{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:05:48Z","timestamp":1790841948321,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T00:00:00Z","timestamp":1654992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute of the National Institutes of Health","doi-asserted-by":"publisher","award":["CA205247"],"award-info":[{"award-number":["CA205247"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute of the National Institutes of Health","doi-asserted-by":"publisher","award":["CA201184"],"award-info":[{"award-number":["CA201184"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute of the National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jerome Foundation (G.M.)","award":["CA205247"],"award-info":[{"award-number":["CA205247"]}]},{"name":"Jerome Foundation (G.M.)","award":["CA201184"],"award-info":[{"award-number":["CA201184"]}]},{"name":"Jerome Foundation (G.M.)","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}]},{"name":"Hoag Foundation (G.M.)","award":["CA205247"],"award-info":[{"award-number":["CA205247"]}]},{"name":"Hoag Foundation (G.M.)","award":["CA201184"],"award-info":[{"award-number":["CA201184"]}]},{"name":"Hoag Foundation (G.M.)","award":["P30CA033572"],"award-info":[{"award-number":["P30CA033572"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Venetoclax (VEN) in combination with hypomethylating agents induces disease remission in patients with de novo AML, however, most patients eventually relapse. AML relapse is attributed to the persistence of drug-resistant leukemia stem cells (LSCs). LSCs need to maintain low intracellular levels of reactive oxygen species (ROS). Arsenic trioxide (ATO) induces apoptosis via upregulation of ROS-induced stress to DNA-repair mechanisms. Elevated ROS levels can trigger the Nrf2 antioxidant pathway to counteract the effects of high ROS levels. We hypothesized that ATO and VEN synergize in targeting LSCs through ROS induction by ATO and the known inhibitory effect of VEN on the Nrf2 antioxidant pathway. Using cell fractionation, immunoprecipitation, RNA-knockdown, and fluorescence assays we found that ATO activated nuclear translocation of Nrf2 and increased transcription of antioxidant enzymes, thereby attenuating the induction of ROS by ATO. VEN disrupted ATO-induced Nrf2 translocation and augmented ATO-induced ROS, thus enhancing apoptosis in LSCs. Using metabolic assays and electron microscopy, we found that the ATO+VEN combination decreased mitochondrial membrane potential, mitochondria size, fatty acid oxidation and oxidative phosphorylation, all of which enhanced apoptosis of LSCs derived from both VEN-sensitive and VEN-resistant AML primary cells. Our results indicate that ATO and VEN cooperate in inducing apoptosis of LSCs through potentiation of ROS induction, suggesting ATO+VEN is a promising regimen for treatment of VEN-sensitive and -resistant AML.<\/jats:p>","DOI":"10.3390\/ijms23126568","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T09:26:48Z","timestamp":1655026008000},"page":"6568","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Arsenic Trioxide and Venetoclax Synergize against AML Progenitors by ROS Induction and Inhibition of Nrf2 Activation"],"prefix":"10.3390","volume":"23","author":[{"given":"Dinh Hoa","family":"Hoang","sequence":"first","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Buettner","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7897-2932","authenticated-orcid":false,"given":"Melissa","family":"Valerio","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Ghoda","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Huei","family":"Kuo","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven T.","family":"Rosen","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8817-6064","authenticated-orcid":false,"given":"John","family":"Burnett","sequence":"additional","affiliation":[{"name":"Center for Gene Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Pullarkat","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le Xuan Truong","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Gehr Family Center for Leukemia Research, Hematology Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.canlet.2012.05.034","article-title":"Acute myelogenous leukemia stem cells: From Bench to Bedside","volume":"338","author":"Hassane","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.stem.2012.12.013","article-title":"BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem 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