positive pressure ventilation to decrease dyspnea and improve physiologic and respiratory measures in patients with a previous exposure to S...
to assess the effectiveness of helium:oxygen mixture adjunct with non-invasive ventilation in sulfur mustard exposed patients with acute decompensation
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An analog of benzilylcholine mustard. It is an alkylating nitrogen mustard analog that binds specifically and irreversibly to cholinergic muscarinic receptors and is used as an affinity label to isolate and study the receptors.
Any of several BRASSICA species that are commonly called mustard. Brassica alba is white mustard, B. juncea is brown or Chinese mustard, and B. nigra is black, brown, or red mustard. The plant is grown both for mustard seed from which oil is extracted and for greens or animal feed. It was formerly used as an emetic, counter-irritant, and carminative. There is no relationship to MUSTARD COMPOUNDS.
Nitrogen mustard analog of quinacrine used primarily as a stain in the studies of chromosomes and chromatin. Fluoresces by reaction with nucleic acids in chromosomes.
A group of alkylating agents derived from mustard gas, with the sulfur replaced by nitrogen. They were formerly used as toxicants and vesicants, but now function as antineoplastic agents. These compounds are also powerful mutagens, teratogens, immunosuppressants, and carcinogens.
Strong alkylating and immunosuppressive agents whose biological activity is based on the presence of bis(2-chloroethyl)- groups. Although otherwise structurally diverse, the compounds have in common the capacity to contribute alkyl groups to DNA. They are generally highly toxic but include among their number many widely used and effective antineoplastic agents.
Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...