{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T02:11:35Z","timestamp":1783476695812,"version":"3.55.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T00:00:00Z","timestamp":1656460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81800174"],"award-info":[{"award-number":["81800174"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of\u00a0Hunan Province","doi-asserted-by":"publisher","award":["2021JJ41056"],"award-info":[{"award-number":["2021JJ41056"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of\u00a0Hunan Province","doi-asserted-by":"publisher","award":["2020JJ5927"],"award-info":[{"award-number":["2020JJ5927"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Venetoclax is used for the priority treatment of elderly patients with acute myeloid leukemia (AML). Resistance or intolerance to venetoclax offsets its clinical benefits in some patients. Combination strategies with other drugs are promising alternatives to overcome the current complications associated with venetoclax use. Hymeglusin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), regulates the mevalonate pathway, which is vital for AML growth and chemosensitivity. The effects of the combination of venetoclax and hymeglusin on AML were explored in this study. The correlations between HMGCS1 and apoptosis-related genes were analyzed using the Gene Expression Profiling Interactive Analysis 2 and The Cancer Genome Atlas databases. Apoptosis and cell viability were detected in HL-60 and KG-1 cells after treatment with gradient concentrations of venetoclax or hymeglusin. The transcriptomic profiles of HL-60 and KG-1 cells were compared <jats:italic>via<\/jats:italic> RNA-Seq analysis. The effects of venetoclax and hymeglusin on apoptosis were validated in primary cells. The results showed that HMGCS1 expression was closely associated with apoptosis-related genes based on the data from large clinical databases. B cell lymphoma (BCL)-2 expression was elevated in AML and negatively associated with overall survival. Hymeglusin decreased BCL2 expression levels in HL-60 and KG-1 cells. Venetoclax and hymeglusin inhibited cell viability in both cell lines, but induced apoptosis in HL-60 cells. This discrepancy in sensitivity to hymeglusin may be attributed to the positive increase in the expression levels of HMGCS1 and multiple upregulated pro-leukemia genes in KG-1 cells. Combination treatment with venetoclax and hymeglusin significantly increased the apoptotic rates compared to single-agent treatment in both AML cell lines and primary AML cells. Furthermore, the combination strategy did not result in remarkably enhanced toxicity in normal mononuclear cells. Collectively, hymeglusin enhanced the effects of venetoclax on apoptosis. This combination strategy showed enhanced antileukemic activity with acceptable toxicity in AML.<\/jats:p>","DOI":"10.3389\/fonc.2022.864430","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T11:47:57Z","timestamp":1656503277000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Hymeglusin Enhances the Pro-Apoptotic Effects of Venetoclax in Acute Myeloid Leukemia"],"prefix":"10.3389","volume":"12","author":[{"given":"Cheng","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuanghui","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,29]]},"reference":[{"key":"B1","unstructured":"Cancer Stat Facts: Leukemia \u2014 Acute Myeloid Leukemia (AML)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1182\/blood.2019001239","article-title":"How I Treat Acute Myeloid Leukemia in the Era of New Drugs","volume":"135","author":"DiNardo","year":"2020","journal-title":"Blood"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-18-1119","article-title":"Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients With Progressive Chronic Lymphocytic Leukemia","volume":"9","author":"Blombery","year":"2019","journal-title":"Cancer Discovery"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5057","DOI":"10.1182\/blood-2019-131637","article-title":"Novel Genetic Mechanism of Venetoclax Resistance in AML: BAX Deletion","volume":"134","author":"Ahmed","year":"2019","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.20517\/cdr.2020.95","article-title":"Resistance to Venetoclax and Hypomethylating Agents in Acute Myeloid Leukemia","volume":"4","author":"Saliba","year":"2021","journal-title":"Cancer Drug Resist"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-01-0395","article-title":"Cholesterol Synthesis and Import Contribute to Protective Cholesterol Increments in Acute Myeloid Leukemia Cells","volume":"104","author":"Banker","year":"2004","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(85)92679-0","article-title":"Hypocholesterolaemia in Malignancy Due to Elevated Low-Density-Lipoprotein-Receptor Activity in Tumour Cells: Evidence From Studies in Patients With Leukaemia","volume":"2","author":"Vitols","year":"1985","journal-title":"Lancet (London England)"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.76","article-title":"The Interplay Between Cell Signalling and the Mevalonate Pathway in Cancer","volume":"16","author":"Mullen","year":"2016","journal-title":"Nat Rev Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.21.7488","article-title":"Inhibition of Hydroxymethylglutaryl-Coenzyme A Synthase by L-659,699","volume":"84","author":"Greenspan","year":"1987","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2003.11.005","article-title":"Binding Site for Fungal Beta-Lactone Hymeglusin on Cytosolic 3-Hydroxy-3-Methylglutaryl Coenzyme A Synthase","volume":"1636","author":"Tomoda","year":"2004","journal-title":"Biochim Biophys Acta"},{"key":"B11","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13045-019-0841-3","article-title":"MiR-612 Regulates Invadopodia of Hepatocellular Carcinoma by HADHA-Mediated Lipid Reprogramming","volume":"13","author":"Liu","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2005.10.096","article-title":"Antidepressant Drugs Activate SREBP and Up-Regulate Cholesterol and Fatty Acid Biosynthesis in Human Glial Cells","volume":"395","author":"Raeder","year":"2006","journal-title":"Neurosci Lett"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.562558","article-title":"Venetoclax-Based Combinations in Acute Myeloid Leukemia: Current Evidence and Future Directions","volume":"10","author":"Samra","year":"2020","journal-title":"Front Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000937","article-title":"Venetoclax for AML: Changing the Treatment Paradigm","volume":"3","author":"Pollyea","year":"2019","journal-title":"Blood Adv"},{"key":"B15","article-title":"Cerivastatin Triggers Tumor-Specific Apoptosis With Higher Efficacy Than Lovastatin","volume":"7","author":"Wong","year":"2001","journal-title":"Clin Cancer Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaq1240","article-title":"Statins Enhance Efficacy of Venetoclax in Blood Cancers","volume":"10","author":"Lee","year":"2018","journal-title":"Sci Transl Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-14-0130","article-title":"Immediate Utility of Two Approved Agents to Target Both the Metabolic Mevalonate Pathway and its Restorative Feedback Loop","volume":"74","author":"Pandyra","year":"2014","journal-title":"Cancer Res"},{"key":"B18","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/s41389-021-00341-y","article-title":"Guanylate-Binding Proteins Induce Apoptosis of Leukemia Cells by Regulating MCL-1 and BAK","volume":"10","author":"Luo","year":"2021","journal-title":"Oncogenesis"},{"key":"B19","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.stem.2018.10.016","article-title":"IKZF2 Drives Leukemia Stem Cell Self-Renewal and Inhibits Myeloid Differentiation","volume":"24","author":"Park","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.174","article-title":"Role of HOXA9 in Leukemia: Dysregulation, Cofactors and Essential Targets","volume":"35","author":"Collins","year":"2016","journal-title":"Oncogene"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/febs.16268","article-title":"Molecular Regulators of HOXA9 in Acute Myeloid Leukemia","author":"Aryal","year":"2021","journal-title":"FEBS J"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-6-72","article-title":"IGF Binding Protein 2 is a Cell-Autonomous Factor Supporting Survival and Migration of Acute Leukemia Cells","volume":"6","author":"Chen","year":"2013","journal-title":"J Hematol Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2011.08.006","article-title":"High Expression of IGFBP2 is Associated With Chemoresistance in Adult Acute Myeloid Leukemia","volume":"35","author":"K\u00fchnl","year":"2011","journal-title":"Leuk Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2019.09.014","article-title":"Identification of STAB1 in Multiple Datasets as a Prognostic Factor for Cytogenetically Normal AML: Mechanism and Drug Indications","volume":"18","author":"Lin","year":"2019","journal-title":"Mol Ther Nucleic Acids"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.864430\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T11:48:04Z","timestamp":1656503284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.864430\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,29]]},"references-count":24,"alternative-id":["10.3389\/fonc.2022.864430"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.864430","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,29]]},"article-number":"864430"}}