The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and the chloroethylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE). 90CE has been shown to kill tumor cells via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function of laromustine has not been delineated. Herein, we show that 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), an analog of laromustine that generates only methyl isocyanate, activates ASK1-JNK/p38 signaling in endothelial cells (EC). We have previously shown that ASK1 forms a complex with reduced thioredoxin (Trx1) in resting EC, and that the Cys residues in ASK1 and Trx1 are critical for their interaction. 101MDCE dissociated ASK1 from Trx1, but not from the phosphoserine-binding inhibitor 14-3-3, in whole cells and in cell lysates, consistent with the known ability of methyl isocyanate to carbamoylate free thiol groups of proteins. 101MDCE had no effect on the kinase activity of purified ASK1, JNK, or the catalytic activity of Trx1. However, 101MDCE, but not 90CE, significantly decreased the activity of Trx reductase-1 (TrxR1). We conclude that methyl isocyanate induces dissociation of ASK1 from Trx1 either directly by carbamoylating the critical Cys groups in the ASK1-Trx1 complex or indirectly by inhibiting TrxR1. Furthermore, 101MDCE (but not 90CE) induced EC death through a non-apoptotic (necroptotic) pathway leading to inhibition of angiogenesis in vitro. Our study has identified methyl isocyanates may contribute to the anticancer activity in part by interfering with tumor angiogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103224 | PLOS |
Arch Environ Contam Toxicol
November 2024
Graduate Division of Nutritional and Environmental Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Isocyanates are used as raw materials for polyurethane foams, paints, and building materials. The isocyanates can cause acute adverse health effects such as irritation of the respiratory tract, skin, and eyes, and induce asthma and sick house syndrome. However, investigations into the potential sources and risk assessments of indoor isocyanates are limited.
View Article and Find Full Text PDFJ Hazard Mater
July 2024
Environmental Laboratory, US Army Engineer Research and Development Center, 3909 Halls Ferry Road, Vicksburg, MS 39180, USA. Electronic address:
Methyl isocyanate (MIC) is a toxic chemical found in many commercial, industrial, and agricultural processes, and was the primary chemical involved in the Bhopal, India disaster of 1984. The atmospheric environmental chemical reactivity of MIC is relatively unknown with only proposed reaction channels, mainly involving OH-initiated reactions. The gas-phase degradation reaction pathways of MIC and its primary product, formyl isocyanate (FIC), were investigated with quantum mechanical (QM) calculations to assess the fate of the toxic chemical and its primary transformation products.
View Article and Find Full Text PDFInt J Mol Sci
March 2024
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, Cali 760042, Colombia.
This study presents the synthesis of four series of novel hybrid chalcones ()- and ()- and six series of 1,3,5-triazine-based pyrimido[4,5-][1,4]diazepines (-)- and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones ,, ,, ,-, - and the pyrimido[4,5-][1,4]diazepines ,, , ,,-, ,,- exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI values between 0.01 and 100 μM and LC values in the range of 4.
View Article and Find Full Text PDFTrans R Soc Trop Med Hyg
July 2024
School of Public Health and Community Medicine, University of Gothenburg, Medicinearegatan, Göteborg 41390, Sweden.
Leakage of methyl isocyanate from the Union Carbide plant in Bhopal, India, killed thousands and left deleterious trans-generational effects. Gas-exposed populations experience higher rates of lung and metabolic diseases, and immune dysregulation, all associated with adverse outcomes in coronavirus disease 2019 (COVID-19). We used publicly available, official data from government sources to estimate COVID-19-associated crude mortality in populations with and without a history of gas exposure.
View Article and Find Full Text PDFJ Antimicrob Chemother
March 2024
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Background: Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown.
Objectives: To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients.
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