{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:17:09Z","timestamp":1791818229273,"version":"4.3.4"},"reference-count":54,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,6,2]],"date-time":"2022-06-02T00:00:00Z","timestamp":1654128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002383","name":"King Saud University","doi-asserted-by":"publisher","award":["RSP-2021\/335"],"award-info":[{"award-number":["RSP-2021\/335"]}],"id":[{"id":"10.13039\/501100002383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiovascular damage induced by anticancer therapy has become the main health problem after tumor elimination. Venetoclax (VTX) is a promising novel agent that has been proven to have a high efficacy in multiple hematological diseases, especially acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Considering its mechanism of action, the possibility that VTX may cause cardiotoxicity cannot be ruled out. Therefore, this study was designed to investigate the toxic effect of VTX on the heart. Male Sprague-Dawley rats were randomly divided into three groups: control, low-dose VTX (50 mg\/kg via oral gavage), and high-dose VTX (100 mg\/kg via oral gavage). After 21 days, blood and tissue samples were collected for histopathological, biochemical, gene, and protein analyses. We demonstrated that VTX treatment resulted in cardiac damages as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, we observed a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2. To the best of our knowledge, this study is the first to report the cardiotoxic effect of VTX. Further experiments and future studies are strongly needed to comprehensively understand the cardiotoxic effect of VTX.<\/jats:p>","DOI":"10.3390\/ijms23116260","type":"journal-article","created":{"date-parts":[[2022,6,3]],"date-time":"2022-06-03T08:01:18Z","timestamp":1654243278000},"page":"6260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Venetoclax Induces Cardiotoxicity through Modulation of Oxidative-Stress-Mediated Cardiac Inflammation and Apoptosis via NF-\u03baB and BCL-2 Pathway"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7569-4287","authenticated-orcid":false,"given":"Abdullah F.","family":"AlAsmari","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9255-8834","authenticated-orcid":false,"given":"Adel","family":"Alghamdi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6525-4202","authenticated-orcid":false,"given":"Nemat","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muath A.","family":"Almeaikl","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan M.","family":"Hakami","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meshal K.","family":"Alyousef","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7653-5683","authenticated-orcid":false,"given":"Mohammed","family":"AlSwayyed","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Metab","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3924-593X","authenticated-orcid":false,"given":"Faleh","family":"Alqahtani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2382-5892","authenticated-orcid":false,"given":"Fawaz","family":"Alasmari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2650-5934","authenticated-orcid":false,"given":"Nasser","family":"Alsaleh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1111\/j.1476-5381.2011.01255.x","article-title":"How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?","volume":"163","author":"Laverty","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1515\/cclm-2020-0566","article-title":"Cardiotoxic effects and myocardial injury: The search for a more precise definition of drug cardiotoxicity","volume":"59","author":"Cardinale","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1753944719843435","DOI":"10.1177\/1753944719843435","article-title":"Cardiotoxicity due to targeted anticancer agents: A growing challenge","volume":"13","author":"Shah","year":"2019","journal-title":"Ther. Adv. Cardiovasc. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4250\/jcu.2018.26.1.1","article-title":"Diagnosis, Treatment, and Prevention of Cardiovascular Toxicity Related to Anti-Cancer Treatment in Clinical Practice: An Opinion Paper from the Working Group on Cardio-Oncology of the Korean Society of Echocardiography","volume":"26","author":"Kim","year":"2018","journal-title":"J. Cardiovasc. Ultrasound"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3389\/fcvm.2018.00009","article-title":"Cardiotoxicity of Anticancer Therapeutics","volume":"5","author":"Dong","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"309","DOI":"10.3322\/caac.21341","article-title":"Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management","volume":"66","author":"Curigliano","year":"2016","journal-title":"CA Cancer J. Clin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s12012-007-0024-2","article-title":"Genotyping the risk of anthracycline-induced cardiotoxicity","volume":"7","author":"Deng","year":"2007","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1097\/MJT.0000000000000453","article-title":"Mechanisms and Genetic Susceptibility of Chemotherapy-Induced Cardiotoxicity in Patients with Breast Cancer","volume":"24","author":"Mihalcea","year":"2017","journal-title":"Am. J. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s11897-012-0083-y","article-title":"Chemotherapy-induced cardiotoxicity","volume":"9","author":"Shaikh","year":"2012","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1089\/ars.2016.6930","article-title":"From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview","volume":"30","author":"Tocchetti","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrcardio.2010.121","article-title":"Cardiotoxicity of anticancer treatments: What the cardiologist needs to know","volume":"7","author":"Ewer","year":"2010","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7573\/dic.212574","article-title":"Venetoclax: Evidence to date and clinical potential","volume":"8","author":"Desai","year":"2019","journal-title":"Drugs Context"},{"key":"ref_13","first-page":"2361","article-title":"Know the enemy as well as the weapons in hand: The aberrant death pathways and therapeutic agents in chronic lymphocytic leukemia","volume":"5","author":"Huang","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4527","DOI":"10.1158\/1078-0432.CCR-16-0955","article-title":"Venetoclax in Patients with Previously Treated Chronic Lymphocytic Leukemia","volume":"23","author":"Roberts","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1006\/bcmd.2000.0372","article-title":"Bcl-2 mediates chemoresistance in matched pairs of primary E(mu)-myc lymphomas in vivo","volume":"27","author":"Schmitt","year":"2001","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1177\/2040620716655350","article-title":"The potential of venetoclax (ABT-199) in chronic lymphocytic leukemia","volume":"7","author":"Itchaki","year":"2016","journal-title":"Ther. Adv. Hematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s40265-016-0596-x","article-title":"Venetoclax: First Global Approval","volume":"76","author":"Deeks","year":"2016","journal-title":"Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.exphem.2018.02.002","article-title":"Venetoclax: A new wave in hematooncology","volume":"61","author":"Mihalyova","year":"2018","journal-title":"Exp. Hematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1158\/1078-0432.CCR-17-3761","article-title":"Comprehensive Safety Analysis of Venetoclax Monotherapy for Patients with Relapsed\/Refractory Chronic Lymphocytic Leukemia","volume":"24","author":"Davids","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_20","first-page":"A11835","article-title":"Abstract 11835: Evaluation of Cardiovascular Adverse Events Associated With Ibrutinib, Venetoclax and Idelalisib Used in Treatment of Chronic Lymphocytic Leukemia","volume":"138","author":"Mahida","year":"2018","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1093\/ckj\/sfy026","article-title":"Renal involvement in chronic lymphocytic leukemia","volume":"11","author":"Wanchoo","year":"2018","journal-title":"Clin. Kidney J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"C45","DOI":"10.1152\/ajpcell.00229.2006","article-title":"Bcl-2 family members and apoptosis, taken to heart","volume":"292","author":"Gustafsson","year":"2007","journal-title":"Am. J. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13045-015-0224-3","article-title":"ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development","volume":"8","author":"Cang","year":"2015","journal-title":"J. Hematol. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.pcad.2006.10.002","article-title":"Doxorubicin-Induced Cardiomyopathy: From the Cardiotoxic Mechanisms to Management","volume":"49","author":"Takemura","year":"2007","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3389\/fonc.2014.00277","article-title":"Serum Biomarkers for the Detection of Cardiac Toxicity after Chemotherapy and Radiation Therapy in Breast Cancer Patients","volume":"4","author":"Tian","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_26","first-page":"27","article-title":"Molecular and cellular mechanisms of cardiotoxicity","volume":"109","author":"Kang","year":"2001","journal-title":"Environ. Health Perspect."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.cardiores.2004.02.013","article-title":"Myocyte hypertrophy and apoptosis: A balancing act","volume":"63","author":"Empel","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.vph.2008.07.004","article-title":"Induction of several cytochrome P450 genes by doxorubicin in H9c2 cells","volume":"49","author":"Zordoky","year":"2008","journal-title":"Vasc. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s12012-014-9266-y","article-title":"Mitogen-Activated Protein Kinases Pathways Mediate the Sunitinib-Induced Hypertrophy in Rat Cardiomyocyte H9c2 Cells","volume":"15","author":"Korashy","year":"2015","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"434","DOI":"10.3389\/fcell.2020.00434","article-title":"Molecular Mechanisms of Cardiomyocyte Death in Drug-Induced Cardiotoxicity","volume":"8","author":"Ma","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1038\/s41418-017-0012-4","article-title":"Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018","volume":"25","author":"Galluzzi","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3722","article-title":"Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy","volume":"15","author":"Czabotar","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nrc.2015.2","article-title":"DNA damage and the balance between survival and death in cancer biology","volume":"16","author":"Roos","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1089\/ars.2012.4905","article-title":"Regulation of the Intrinsic Apoptosis Pathway by Reactive Oxygen Species","volume":"19","author":"Wu","year":"2013","journal-title":"Antioxidants Redox Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1111\/jdi.12250","article-title":"Diabetic cardiomyopathy and its mechanisms: Role of oxidative stress and damage","volume":"5","author":"Liu","year":"2014","journal-title":"J. Diabetes Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9030563","DOI":"10.1155\/2019\/9030563","article-title":"Oxidative Stress in Cell Death and Cardiovascular Diseases","volume":"2019","author":"Xu","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1139\/Y10-016","article-title":"Oxidative stress: A key contributor to diabetic cardiomyopathy","volume":"88","author":"Khullar","year":"2010","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1159\/000289198","article-title":"Role of TNF in pathologies induced by nuclear factor kappaB deficiency","volume":"11","author":"Vlantis","year":"2010","journal-title":"Curr. Dir. Autoimmun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1038\/labinvest.3700669","article-title":"Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations","volume":"87","year":"2007","journal-title":"Lab. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.yjmcc.2010.10.033","article-title":"Transforming growth factor (TGF)-beta signaling in cardiac remodeling","volume":"51","author":"Dobaczewski","year":"2011","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tox.2006.11.067","article-title":"Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats","volume":"231","author":"Liu","year":"2007","journal-title":"Toxicology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.fct.2009.10.042","article-title":"Protective effect of Solanum torvum on doxorubicin-induced nephrotoxicity in rats","volume":"48","author":"Mohan","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e1721","DOI":"10.1038\/cddis.2015.97","article-title":"BCL-2 is dispensable for thrombopoiesis and platelet survival","volume":"6","author":"Debrincat","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nm.3048","article-title":"ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets","volume":"19","author":"Souers","year":"2013","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J. Basic Clin. Pharm."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3738","DOI":"10.1182\/blood-2014-05-574566","article-title":"ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia","volume":"124","author":"Peirs","year":"2014","journal-title":"Blood"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1158\/2159-8290.CD-13-0609","article-title":"Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia","volume":"4","author":"Pan","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_48","first-page":"481","article-title":"Comparison of ketamine-xylazine and ketamine-dexmedetomidine anesthesia and intraperitoneal tolerance in rats","volume":"52","author":"Wellington","year":"2013","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"719","DOI":"10.3389\/fimmu.2017.00719","article-title":"Toll-Like Receptor 4 Inhibition Improves Oxidative Stress and Mitochondrial Health in Isoproterenol-Induced Cardiac Hypertrophy in Rats","volume":"8","author":"Katare","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"658958","DOI":"10.4061\/2011\/658958","article-title":"Histologically Measured Cardiomyocyte Hypertrophy Correlates with Body Height as Strongly as with Body Mass Index","volume":"2011","author":"Tracy","year":"2011","journal-title":"Cardiol. Res. Pract."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/0003-2697(68)90092-4","article-title":"Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman\u2019s reagent","volume":"25","author":"Sedlak","year":"1968","journal-title":"Anal. Biochem."},{"key":"ref_54","unstructured":"Claiborne, A.J.F.C.P. (1985). Handbook of Methods for Oxygen Radical Research, CRC Press."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6260\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:24:07Z","timestamp":1760138647000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/6260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,2]]},"references-count":54,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23116260"],"URL":"https:\/\/doi.org\/10.3390\/ijms23116260","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,2]]}}}