Portal de investigación
Combination of palbociclib with navitoclax based-therapies enhances in vivo antitumoral activity in triple-negative breast cancer.
Fecha de publicación:
Fecha Ahead of Print:
Autores de CIPF
Grupos de Investigación
Abstract
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.
Datos de la publicación
- ISSN/ISSNe:
- 1043-6618, 1096-1186
- Tipo:
- Article
- Páginas:
- 106628-106628
- PubMed:
- 36566002
PHARMACOLOGICAL RESEARCH Elsevier Inc.
Citas Recibidas en Web of Science: 21
Documentos
- No hay documentos
Filiaciones
Keywords
- Navitoclax, Palbociclib, Pro-drug, Senescence, Senolytic, TNBC
Proyectos asociados
Ensuring long-term sustainability of excellence in chemical biology within Europe and beyond
Investigador Principal: MARIA JESUS VICENT DOCON
COMMISSION OF EUROPEAN COMMUNITIES . 2019
MEMBDEATH: Muerte celular y membranas: un nuevo nicho en la lucha contra el cáncer. Colab con la UV, no recibimos financiación
Investigador Principal: MARIA MAR ORZÁEZ CALATAYUD
CONSELLERIA DE EDUCACION . 2019
El interactoma de membrana de las proteínas de la familia Bcl-2 como diana antitumoral
Investigador Principal: MARIA MAR ORZÁEZ CALATAYUD
MINISTERIO DE CIENCIA, INNOVACION Y UNIVERSIDADES . 2021
VALORIZATION OF A FIRST-IN-CLASS MCL-1 INHIBITOR
Investigador Principal: MARIA MAR ORZÁEZ CALATAYUD
MINISTERIO DE CIENCIA, INNOVACION Y UNIVERSIDADES . 2021
Nanoplataforma Polipeptídica Multimodal de Precisión para el Tratamiento y Monitorización de Tumores Metastásicos. Colab I-36, I-12, I-63, servicio citómica, uji y gva (Esther Roselló)
Investigador Principal: MARIA JESUS VICENT DOCON
CONSELLERIA DE EDUCACION . 2022