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Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer

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العنوان: Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer
المؤلفون: Estepa-Fernández, Alejandra, García-Fernández, Alba, Lerida-Viso, Araceli, Blandez, Juan F., Galiana, Irene, Sancenón Galarza, Félix, Orzaez, Mar, Martínez-Máñez, Ramón
المساهمون: Universitat Politècnica de València. Escuela Técnica Superior de Ingenieros Industriales - Escola Tècnica Superior d'Enginyers Industrials, Generalitat Valenciana, Instituto de Salud Carlos III, Agencia Estatal de Investigación, European Regional Development Fund, Universitat Politècnica de València, Ministerio de Educación, Cultura y Deporte
بيانات النشر: Elsevier
سنة النشر: 2023
المجموعة: Universitat Politécnica de Valencia: RiuNet / Politechnical University of Valencia
مصطلحات موضوعية: Navitoclax, Palbociclib, Pro-drug, Senescence, Senolytic, TNBC, QUIMICA ORGANICA, QUIMICA INORGANICA
الوصف: [EN] Triple-negative breast cancer (TNBC) is a very aggressive subtype of breast cancer with a poor prognosis and limited effective therapeutic options. Induction of senescence, arrest of cell proliferation, has been explored as an effective method to limit tumor progression in metastatic breast cancer. However, relapses occur in some patients, possibly as a result of the accumulation of senescent tumor cells in the body after treatment, which promote metastasis. In this study, we explored the combination of senescence induction and the subsequent removal of senescent cells (senolysis) as an alternative approach to improve outcomes in TNBC patients. We demonstrate that a combination treatment, using the senescence-inducer palbociclib and the senolytic agent navitoclax, delays tumor growth and reduces metastases in a mouse xenograft model of aggressive human TNBC (hTNBC). Furthermore, considering the off-target effects and toxicity derived from the use of navitoclax, we propose a strategy aimed at minimizing the associated side effects. We use a galacto-conjugated navitoclax (nav-Gal) as a senolytic prodrug that can preferentially be activated by ß-galactosidase overexpressed in senescent cells. Concomitant treatment with palbociclib and nav-Gal in vivo results in the eradication of senescent hTNBC cells with consequent reduction of tumor growth, while reducing the cytotoxicity of navitoclax. Taken together, our results support the efficacy of combination therapy of senescence-induction with senolysis for hTNBC, as well as the development of a targeted approach as an effective and safer therapeutic opportunity ; This work was supported by the Spanish Government projects (RTI2018-100910-B-C41, RTI2018-101599-B-C22 and PID2020 -115048RB-I00 (MCUI/FEDER, EU) ) and the Generalitat Valenciana (PROMETEO 2018/024 and PROMETEO/2019/065) . A.E-F. is grateful to the Spanish Government for her Ph.D. grant (FPU17/05454) , A.L-V. is grateful to the Instituto de Salud Carlos III for her Ph.D. i-PFIS grant (IFI17/00039) . J.B. ...
نوع الوثيقة: article in journal/newspaper
اللغة: English
تدمد: 1043-6618
Relation: Pharmacological Research; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115048RB-I00/ES/EL INTERACTOMA DE MEMBRANA DE LAS PROTEINAS DE LA FAMILIA BCL-2 COMO DIANA ANTITUMORAL/; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-100910-B-C41/ES/MATERIALES POROSOS INTELIGENTES MULTIFUNCIONALES Y DISPOSITIVOS ELECTRONICOS PARA LA LIBERACION DE FARMACOS, DETECCION DE DROGAS Y BIOMARCADORES Y COMUNICACION A NANOESCALA/; info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-101599-B-C22/ES/DESARROLLO Y APLICACION DE SISTEMAS ANTIMICROBIANOS PARA LA INDUSTRIA ALIMENTARIA BASADOS EN SUPERFICIES FUNCIONALIZADAS Y SISTEMAS DE LIBERACION CONTROLADA/; info:eu-repo/grantAgreement/GVA//PROMETEO2018%2F024/; info:eu-repo/grantAgreement/GVA//IDIFEDER%2F2021%2F044/; info:eu-repo/grantAgreement/GVA//PROMETEO%2F2019%2F065/; info:eu-repo/grantAgreement/ISCIII//IFI17%2F00039//i-PFIS grant/; info:eu-repo/grantAgreement/ISCIII//CD19%2F00038/; info:eu-repo/grantAgreement/MECD//FPU17%2F05454//AYUDA CONTRATOS PREDOCTORALES FPU-ESTEPA FERNANDEZ. PROYECTO: NUEVOS MATERIALES HIBRIDOS PARA LA ELIMINACION DE CELULAS SENESCENTES EN MODELOS DE ENFERMEDAD/; https://doi.org/10.1016/j.phrs.2022.106628; urn:issn:1043-6618; http://hdl.handle.net/10251/203300
DOI: 10.1016/j.phrs.2022.106628
الاتاحة: http://hdl.handle.net/10251/203300
https://doi.org/10.1016/j.phrs.2022.106628
Rights: http://creativecommons.org/licenses/by-nc-nd/4.0/ ; info:eu-repo/semantics/openAccess
رقم الانضمام: edsbas.340C8B97
قاعدة البيانات: BASE
الوصف
تدمد:10436618
DOI:10.1016/j.phrs.2022.106628