A expressão de nucleolina permite a entrega intracelular de fármacos em células de glioblastoma

Um dos principais desafios da terapia do glioblastoma (GBM) está relacionado com a existência de células do tipo estaminal (GSC), conhecidas por serem quimio e radiorresistentes. No nosso trabalho, a sobre-expressão de nucleolina em células de GBM conduziu a uma maior associação dos lipossomas que têm com alvo a nucleolina. Além disso, a nucleolina foi sugerida como um potencial marcador em GSCs e nas células GBM não-estaminais correspondentes. A doxorrubicina administrada através dos lipossomas dirigidos à nucleolina permitiu um nível mais elevado de citotoxicidade. É importante realçar que uma sobre-expressão de nucleolina também foi observada em células de amostras derivadas de doentes, em comparação com o cérebro normal.

No geral, estes resultados sugeriram a nucleolina como um alvo terapêutico no GBM.

Autores e Afiliações:

Balça-Silva J¹, do Carmo A², Tão H³, Rebelo O⁴, Barbosa M⁵, Moura-Neto V⁶, Sarmento-Ribeiro AB⁷, Lopes MC⁸, Moreira JN⁹

¹ CNC.IBILI - Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, Coimbra, Portugal; FMUC - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; IECPN - Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil;

² CNC.IBILI - Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, Coimbra, Portugal; CHUC - Clinical Pathology Department, Coimbra Hospital and Universitary Center, Coimbra, Portugal;

³ CHUC - Neurosurgery Service, Coimbra Hospital and Universitary Center, Coimbra, Portugal;

⁴ CHUC - Neuropathology Laboratory, Neurology Service, Coimbra Hospital and Universitary Center, Coimbra, Portugal;

⁵ FMUC - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CHUC - Neurosurgery Service, Coimbra Hospital and Universitary Center, Coimbra, Portugal;

⁶ IECPN - Instituto Estadual do Cérebro Paulo Niemeyer, Secretaria de Estado de Saúde, Rio de Janeiro, Brazil;

⁷ FMUC, Laboratory of Oncobiology and Hematology and University Clinic of Hematology/ Faculty of Medicine, University of Coimbra, Coimbra, Portugal; iCBR, CIMAGO - Coimbra Institute for Clinical and Biomedical Research - Group of Environment, Genetics and Oncobiology - FMUC, Coimbra, Portugal; CHUC - Clinical Hematology Department/Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal;

⁸ CNC.IBILI - Center for Neuroscience and Cell Biology and Institute for Biomedical Imaging and Life Sciences, Coimbra, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal;

⁹ CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; FFUC - Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal.

Abstract:

One of the major challenges in Glioblastoma (GBM) therapy relates with the existence of glioma stem-like cells (GSCs), known to be chemo- and radio-resistant. GSCs and non-stem GBM cells have the ability to interchange, emphasizing the importance of identifying common molecular targets among those cell sub-populations. Nucleolin overexpression has been recently associated with breast cancer sub-populations with different stem-like phenotype. The goal of this work was to evaluate the potential of cell surface nucleolin as a target in GBM cells. Different levels of nucleolin expression resulted in a 3.4-fold higher association of liposomes targeting nucleolin (functionalized with the nucleolin-binding F3 peptide) in U87, relative to GBM11 glioblastoma cells. Moreover, nucleolin was suggested as a potential marker in OCT4-, NANOG-positive GSC, and in the corresponding non-stem GBM cells, as well as in SOX2-positive GSC. Doxorubicin delivered by liposomes targeting nucleolin enabled a level of cytotoxicity that was 2.5- or 4.6-fold higher compared to the non-targeted counterparts. Importantly, an overexpression of nucleolin was also observed in cells of patient-derived samples, as compared with normal brain. Overall, these results suggested nucleolin as a therapeutic target in GBM.

Revista: Experimental Cell Research

Link: https://www.ncbi.nlm.nih.gov/pubmed/29902537