Lopes-Coelho, FilipaMartins, FilipaHipólito, AnaMendes, CindySequeira, Catarina O.Pires, Rita F.Almeida, António M.Bonifácio, Vasco D.B.Pereira, Sofia A.SA, PereiraSerpa, JacintaSerpa, Jacinta2021-06-182021-06-182021-05-102234-943XPURE: 31841566PURE UUID: 8dcd8bcd-4c56-4a7a-88bb-98f7cbb92a78Scopus: 85107046284ORCID: /0000-0002-8456-9995/work/95733354ORCID: /0000-0002-1548-5907/work/95733459PubMed: 34041026WOS: 000653144600001http://hdl.handle.net/10362/119581Funding: The project was funded by IPOLFG EPE and by iNOVA4Health (UID/Multi/04462/2019) a program financially supported by Fundação para a Ciência e Tecnologia (FCT)/Ministério da Educação e Ciência, through national funds. We also acknowledge funding from FCT-MCTES through the project DREAM—PTDC/MEC-ONC/29327/2017. FL-C PhD fellowship was funded by FCT (PD/BD/128337/2017).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.14421224engangiogenesisendothelial cell hyperactivationferroptosislipid peroxidationoxidative stresspolyurea dendrimerspropranololtumor vasculature stabilizersOncologyCancer ResearchSDG 3 - Good Health and Well-beingjournal article10.3389/fonc.2021.656229https://www.scopus.com/pages/publications/85107046284