{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:16:01Z","timestamp":1780658161992,"version":"3.54.1"},"reference-count":83,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:00:00Z","timestamp":1658534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Coordination for the Improvement of Higher Education Personnel","award":["404213\/2021-9"],"award-info":[{"award-number":["404213\/2021-9"]}]},{"name":"National Council of Technological and Scientific Development","award":["404213\/2021-9"],"award-info":[{"award-number":["404213\/2021-9"]}]},{"name":"Foundation for Support Research in the State of Rio de Janeiro","award":["404213\/2021-9"],"award-info":[{"award-number":["404213\/2021-9"]}]},{"name":"PROPESP\/UFPA","award":["404213\/2021-9"],"award-info":[{"award-number":["404213\/2021-9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The multidrug resistance (MDR) phenotype is one of the major obstacles in the treatment of chronic myeloid leukemia (CML) in advantage stages such as blast crisis. In this scenario, more patients develop resistance mechanisms during the course of the disease, making tyrosine kinase inhibitors (TKIs) target therapies ineffective. Therefore, the aim of the study was to examine the pharmacological role of CNN1, a para-naphthoquinone, in a leukemia multidrug resistant cell line. First, the in vitro cytotoxic activity of Imatinib Mesylate (IM) in K-562 and FEPS cell lines was evaluated. Subsequently, membrane integrity and mitochondrial membrane potential assays were performed to assess the cytotoxic effects of CNN1 in K-562 and FEPS cell lines, followed by cell cycle, alkaline comet assay and annexin V-Alexa Fluor\u00ae\u00a0488\/propidium iodide assays (Annexin\/PI) using flow cytometry. RT-qPCR was used to evaluate the H2AFX gene expression. The results demonstrate that CNN1 was able to induce apoptosis, cell membrane rupture and mitochondrial membrane depolarization in leukemia cell lines. In addition, CNN1 also induced genotoxic effects and caused DNA fragmentation, cell cycle arrest at the G2\/M phase in leukemia cells. No genotoxicity was observed on peripheral blood mononuclear cells (PBMC). Additionally, CNN1 increased mRNA levels of H2AFX. Therefore, CNN1 presented anticancer properties against leukemia multidrug resistant cell line being a potential anticancer agent for the treatment of resistant CML.<\/jats:p>","DOI":"10.3390\/ijms23158105","type":"journal-article","created":{"date-parts":[[2022,7,24]],"date-time":"2022-07-24T22:49:02Z","timestamp":1658702942000},"page":"8105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["1,4-Naphthoquinone (CNN1) Induces Apoptosis through DNA Damage and Promotes Upregulation of H2AFX in Leukemia Multidrug Resistant Cell Line"],"prefix":"10.3390","volume":"23","author":[{"given":"Adrhyann Jullyanne","family":"de Sousa Portilho","sequence":"first","affiliation":[{"name":"Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Cear\u00e1, Fortaleza 60430-275, CE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5761-8413","authenticated-orcid":false,"given":"Emerson Lucena","family":"da Silva","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Cear\u00e1, Fortaleza 60430-275, CE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuel Cintra Austreg\u00e9silo","family":"Bezerra","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Cear\u00e1, Fortaleza 60430-275, CE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carinne Borges de Souza","family":"Moraes Rego Gomes","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Federal University Fluminense, S\u00e3o Jo\u00e3o Batista St., 188-Niter\u00f3i, Rio de Janeiro 24220-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2166-766X","authenticated-orcid":false,"given":"Vitor","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Federal University Fluminense, S\u00e3o Jo\u00e3o Batista St., 188-Niter\u00f3i, Rio de Janeiro 24220-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elisabete Amaral","family":"de Moraes","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Cear\u00e1, Fortaleza 60430-275, CE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7928-8646","authenticated-orcid":false,"given":"David Rodrigues","family":"da Rocha","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, Federal University Fluminense, S\u00e3o Jo\u00e3o Batista St., 188-Niter\u00f3i, Rio de Janeiro 24220-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4872-234X","authenticated-orcid":false,"given":"Rommel M\u00e1rio Rodriguez","family":"Burbano","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Oncology Research Center, Federal University of Par\u00e1, Bel\u00e9m 66073-005, PA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5845-3481","authenticated-orcid":false,"given":"Caroline Aquino","family":"Moreira-Nunes","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Cear\u00e1, Fortaleza 60430-275, CE, Brazil"},{"name":"Department of Biological Sciences, Oncology Research Center, Federal University of Par\u00e1, Bel\u00e9m 66073-005, PA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel Carvalho","family":"Montenegro","sequence":"additional","affiliation":[{"name":"Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Cear\u00e1, Fortaleza 60430-275, CE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1038\/leu.2016.104","article-title":"European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia","volume":"30","author":"Steegmann","year":"2016","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1002\/ajh.25792","article-title":"Chronic myeloid leukemia: 2020 update on diagnosis, therapy and monitoring","volume":"95","author":"Jabbour","year":"2020","journal-title":"Am. 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