{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T16:48:24Z","timestamp":1785775704508,"version":"3.56.0"},"reference-count":45,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T00:00:00Z","timestamp":1779321600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    While venetoclax\u2010based combinations have shown promising results in acute myeloid leukemia (AML), the remission duration is generally short, warranting strategies to further improve efficacy and overcome resistance. Here, we show that the natural quassinoid brusatol induces cell\u2010cycle arrest and apoptosis in multiple AML cell lines while enhancing venetoclax efficacy irrespective of inherent or acquired resistance. Mechanistically, brusatol increased p53 protein expression, leading to upregulation of its target genes\/proteins, including\n                    <jats:italic>CDKN1A<\/jats:italic>\n                    (p21) and\n                    <jats:italic>BBC3<\/jats:italic>\n                    (PUMA). Genetic deletion of\n                    <jats:italic>TP53<\/jats:italic>\n                    attenuated brusatol\u2010induced apoptosis and its synergy with venetoclax, supporting p53 activation as a central mechanism underlying the anti\u2010leukemia response. Furthermore, the combination synergistically decreased mitochondrial membrane potential and respiratory activity, causing accumulation of reactive oxygen species in AML cells. Although brusatol and venetoclax exhibited limited effects individually, their combination markedly reduced leukemia burden and significantly prolonged survival in three independent cell line\u2010derived xenograft models, including venetoclax\u2010resistant and \u2010refractory models. Notably, brusatol increased normal leukocyte and platelet counts while reducing leukemic infiltration in both bone marrow and extramedullary sites. These findings provide mechanistic insight into the synergistic effects of the brusatol\u2010venetoclax combination, supporting further evaluation of this therapeutic strategy in myeloid leukemias.\n                  <\/jats:p>","DOI":"10.1111\/cas.70423","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T01:25:07Z","timestamp":1779413107000},"page":"2274-2288","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Natural Quassinoid Brusatol Enhances Venetoclax Efficacy and Overcomes Resistance in Myeloid Leukemias"],"prefix":"10.1111","volume":"117","author":[{"given":"Shin\u2010ichiro","family":"Kawaguchi","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Medicine Jichi Medical University  Tochigi 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