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Targeting tyrosine kinase activity of BCR\u2013ABL with imatinib is an effective therapy for the newly diagnosed CML patients; however, 20%\u201330% of the patients initially treated with imatinib eventually experience treatment failure. Therefore, early identification of these patients is of high clinical relevance. In the present study, we by undertaking a direct comparison of inducible NOS (iNOS) status in neutrophils from healthy volunteers, newly diagnosed, imatinib responder, and resistant CML patients as well as by conducting in vitro studies in K562 cells demonstrated that inhibition of BCR\u2013ABL by imatinib or siRNA significantly enhanced NO generation and iNOS expression. Indeed, patients exhibiting treatment failure or imatinib resistance were less likely to induce NO generation\/iNOS expression. Our findings further demonstrated that imatinib mediated antiproliferative and proapoptotic effect in BCR\u2013ABL+ cells associated with enhanced iNOS expression, and it was significantly prevented in the presence of L-NAME, 1400W, or iNOS siRNA. Overexpression of iNOS in K562 cells expectedly enhanced imatinib sensitivity on cytostasis and apoptosis, even at lower concentration (0.1\u00a0\u03bcM) of imatinib. Mechanistically, imatinib or BCR\u2013ABL siRNA following deglutathionylation of NF-\u03baB, enhanced its binding to iNOS promoter and induced iNOS transcription. Deglutathionylation of procaspase-3 however associated with increased caspase-3 activity and cell apoptosis. Taken together, results obtained suggest that monitoring NO\/iNOS level could be useful to identify patients likely to be responsive or resistant to imatinib and can be used to personalized alternative therapy.<\/jats:p>","DOI":"10.1002\/jlb.1a0820-514r","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T04:09:29Z","timestamp":1612411769000},"page":"853-866","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Expression of inducible NOS is indispensable for the antiproliferative and proapoptotic effect of imatinib in BCR\u2013ABL positive cells"],"prefix":"10.1093","volume":"110","author":[{"given":"Abhishek Kumar","family":"Singh","sequence":"first","affiliation":[{"name":"Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepika","family":"Awasthi","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megha","family":"Dubey","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheela","family":"Nagarkoti","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tulika","family":"Chandra","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, King George's Medical University , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj Kumar","family":"Barthwal","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil Kumar","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, Dr. Ram Manohar Lohia Institute of Medical Sciences , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhu","family":"Dikshit","sequence":"additional","affiliation":[{"name":"Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,2,2]]},"reference":[{"key":"2023032108465246100_","doi-asserted-by":"crossref","DOI":"10.18632\/oncotarget.2525","article-title":"Regulation of NADPH-dependent nitric oxide and reactive oxygen species signalling in endothelial and melanoma cells by a photoactive NADPH 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