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3 results on '"chemotherapy-induced senescence"'

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

Author

Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Cancer Research UK, Medical Research Council, Royal Society, González-Gualda, E., Páez-Ribes, M., Lozano-Torres, B., Macías, David, Wilson III, J. R., González-López, C., Ou, H. L., Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Cancer Research UK, Medical Research Council, Royal Society, González-Gualda, E., Páez-Ribes, M., Lozano-Torres, B., Macías, David, Wilson III, J. R., González-López, C., and Ou, H. L.

Published
2020

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

Author

Universitat Politècnica de València. Departamento de Química - Departament de Química, Royal Society, Reino Unido, Generalitat Valenciana, Ministerio de Educación, Cancer Research, Reino Unido, Agencia Estatal de Investigación, Ministerio de Economía y Empresa, Medical Research Council, Reino Unido, González-Gualda, Estela, Pàez-Rives, Marta, Lozano-Torres, Beatriz, Macias, David, Wilson III, Joseph R., González-López, Cristina, Ou, Hui-Ling, MIrón-Barroso, Sofía, Zhang, Zhenguang, Lérida-Viso, Araceli, Blandez, Juan F., Bernardos Bau, Andrea, Sancenón Galarza, Félix, Rovira, Miguel, Fruk, Ljiljana, Martins, Carla P., Serrano, Manuel, Doherty, Gary J., Martínez-Máñez, Ramón, Muñoz-Espín, Daniel, Universitat Politècnica de València. Departamento de Química - Departament de Química, Royal Society, Reino Unido, Generalitat Valenciana, Ministerio de Educación, Cancer Research, Reino Unido, Agencia Estatal de Investigación, Ministerio de Economía y Empresa, Medical Research Council, Reino Unido, González-Gualda, Estela, Pàez-Rives, Marta, Lozano-Torres, Beatriz, Macias, David, Wilson III, Joseph R., González-López, Cristina, Ou, Hui-Ling, MIrón-Barroso, Sofía, Zhang, Zhenguang, Lérida-Viso, Araceli, Blandez, Juan F., Bernardos Bau, Andrea, Sancenón Galarza, Félix, Rovira, Miguel, Fruk, Ljiljana, Martins, Carla P., Serrano, Manuel, Doherty, Gary J., Martínez-Máñez, Ramón, and Muñoz-Espín, Daniel

Abstract

[EN] 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.

Published
2020

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

Author

Universitat Politècnica de València. Departamento de Química - Departament de Química, Royal Society, Reino Unido, UK Research and Innovation, Generalitat Valenciana, Cancer Research, Reino Unido, Agencia Estatal de Investigación, Medical Research Council, Reino Unido, Ministerio de Educación, Cultura y Deporte, Ministerio de Economía y Competitividad, González-Gualda, Estela, Pàez-Rives, Marta, Lozano-Torres, Beatriz, Macias, David, Wilson III, Joseph R., González-López, Cristina, Ou, Hui-Ling, MIrón-Barroso, Sofía, Zhang, Zhenguang, Lérida-Viso, Araceli, Blandez, Juan F., Bernardos Bau, Andrea, Sancenón Galarza, Félix, Rovira, Miguel, Fruk, Ljiljana, Martins, Carla P., Serrano, Manuel, Doherty, Gary J., Martínez-Máñez, Ramón, Muñoz-Espín, Daniel, Universitat Politècnica de València. Departamento de Química - Departament de Química, Royal Society, Reino Unido, UK Research and Innovation, Generalitat Valenciana, Cancer Research, Reino Unido, Agencia Estatal de Investigación, Medical Research Council, Reino Unido, Ministerio de Educación, Cultura y Deporte, Ministerio de Economía y Competitividad, González-Gualda, Estela, Pàez-Rives, Marta, Lozano-Torres, Beatriz, Macias, David, Wilson III, Joseph R., González-López, Cristina, Ou, Hui-Ling, MIrón-Barroso, Sofía, Zhang, Zhenguang, Lérida-Viso, Araceli, Blandez, Juan F., Bernardos Bau, Andrea, Sancenón Galarza, Félix, Rovira, Miguel, Fruk, Ljiljana, Martins, Carla P., Serrano, Manuel, Doherty, Gary J., Martínez-Máñez, Ramón, and Muñoz-Espín, Daniel

Abstract

[EN] 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.

Published
2020

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