{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:06:24Z","timestamp":1790798784539,"version":"4.1.0"},"reference-count":25,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T00:00:00Z","timestamp":1777161600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015624","name":"University of Jeddah","doi-asserted-by":"publisher","award":["UJ-24-SUTU-2716"],"award-info":[{"award-number":["UJ-24-SUTU-2716"]}],"id":[{"id":"10.13039\/501100015624","id-type":"DOI","asserted-by":"publisher"}]},{"award":["UJ-24-SUTU-2716"],"award-info":[{"award-number":["UJ-24-SUTU-2716"]}],"id":[{"id":"https:\/\/ror.org\/015ya8798","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is a complex blood cancer that primarily affects relapsing or refractory patients receiving conventional chemotherapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer properties with restricted clinical efficacy attributable to cyclooxygenase (COX)-induced toxicities. To address this issue, a group of benzylamide analogs of the classical NSAIDs (NSI-1\u2013NSI-9) were developed and synthesized to mask the carboxylic acid moiety and minimize COX-induced adverse effects while maintaining anticancer activity. The cytotoxic effect of such substances has been demonstrated in some leukemia cell lines (HL-60, MV4-11, KG1a, and K562). NSI-5 exerted the highest anti-leukemic activity among these sulindac analogs, as determined at a sub-micromolar level in all cell lines studied, by IC50. This mechanistic data also demonstrated that NSI-5 induced apoptosis that was dose-dependent, especially in HL-60 cell lines, and increased the sub-G1 cell fraction. This apoptotic process was also accompanied by a significant decrease in mitochondrial membrane potential, which is characteristic of the induction of the intrinsic apoptotic process. Interestingly, NSI-5 decreased the intracellular reactive oxygen species (ROS) and the expression of most antioxidants (catalase and glutathione synthetase), as well as the redox balance. Gene characterization in vitro also suggested activation of apoptotic pathways, where expression of Bax, Bak1, and Caspase-3 increased, suggesting a potential p53-independent apoptotic pathway, in contrast to control for Bcl-2 expression. Collectively, these findings indicate that NSI-5 is a promising in vitro anti-leukemic lead compound, with activity associated with mitochondrial dysfunction and altered redox regulation. The observed effects are consistent with previously reported COX-independent activity of structurally related NSAID derivatives, and support further investigation of NSI-5 in preclinical models.<\/jats:p>","DOI":"10.3390\/ijms27093850","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel NSAID Analogs Exhibit Anti-Leukemic Activity Through Modulation of Apoptotic and Survival Pathways"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8082-838X","authenticated-orcid":false,"given":"Hind A.","family":"Alkhatabi","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, College of Science, University of Jeddah, Jeddah 21956, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1925-0424","authenticated-orcid":false,"given":"Mohammed","family":"Basabrain","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa G.","family":"Alahmadi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Science, University of Jeddah, Jeddah 21956, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-9921","authenticated-orcid":false,"given":"Shiekhah M.","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosra A.","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Almuhaiyawi","sequence":"additional","affiliation":[{"name":"Collage of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah 22384, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha M.","family":"Alreemi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem M.","family":"Alotibi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Science, University of Jeddah, Jeddah 21956, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roaa M.","family":"Alreemi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Science, University of Jeddah, Jeddah 21956, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba A.","family":"Alkhattabi","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem N.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wedad M.","family":"Al-Bishri","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Science, University of Jeddah, Jeddah 21956, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"El-Mezgueldi","sequence":"additional","affiliation":[{"name":"Randall Centre for Cell & Molecular Biophysics, King\u2019s College London, New Hunt\u2019s House, Room3\/28a, London SE1 1UL, UK"},{"name":"College of Health and Life Sciences, School of Biosciences, University of Aston, Birmingham B4 7ET, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdelsattar M.","family":"Omar","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia"},{"name":"King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"310","DOI":"10.14740\/jocmr5205","article-title":"Mapping the Grounds for Mortalities in Acute Myeloid Leukemia Through Registry Analyses: A Retrospective Cohort Study of Children, Adolescents, and Young Adults Patients","volume":"16","author":"Elgenidy","year":"2024","journal-title":"J. Clin. Med. Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"R\u00e9cher, C. (2021). Clinical implications of inflammation in acute myeloid leukemia. Front. 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