Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity.
Wilson, Joseph R
Blandez, Juan F
Martins, Carla P
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González-Gualda, E., Pàez-Ribes, M., Lozano-Torres, B., Macias, D., Wilson, J. R., González-López, C., Ou, H., et al. (2020). Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity.. Aging cell, 19 (4), e13142. https://doi.org/10.1111/acel.13142
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 b-galactosidase (SA-b-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-b-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 non-senescent 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 thrombocytopaenia 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.
Royal Society (160806)
Cancer Research UK (A26989)
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External DOI: https://doi.org/10.1111/acel.13142
This record's URL: https://www.repository.cam.ac.uk/handle/1810/303708
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/