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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: SFRH/BD/85554/2012 
POCI-01-0145-FEDER-016390 (CancelStem), Euronanomed (FCT reference ENMed/0005/2015), 
CENTRO-01-0145-FEDER-000012- HealthyAging2020, CIBB (FCT reference UIDB/04539/2020) 
POCI-01-0145-FEDER-029311 (ref.: PTDC/BTM-TEC/29311/2017) 
The National Mass Spectrometry Network (RNEM) under the contract POCI-01-0145-FEDER-402-022125 (ref.: ROTEIRO/0028/2013) 
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.
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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