{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:23:25Z","timestamp":1790922205788,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T00:00:00Z","timestamp":1681344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PPGCF\/UFRGS (Programa de P\u00f3s-gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas da Universidade Federal do Rio Grande do Sul)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"PPGCF\/UFRGS (Programa de P\u00f3s-gradua\u00e7\u00e3o em Ci\u00eancias Farmac\u00eauticas da Universidade Federal do Rio Grande do Sul)","award":["0186\/2022"],"award-info":[{"award-number":["0186\/2022"]}]},{"name":"PROPESQ\/UFRGS (Pr\u00f3-Reitoria de Pesquisa da Universidade Federal do Rio Grande do Sul)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"PROPESQ\/UFRGS (Pr\u00f3-Reitoria de Pesquisa da Universidade Federal do Rio Grande do Sul)","award":["0186\/2022"],"award-info":[{"award-number":["0186\/2022"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","award":["0186\/2022"],"award-info":[{"award-number":["0186\/2022"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2013Brazil (CAPES)","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2013Brazil (CAPES)","award":["0186\/2022"],"award-info":[{"award-number":["0186\/2022"]}]},{"name":"PROEX\u2014CAPES","award":["001"],"award-info":[{"award-number":["001"]}]},{"name":"PROEX\u2014CAPES","award":["0186\/2022"],"award-info":[{"award-number":["0186\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the formation of the BCR-ABL (breakpoint cluster region-Abelson) oncoprotein. As many patients display therapeutic resistance, the development of new drugs based on semisynthetic products represents a new potential therapeutic approach for treating the disease. In this study, we investigated the cytotoxic activity, possible mechanism of action of a hybrid compound of betulinic acid (BA) and brosimine B in CML cell lines that are sensitive (K-562) and resistant (K-562R) to imatinib, in addition to evaluating lower doses of imatinib in combination with the hybrid compound. The effects of the compound, and its combination with imatinib, on apoptosis, cell cycle, autophagy and oxidative stress were determined. The compound was cytotoxic in K-562 (23.57 \u00b1 2.87 \u03bcM) and K-562R (25.80 \u00b1 3.21 \u03bcM) cells, and a synergistic effect was observed when it was associated with imatinib. Apoptosis was mediated by the caspase 3 and 9 intrinsic pathway, and cell cycle evaluation showed arrest at G0\/G1. In addition, the hybrid compound increased the production of reactive oxygen species and induced autophagy by increasing LC3II and Beclin-1 mRNA levels. Results suggest that this hybrid compound causes the death of both imatinib-sensitive and -resistant cell lines and may hold potential as a new anticancer treatment against CML.<\/jats:p>","DOI":"10.3390\/ph16040586","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T02:03:38Z","timestamp":1681437818000},"page":"586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Betulinic Acid-Brosimine B Hybrid Compound Has a Synergistic Effect with Imatinib in Chronic Myeloid Leukemia Cell Line, Modulating Apoptosis and Autophagy"],"prefix":"10.3390","volume":"16","author":[{"given":"Julia Biz","family":"Willig","sequence":"first","affiliation":[{"name":"Post-Graduation of Pharmaceutical Science Program, Faculty of Farmacy, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"},{"name":"Laboratory Biochemical and Cytological Analysis, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0346-5615","authenticated-orcid":false,"given":"N\u00e1dia Mil\u00e9o Garc\u00eas","family":"de Couto","sequence":"additional","affiliation":[{"name":"Post-Graduation of Pharmaceutical Science Program, Faculty of Farmacy, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"},{"name":"Laboratory of Phytochemistry and Organic Synthesis, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9bora Renz Barreto","family":"Vianna","sequence":"additional","affiliation":[{"name":"Post-Graduation of Pharmaceutical Science Program, Faculty of Farmacy, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"},{"name":"Laboratory Biochemical and Cytological Analysis, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila da Silveira","family":"Mariot","sequence":"additional","affiliation":[{"name":"Laboratory Biochemical and Cytological Analysis, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8806-3182","authenticated-orcid":false,"given":"Simone Cristina Baggio","family":"Gnoatto","sequence":"additional","affiliation":[{"name":"Post-Graduation of Pharmaceutical Science Program, Faculty of Farmacy, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"},{"name":"Laboratory of Phytochemistry and Organic Synthesis, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9ia","family":"Buffon","sequence":"additional","affiliation":[{"name":"Laboratory Biochemical and Cytological Analysis, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6773-6480","authenticated-orcid":false,"given":"Diogo Andr\u00e9","family":"Pilger","sequence":"additional","affiliation":[{"name":"Post-Graduation of Pharmaceutical Science Program, Faculty of Farmacy, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"},{"name":"Laboratory Biochemical and Cytological Analysis, Federal University of Rio Grande do Sul, Porto Alegre 90610-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"ref_1","first-page":"63","article-title":"Targeted treatment of chronic myeloid leukemia: Role of imatinib","volume":"2","author":"Tamascar","year":"2009","journal-title":"OncoTargets Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1182\/blood-2008-07-077958","article-title":"Translation of the Philadelphia chromosome into therapy for CML","volume":"112","author":"Druker","year":"2008","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13045-018-0624-2","article-title":"Past, present, and future of Bcr-Abl inhibitors: From chemical development to clinical efficacy","volume":"11","author":"Rossari","year":"2018","journal-title":"J. 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