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

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dc.contributor.author Estepa-Fernández, Alejandra es_ES
dc.contributor.author García-Fernández, Alba es_ES
dc.contributor.author Lerida-Viso, Araceli es_ES
dc.contributor.author Blandez, Juan F. es_ES
dc.contributor.author Galiana, Irene es_ES
dc.contributor.author Sancenón Galarza, Félix es_ES
dc.contributor.author Orzaez, Mar es_ES
dc.contributor.author Martínez-Máñez, Ramón es_ES
dc.date.accessioned 2024-04-11T07:22:19Z
dc.date.available 2024-04-11T07:22:19Z
dc.date.issued 2023-01 es_ES
dc.identifier.issn 1043-6618 es_ES
dc.identifier.uri http://hdl.handle.net/10251/203300
dc.description.abstract [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 es_ES
dc.description.sponsorship 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. thanks to the Instituto de Salud Carlos III for his Sara Borrell contract (CD19/00038) . Thank the financial support from the FEDER found of European Union (IDIFEDER/2021/044) . The authors thank Alberto Herna?ndez for the confocal microscope, Alicia Martinez for flow cytometry, and Viviana Bisbal for veterinary assistance. The authors thank for the use of Biorender.com in the graphical abstract Fig. 2 and Fig. 3. es_ES
dc.language Inglés es_ES
dc.publisher Elsevier es_ES
dc.relation.ispartof Pharmacological Research es_ES
dc.rights Reconocimiento - No comercial - Sin obra derivada (by-nc-nd) es_ES
dc.subject Navitoclax es_ES
dc.subject Palbociclib es_ES
dc.subject Pro-drug es_ES
dc.subject Senescence es_ES
dc.subject Senolytic es_ES
dc.subject TNBC. es_ES
dc.subject.classification QUIMICA ORGANICA es_ES
dc.subject.classification QUIMICA INORGANICA es_ES
dc.title Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.1016/j.phrs.2022.106628 es_ES
dc.relation.projectID 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/ es_ES
dc.relation.projectID 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/ es_ES
dc.relation.projectID 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/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/GVA//PROMETEO2018%2F024/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/GVA//IDIFEDER%2F2021%2F044/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/GVA//PROMETEO%2F2019%2F065/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/ISCIII//IFI17%2F00039//i-PFIS grant/ es_ES
dc.relation.projectID info:eu-repo/grantAgreement/ISCIII//CD19%2F00038/ es_ES
dc.relation.projectID 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/ es_ES
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Escuela Técnica Superior de Ingenieros Industriales - Escola Tècnica Superior d'Enginyers Industrials es_ES
dc.description.bibliographicCitation Estepa-Fernández, A.; García-Fernández, A.; Lerida-Viso, A.; Blandez, JF.; Galiana, I.; Sancenón Galarza, F.; Orzaez, M.... (2023). Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer. Pharmacological Research. 187. https://doi.org/10.1016/j.phrs.2022.106628 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion https://doi.org/10.1016/j.phrs.2022.106628 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 187 es_ES
dc.relation.pasarela S\485220 es_ES
dc.contributor.funder Generalitat Valenciana es_ES
dc.contributor.funder Instituto de Salud Carlos III es_ES
dc.contributor.funder Agencia Estatal de Investigación es_ES
dc.contributor.funder European Regional Development Fund es_ES
dc.contributor.funder Universitat Politècnica de València es_ES
dc.contributor.funder Ministerio de Educación, Cultura y Deporte es_ES


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