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Cells Jul 2023Sulfur mustard (SM) and nitrogen mustard (NM) are vesicant agents that cause skin injury and blistering through complicated cellular events, involving DNA damage, free...
Sulfur mustard (SM) and nitrogen mustard (NM) are vesicant agents that cause skin injury and blistering through complicated cellular events, involving DNA damage, free radical formation, and lipid peroxidation. The development of therapeutic approaches targeting the multi-cellular process of tissue injury repair can potentially provide effective countermeasures to combat vesicant-induced dermal lesions. MG53 is a vital component of cell membrane repair. Previous studies have demonstrated that topical application of recombinant human MG53 (rhMG53) protein has the potential to promote wound healing. In this study, we further investigate the role of MG53 in NM-induced skin injury. Compared with mice, mice are more susceptible to NM-induced dermal injuries, whereas mice with sustained elevation of MG53 in circulation are resistant to dermal exposure of NM. Exposure of keratinocytes and human follicle stem cells to NM causes elevation of oxidative stress and intracellular aggregation of MG53, thus compromising MG53's intrinsic cell membrane repair function. Topical rhMG53 application mitigates NM-induced dermal injury in mice. Histologic examination reveals the therapeutic benefits of rhMG53 are associated with the preservation of epidermal integrity and hair follicle structure in mice with dermal NM exposure. Overall, these findings identify MG53 as a potential therapeutic agent to mitigate vesicant-induced skin injuries.
Topics: Mice; Humans; Animals; Mechlorethamine; Irritants; Keratinocytes; Wound Healing; Membrane Proteins
PubMed: 37508578
DOI: 10.3390/cells12141915 -
Annals of the New York Academy of... Nov 2020Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to... (Review)
Review
Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation-driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation.
Topics: Animals; Chemical Warfare Agents; Dietary Supplements; Disease Models, Animal; Humans; Irritants; Mechlorethamine; Mustard Gas; Pulmonary Fibrosis
PubMed: 32725637
DOI: 10.1111/nyas.14442 -
Toxicology Mar 2023Mechlorethamine (HN2) is a derivative of the chemical warfare agent sulfur mustard (SM) and cutaneous exposure to HN2 is associated with dermal-epidermal junction (DEJ)...
Mechlorethamine (HN2) is a derivative of the chemical warfare agent sulfur mustard (SM) and cutaneous exposure to HN2 is associated with dermal-epidermal junction (DEJ) disruption (vesication). The primary purpose of the present study was to investigate the effect of HN2 on the mammalian target of rapamycin (mTOR) signaling pathway using an in vivo mouse ear vesicant model (MEVM). To this end, the ears of male C57BL/ 6 J mice were exposed to a single topical dose of HN2 (100 mM) or vehicle control (DMSO). Mice were then euthanized 30 min, 1 h or 24 h following exposure. Mouse ear skin exposed to HN2 and biopsied 24 h thereafter exhibited increased tissue expression of Raptor, an important member of the mTORC1 complex, relative to vehicle treated samples. HN2 reduced the downstream effectors phospho S6 (Ser 240/244) ribosomal protein and phospho 4E-BP1 (Thr 37/46) of the mTOR pathway in the epidermis at 30 min, 1 h and 24 h following HN2 exposure but not in the dermis. These results support the hypothesis that HN2-mediated cutaneous toxicity involves dysregulation of the mTOR signaling pathway in the epidermis.
Topics: Male; Mice; Animals; Mechlorethamine; Sirolimus; Mice, Inbred C57BL; Skin; TOR Serine-Threonine Kinases; Mammals
PubMed: 36708981
DOI: 10.1016/j.tox.2023.153434 -
The Journal of Investigative Dermatology Dec 2021Sézary syndrome is an aggressive and disseminated form of cutaneous T-cell lymphoma associated with dismal prognosis in which the histone deacetylase inhibitor...
Sézary syndrome is an aggressive and disseminated form of cutaneous T-cell lymphoma associated with dismal prognosis in which the histone deacetylase inhibitor romidepsin has shown remarkable activity as a single agent. However, clinical responses to romidepsin are typically transient, highlighting the need for more effective therapies. In this study, we show synergistic antilymphoma effects of romidepsin in combination with mechlorethamine, an alkylating agent, in cutaneous T-cell lymphoma cell lines and primary samples with strong antitumor effects in an in vivo model of Sézary syndrome. Mechanistically, gene expression profiling points to abrogation of Jak/signal transducer and activator of transcription (STAT) signaling as an important mediator of this interaction. Consistently, the combination of mechlorethamine plus romidepsin resulted in downregulation of STAT5 phosphorylation in romidepsin-sensitive cell lines and primary Sézary syndrome samples, but not in romidepsin-resistant tumors. Moreover, in further support of Jak/STAT signaling as a modulator of romidepsin activity in cutaneous T-cell lymphoma, treatment with romidepsin in combination with Jak inhibitors resulted in markedly increased therapeutic responses. Overall, these results support a role for romidepsin plus mechlorethamine in combination in the treatment of cutaneous T-cell lymphoma and uncover a previously unrecognized role for Jak/STAT signaling in the response to romidepsin and romidepsin-based combination therapies in Sézary syndrome.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Depsipeptides; Drug Synergism; Humans; Janus Kinase Inhibitors; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Mice; STAT Transcription Factors; Signal Transduction; Skin Neoplasms
PubMed: 34089720
DOI: 10.1016/j.jid.2021.04.023 -
Current Opinion in Pharmacology Aug 2018DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in... (Review)
Review
DNA crosslinking agents make up a broad class of chemotherapy agents that target rapidly dividing cancer cells by disrupting DNA synthesis. These drugs differ widely in both chemical structure and biological effect. In cells, crosslinking agents can form multiple types of DNA lesions with varying efficiencies. Inter-strand crosslinks (ICLs) are considered to be the most cytotoxic lesion, creating a covalent roadblock to replication and transcription. Despite over 50 years in the clinic, the use of crosslinking agents that specialize in the formation of ICLs remains limited, largely due to high toxicity in patients. Current ICL-based therapeutics have focused on late-stage and drug-resistant tumors, or localized treatments that limit exposure. In this article, we review the development of clinical crosslinking agents, our understanding of how cells respond to different lesions, and the potential to improve ICL-based chemotherapeutics in the future.
Topics: Antineoplastic Agents; Cross-Linking Reagents; DNA; Furocoumarins; Humans; Mechlorethamine; Mitomycins; Neoplasms
PubMed: 29679802
DOI: 10.1016/j.coph.2018.04.004 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Antineoplastic Agents, Alkylating; Carcinogenicity Tests; Carcinogens, Environmental; Environmental Exposure; Government Regulation; Guidelines as Topic; Humans; Mechlorethamine; Mice; Molecular Structure; Neoplasms; Occupational Exposure; Rats
PubMed: 21860500
DOI: No ID Found -
American Journal of Hematology Jan 2016Hodgkin lymphoma is a rare lymphoid malignancy affecting ∼9,200 new patients in the United States annually. Progress in the management of this disease over the past 50... (Review)
Review
Hodgkin lymphoma is a rare lymphoid malignancy affecting ∼9,200 new patients in the United States annually. Progress in the management of this disease over the past 50 years has been remarkable and the prognosis of this malignancy has changed from a uniformly fatal process to one in which the vast majority of patients are expected to be cured. This remarkable progress has been due to the use of combination approaches incorporating chemotherapy and radiation therapy, and now more recently antibody-drug conjugates and immune checkpoint inhibitors. The goal for the future is to develop treatment combinations that successfully treat all patients and markedly decrease the long-term side effects.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Clinical Trials as Topic; Dacarbazine; Disease-Free Survival; Doxorubicin; Hodgkin Disease; Humans; Mechlorethamine; Molecular Targeted Therapy; Prednisone; Procarbazine; Programmed Cell Death 1 Receptor; Vinblastine; Vincristine
PubMed: 26505486
DOI: 10.1002/ajh.24226 -
Chemical Research in Toxicology Apr 2022Cytotoxic blistering agents such as sulfur mustard and nitrogen mustard (HN2) were synthesized for chemical warfare. Toxicity is due to reactive chloroethyl side chains...
Cytotoxic blistering agents such as sulfur mustard and nitrogen mustard (HN2) were synthesized for chemical warfare. Toxicity is due to reactive chloroethyl side chains that modify and damage cellular macromolecules including DNA and proteins. In response to DNA damage, cells initiate a DNA damage response directed at the recruitment and activation of repair-related proteins. A central mediator of the DNA damage response is p53, a protein that plays a critical role in regulating DNA repair. We found that HN2 causes cytosolic and nuclear accumulation of p53 in HaCaT keratinocytes; HN2 also induced post-translational modifications on p53 including S15 phosphorylation and K382 acetylation, which enhance p53 stability, promote DNA repair, and mediate cellular metabolic responses to stress. HN2 also cross-linked p53, forming dimers and high-molecular-weight protein complexes in the cells. Cross-linked multimers were also modified by K48-linked ubiquitination indicating that they are targets for proteasome degradation. HN2-induced modifications transiently suppressed the transcriptional activity of p53. Using recombinant human p53, HN2 alkylation was found to be concentration- and redox status-dependent. Dithiothreitol-reduced protein was more efficiently cross-linked indicating that p53 cysteine residues play a key role in protein modification. LC-MS/MS analysis revealed that HN2 directly alkylated p53 at C124, C135, C141, C176, C182, C275, C277, H115, H178, K132, and K139, forming both monoadducts and cross-links. The formation of intermolecular complexes was a consequence of HN2 cross-linked cysteine residues between two molecules of p53. Together, these data demonstrate that p53 is a molecular target for mustard vesicants. Modification of p53 likely mediates cellular responses to HN2 including DNA repair and cell survival contributing to vesicant-induced cytotoxicity.
Topics: Chromatography, Liquid; Cysteine; Humans; Keratinocytes; Mechlorethamine; Tandem Mass Spectrometry; Tumor Suppressor Protein p53
PubMed: 35312310
DOI: 10.1021/acs.chemrestox.1c00420 -
Blood Apr 1983Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of... (Comparative Study)
Comparative Study Review
Fifteen compounds reported to be inhibitors of gelation or sickling were studied by standard methods. These tests included (1) the determination of the solubility of deoxyhemoglobin S or Csat, (2) evaluation of sickling in whole SS blood at various pO2s, (3) measurement of the oxygen affinity of hemoglobin and blood, and (4) examination of red cell indices and morphology. Among the 4 noncovalent agents tested, butylurea was the most potent inhibitor of gelation and sickling in vitro; however, relatively high concentrations were required compared to the covalent agents. In the latter group, bis-(3,5 dibromosalicyl)-fumarate, nitrogen mustard, and dimethyladipimidate were especially effective inhibitors of gelation and/or sickling. All of these compounds require further development before they can be considered for clinical use.
Topics: Anemia, Sickle Cell; Antisickling Agents; Aspirin; Azepines; Carbamyl Phosphate; Cyanates; Cystamine; Dimethyl Adipimidate; Drug Evaluation; Erythrocyte Indices; Glyceraldehyde; Hemoglobins; Humans; Imidoesters; Mechlorethamine; Oxygen Consumption; Phenylalanine; Pyridoxal; Solubility; Urea
PubMed: 6338971
DOI: No ID Found -
Journal of Cellular and Molecular... Apr 2022Nitrogen mustard (NM) is an alkylating vesicant that causes severe pulmonary injury. Currently, there are no effective means to counteract vesicant-induced lung injury....
Nitrogen mustard (NM) is an alkylating vesicant that causes severe pulmonary injury. Currently, there are no effective means to counteract vesicant-induced lung injury. MG53 is a vital component of cell membrane repair and lung protection. Here, we show that mice with ablation of MG53 are more susceptible to NM-induced lung injury than the wild-type mice. Treatment of wild-type mice with exogenous recombinant human MG53 (rhMG53) protein ameliorates NM-induced lung injury by restoring arterial blood oxygen level, by improving dynamic lung compliance and by reducing airway resistance. Exposure of lung epithelial and endothelial cells to NM leads to intracellular oxidative stress that compromises the intrinsic cell membrane repair function of MG53. Exogenous rhMG53 protein applied to the culture medium protects lung epithelial and endothelial cells from NM-induced membrane injury and oxidative stress, and enhances survival of the cells. Additionally, we show that loss of MG53 leads to increased vulnerability of macrophages to vesicant-induced cell death. Overall, these findings support the therapeutic potential of rhMG53 to counteract vesicant-induced lung injury.
Topics: Acute Lung Injury; Animals; Endothelial Cells; Lung; Mechlorethamine; Membrane Proteins; Mice; Recombinant Proteins
PubMed: 35199443
DOI: 10.1111/jcmm.16917