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Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity

Fecha de publicación: Fecha Ahead of Print:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Gonzalez-Gualda, E
  • Paez-Ribes, M
  • Lozano-Torres, B
  • Macias, D
  • Wilson, III
  • Gonzalez-Lopez, C
  • Ou, HL
  • Miron-Barroso, S
  • Zhang, ZG
  • Blandez, JF
  • Bernardos, A
  • Rovira, M
  • Fruk, L
  • Martins, CP
  • Serrano, M
  • Doherty, GJ
  • Munoz-Espin, D

Grupos

Abstract

Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence-associated lysosomal beta-galactosidase (SA-beta-gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose-encapsulated nanoparticles within these cells. Here, we show that galacto-conjugation of the BCL-2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav-Gal), that can be preferentially activated by SA-beta-gal activity in a wide range of cell types. Nav-Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav-Gal enhances the cytotoxicity of standard senescence-inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav-Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto-conjugation reduces Navitoclax-induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.

Datos de la publicación

ISSN/ISSNe:
1474-9718, 1474-9726

Aging cell  WILEY

Tipo:
Article
Páginas:
-
Factor de Impacto:
3,103 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 96

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Keywords

  • cellular senescence; chemotherapy-induced senescence; lung cancer; Navitoclax (ABT-263); prodrug; senolytics; thrombocytopenia

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PROGRAMA TÉCNICO DE APOYO. MODALIDAD INFRAESTRUCTURA.

Investigador Principal: RAMÓN MARTÍNEZ MÁÑEZ

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Contrato I-PFIS: Predoctorales de formación en investigación en salud.

Investigador Principal: RAMÓN MARTÍNEZ MÁÑEZ

IFI17/00039 . INSTITUTO DE SALUD CARLOS III . 2018

Contrato Post FSE (Rio Hortega)

Investigador Principal: RAMÓN MARTÍNEZ MÁÑEZ

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PLATAFORMA PARA LA DETECCIÓN DE PATÓGENOS BASADA EN MATERIALES CON PUERTAS MOLECULARES (PATH-GATE).

Investigador Principal: RAMÓN MARTÍNEZ MÁÑEZ

DTS18/00090 . INSTITUTO DE SALUD CARLOS III . 2019

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