Pivarubicin is more effective than doxorubicin against triple-negative breast cancer in vivo

Pivarubicin is more effective than doxorubicin against triple-negative breast cancer in vivo | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Pivarubicin is more effective than doxorubicin against triple-negative breast cancer in vivo Leonard Lothstein, Judith Ellen Soberman, Deanna Parke, Jatin Gandhi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.13608/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Dec, 2020 Read the published version in Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics → Version 1 posted You are reading this latest preprint version Abstract Background: Triple-negative breast cancer (TNBC) is unresponsive to anti-estrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20-40%, a consequence of drug resistance and cumulative dose limitations necessitated by the irreversible cardiotoxic effects of anthracyclines and other cytotoxic agents. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanism of action and in vivo efficacy of pivarubicin, a structurally and functionally novel anthracycline, to determine whether pivarubicin is potentially more effective and safer than doxorubicin against human primary TNBC. Methods: Hydrolytic stability, mechanism and ability of pivarubicin to circumvent mechanisms of resistance are tested in multiple tumor lines through modulation of PKC-delta activity and assessment of drug cytotoxicity. Comparative in vivo efficacy is tested in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses of pivarubicin and doxorubicin, followed by monitoring of tumor growth by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity is assessed histologically by identifying microvacuolization in ventricular cardiomyocytes. Results: The trimethylester moiety of pivarubicin confers hydrolytic stability relative to the closely related congener, AD 198, but retains the ability of other N -alkylbenzyladriamycin compounds to directly activate PKC-delta and trigger rapid mitochondrial-dependent apoptosis. The structure and function of pivarubicin permits circumvention of resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X L and Bcr-Abl. Primary tumors treated with the multiple rounds of the maximum tolerated dose (MTD) of doxorubicin failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at this therapeutic dose. Conclusion: These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated. Cancer Biology Pivarubicin Doxorubicin Apoptosis Triple-Negative Breast Cancer Chemotherapy Cardiotoxicity Full text The authors have retracted the full text of this preprint until journal publication Cite Share Download PDF Status: Published Journal Publication published 10 Dec, 2020 Read the published version in Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4317","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":140159,"identity":"4e55415d-c6be-4745-985f-493d3cdad354","order_by":1,"name":"Leonard Lothstein","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIie3NsQrCQAyA4chBupzteqB4r3ClID5Oi+BUQRAEl1o4yOQDKD6FizhWCrrYvasITi4iOHWwOkurm8P9Uwj5CIDJ9IfZFgB7DQgsgUb8XqpKggwa+nWEgD7sfiIAXH1L2OE8KoqO3Zo/WrdtJMHSG1FNMNBLUh62s43YHVM35vtJDeGubsYqIDEsCSU+iLBbT3ihZiTCS0kiH+T1G4LKRxFiSVj5hdcRDFZN8lwSA6+XUeoSH4x7VcSxdHLnRUfKRf+UTymSjpWu8yry4e9v5yaTyWT61BPygz27FLgGIQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-6854-0842","institution":"University of Tennessee Health Science Center College of Medicine Memphis","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Leonard","middleName":"","lastName":"Lothstein","suffix":""},{"id":140160,"identity":"2b23003b-8b89-4c7b-8342-35af2a484d1b","order_by":2,"name":"Judith Ellen Soberman","email":"","orcid":"","institution":"University of Tennessee Health Science Center College of Medicine Memphis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Judith","middleName":"Ellen","lastName":"Soberman","suffix":""},{"id":140161,"identity":"d2e33f1e-eff5-4835-ba8a-3a8912d1d82f","order_by":3,"name":"Deanna Parke","email":"","orcid":"","institution":"University of Tennessee Health Science Center College of Medicine Memphis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Deanna","middleName":"","lastName":"Parke","suffix":""},{"id":140162,"identity":"317c8d11-0614-477f-9cf9-e269fb7574b4","order_by":4,"name":"Jatin Gandhi","email":"","orcid":"","institution":"University of Tennessee Health Science Center College of Medicine Memphis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jatin","middleName":"","lastName":"Gandhi","suffix":""},{"id":140163,"identity":"9f42c983-c84e-4ea9-9764-bfdbc5e5687f","order_by":5,"name":"Trevor Sweatman","email":"","orcid":"","institution":"University of Tennessee Health Science Center College of Medicine Memphis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Trevor","middleName":"","lastName":"Sweatman","suffix":""},{"id":140164,"identity":"9d6c3a14-6ba3-4578-8e6a-908e424b9c9b","order_by":6,"name":"Tiffany Seagroves","email":"","orcid":"","institution":"University of Tennessee Health Science Center College of Medicine Memphis","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tiffany","middleName":"","lastName":"Seagroves","suffix":""}],"badges":[],"createdAt":"2019-08-22 14:27:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.2.13608/v1","doiUrl":"https://doi.org/10.21203/rs.2.13608/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.3727/096504020X15898794315356","type":"published","date":"2020-12-10T18:50:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":13471494,"identity":"fb1030d7-4a4e-4603-b072-f799e8870ec2","added_by":"auto","created_at":"2021-09-16 21:09:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":126631,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4317/v1/c012ee46-d005-4b08-b64c-a99b80749c32.pdf"}],"financialInterests":"","formattedTitle":"Pivarubicin is more effective than doxorubicin against triple-negative breast cancer in vivo","fulltext":[{"header":"Full text","content":"\u003cp\u003eThe authors have retracted the full text of this preprint until journal publication\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":true,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pivarubicin, Doxorubicin, Apoptosis, Triple-Negative Breast Cancer, Chemotherapy, Cardiotoxicity","lastPublishedDoi":"10.21203/rs.2.13608/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.13608/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: Triple-negative breast cancer (TNBC) is unresponsive to anti-estrogen and anti-HER2 therapies, requiring the use of cytotoxic drug combinations of anthracyclines, taxanes, cyclophosphamide and platinum compounds. Multidrug therapies achieve pathological cure rates of only 20-40%, a consequence of drug resistance and cumulative dose limitations necessitated by the irreversible cardiotoxic effects of anthracyclines and other cytotoxic agents. Safer and more effective treatments for TNBC are required to achieve durable therapeutic responses. This study describes the mechanism of action and in vivo efficacy of pivarubicin, a structurally and functionally novel anthracycline, to determine whether pivarubicin is potentially more effective and safer than doxorubicin against human primary TNBC.\n \nMethods: Hydrolytic stability, mechanism and ability of pivarubicin to circumvent mechanisms of resistance are tested in multiple tumor lines through modulation of PKC-delta activity and assessment of drug cytotoxicity. Comparative in vivo efficacy is tested in an orthotopic NSG mouse model implanted with MDA-MB-231 human TNBC cells and treated with the maximum tolerated doses of pivarubicin and doxorubicin, followed by monitoring of tumor growth by digital caliper measurements and determination of endpoint tumor weight and volume. Endpoint cardiotoxicity is assessed histologically by identifying microvacuolization in ventricular cardiomyocytes.\n \nResults: The trimethylester moiety of pivarubicin confers hydrolytic stability relative to the closely related congener, AD 198, but retains the ability of other N -alkylbenzyladriamycin compounds to directly activate PKC-delta and trigger rapid mitochondrial-dependent apoptosis. The structure and function of pivarubicin permits circumvention of resistance conferred by overexpression of P-glycoprotein, Bcl-2, Bcl-X L and Bcr-Abl. Primary tumors treated with the multiple rounds of the maximum tolerated dose (MTD) of doxorubicin failed to inhibit tumor growth compared with vehicle-treated tumors. However, administration of a single MTD of pivarubicin produced significant inhibition of tumor growth and tumor regression relative to tumor volume prior to initiation of treatment. Histological analysis of hearts excised from drug- and vehicle-treated mice revealed that pivarubicin produced no evidence of myocardial damage at this therapeutic dose. \n \nConclusion: These results support the development of pivarubicin as a safer and more effective replacement for doxorubicin against TNBC as well as other malignancies for which doxorubicin therapy is indicated.","manuscriptTitle":"Pivarubicin is more effective than doxorubicin against triple-negative breast cancer in vivo","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2019-08-29 01:30:27","doi":"10.21203/rs.2.13608/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2db9c645-ae26-4e95-aa2b-08923657de46","owner":[],"postedDate":"August 29th, 2019","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":23405,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2021-07-22T18:50:35+00:00","versionOfRecord":{"articleIdentity":"rs-4317","link":"https://doi.org/10.3727/096504020X15898794315356","journal":{"identity":"oncology-research-featuring-preclinical-and-clinical-cancer-therapeutics","isVorOnly":true,"title":"Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics"},"publishedOn":"2020-12-10 18:50:35","publishedOnDateReadable":"December 10th, 2020"},"versionCreatedAt":"2019-08-29 01:30:27","video":"","vorDoi":"10.3727/096504020X15898794315356","vorDoiUrl":"https://doi.org/10.3727/096504020X15898794315356","workflowStages":[]},"version":"v1","identity":"rs-4317","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-4317","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}