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https://hdl.handle.net/10316/103812
Title: | The Enhanced Efficacy of Intracellular Delivery of Doxorubicin/C6-Ceramide Combination Mediated by the F3 Peptide/Nucleolin System Is Supported by the Downregulation of the PI3K/Akt Pathway | Authors: | Cruz, Ana F. Caleiras, Mariana B. Fonseca, Nuno A. Gonçalves, Nélio Mendes, Vera M. Sampaio, Susana F. Moura, Vera Melo, Joana B. Almeida, Ramiro D. Manadas, Bruno Simões, Sérgio Paulo Moreira, João N. |
Keywords: | nucleolin; ovarian cancer; doxorubicin; C6-ceramide; synergistic combination; phospho-Akt downregulation | Issue Date: | 18-Jun-2021 | Publisher: | MDPI | Project: | CENTRO-01-0247-FEDER-017646 POCI-01-0145-FEDER-016390 CENTRO-01-0145-FEDER-000012 UIDB/04539/2020 POCI-01-0145-FEDER-029311 POCI-01-0145-FEDER-402-022125 ItemCrisRefDisplayStrategy.project.deleted.icon |
Serial title, monograph or event: | Cancers | Volume: | 13 | Issue: | 12 | Abstract: | Targeting multiple cellular populations is of high therapeutic relevance for the tackling of solid tumors heterogeneity. Herein, the ability of pegylated and pH-sensitive liposomes, functionalized with the nucleolin-binding F3 peptide and containing doxorubicin (DXR)/C6-ceramide synergistic combination, to target, in vitro, ovarian cancer, including ovarian cancer stem cells (CSC), was assessed. The underlying molecular mechanism of action of the nucleolin-mediated intracellular delivery of C6-ceramide to cancer cells was also explored. The assessment of overexpression of surface nucleolin expression by flow cytometry was critical to dissipate differences identified by Western blot in membrane/cytoplasm of SKOV-3, OVCAR-3 and TOV-112D ovarian cancer cell lines. The former was in line with the significant extent of uptake into (bulk) ovarian cancer cells, relative to non-targeted and non-specific counterparts. This pattern of uptake was recapitulated with putative CSC-enriched ovarian SKOV-3 and OVCAR-3 sub-population (EpCAMhigh/CD44high). Co-encapsulation of DXR:C6-ceramide into F3 peptide-targeted liposomes improved cytotoxic activity relative to liposomes containing DXR alone, in an extent that depended on the intrinsic resistance to DXR and on the incubation time. The enhanced cytotoxicity of the targeted combination was mechanistically supported by the downregulation of PI3K/Akt pathway by C6-ceramide, only among the nucleolin-overexpressing cancer cells presenting a basal p-Akt/total Akt ratio lower than 1. | URI: | https://hdl.handle.net/10316/103812 | ISSN: | 2072-6694 | DOI: | 10.3390/cancers13123052 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais I&D CIBB - Artigos em Revistas Internacionais FFUC- Artigos em Revistas Internacionais IIIUC - Artigos em Revistas Internacionais |
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