The activation of endothelial cells relies on a ferroptosis-like mechanism: novel perspectives in management of angiogenesis and cancer therapy

Filipa Lopes-Coelho, Filipa Martins, Ana Hipólito, Cindy Mendes, Catarina O. Sequeira, Rita F. Pires, António M. Almeida, Vasco D. B. Bonifácio, Sofia A. Pereira, Jacinta Serpa*

*Autor correspondente para este trabalho

Resultado de pesquisarevisão de pares

14 Citações (Scopus)

Resumo

The activation of endothelial cells (ECs) is a crucial step on the road map of tumor angiogenesis and expanding evidence indicates that a pro-oxidant tumor microenvironment, conditioned by cancer metabolic rewiring, is a relevant controller of this process. Herein, we investigated the contribution of oxidative stress-induced ferroptosis to ECs activation. Moreover, we also addressed the anti-angiogenic effect of Propranolol. We observed that a ferroptosis-like mechanism, induced by xCT inhibition with Erastin, at a non-lethal level, promoted features of ECs activation, such as proliferation, migration and vessel-like structures formation, concomitantly with the depletion of reduced glutathione (GSH) and increased levels of oxidative stress and lipid peroxides. Additionally, this ferroptosis-like mechanism promoted vascular endothelial cadherin (VE-cadherin) junctional gaps and potentiated cancer cell adhesion to ECs and transendothelial migration. Propranolol was able to revert Erastin-dependent activation of ECs and increased levels of hydrogen sulfide (H2S) underlie the mechanism of action of Propranolol. Furthermore, we tested a dual-effect therapy by promoting ECs stability with Propranolol and boosting oxidative stress to induce cancer cell death with a nanoformulation comprising selenium-containing chrysin (SeChry) encapsulated in a fourth generation polyurea dendrimer (SeChry@PUREG4). Our data showed that novel developments in cancer treatment may rely on multi-targeting strategies focusing on nanoformulations for a safer induction of cancer cell death, taking advantage of tumor vasculature stabilization.
Idioma originalEnglish
Número do artigo656229
RevistaFrontiers in Oncology
Volume11
DOIs
Estado da publicaçãoPublicado - 10 mai 2021
Publicado externamenteSim

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