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dc.contributor.author
Pascual Pasto G.
dc.contributor.author
Castillo Ecija, Helena
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Unceta, Nora
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Aschero, Rosario
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Resa Pares, Claudia
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Gómez Caballero, Alberto
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Vila Ubach, Monica
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Muñoz Aznar, Oscar
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Suñol, Mariona
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Burgueño, Victor
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Gomez Gonzalez, Soledad
dc.contributor.author
Sosnik, Alejandro
dc.contributor.author
Ibarra, Manuel
dc.contributor.author
Schaiquevich, Paula Susana
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de Álava, Enrique
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Tirado, Oscar M.
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Mora, Jaume
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Carcaboso, Angel M.
dc.date.available
2023-02-08T13:19:33Z
dc.date.issued
2022-02
dc.identifier.citation
Pascual Pasto G.; Castillo Ecija, Helena; Unceta, Nora; Aschero, Rosario; Resa Pares, Claudia; et al.; SPARC-mediated long-term retention of nab-paclitaxel in pediatric sarcomas; Elsevier Science; Journal of Controlled Release; 342; 2-2022; 81-92
dc.identifier.issn
0168-3659
dc.identifier.uri
http://hdl.handle.net/11336/187289
dc.description.abstract
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein overexpressed by several cancers. Because SPARC shows high binding affinity to albumin, we reasoned that pediatric sarcoma xenografts expressing SPARC would show enhanced uptake and accumulation of nanoparticle albumin-bound (nab)-paclitaxel, a potent anticancer drug formulation. We first evaluated the expression of SPARC in patient-derived xenografts (PDXs) of Ewing sarcoma, rhabdomyosarcoma and osteosarcoma, finding variable SPARC gene expression that correlated well with SPARC protein measured by immunoblotting. We revealed that the activity of the fusion gene chimera EWSR1-FLI1, the genetic driver of Ewing sarcoma, leads to lower expression of the gene SPARC in these tumors, likely due to enriched acetylation marks of the histone H3 lysine 27 at regions including the SPARC promoter and potential enhancers. Then, we used SPARC-edited Ewing sarcoma cells (A673 line) to demonstrate that SPARC knocked down (KD) cells accumulated significantly less amount of nab-paclitaxel in vitro than SPARC wild type (WT) cells. In vivo, SPARC KD and SPARC WT subcutaneous xenografts in mice achieved similar maximum intratumoral concentrations of nab-paclitaxel, though drug clearance from SPARC WT tumors was significantly slower. We confirmed such SPARC-mediated long-term intratumoral accumulation of nab-paclitaxel in Ewing sarcoma PDX with high expression of SPARC, which accumulated significantly more nab-paclitaxel than SPARC-low PDX. SPARC-high PDX responded better to nab-paclitaxel than SPARC-low tumors, although these results should be taken cautiously, given that the PDXs were established from different patients that could have specific determinants predisposing response to paclitaxel. In addition, SPARC KD Ewing sarcoma xenografts responded better to soluble docetaxel and paclitaxel than to nab-paclitaxel, while SPARC WT ones showed similar response to soluble and albumin-carried drugs. Overall, our results show that pediatric sarcomas expressing SPARC accumulate nab-paclitaxel for longer periods of time, which could have clinical implications for chemotherapy efficacy.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier Science
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dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
ALBUMIN NANOPARTICLES
dc.subject
EWING SARCOMA
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EWSR1-FLI1
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NAB-PACLITAXEL
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PATIENT-DERIVED XENOGRAFT (PDX)
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PEDIATRIC SOLID TUMORS
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RHABDOMYOSARCOMA
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SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE (SPARC)
dc.subject.classification
Farmacología y Farmacia
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
SPARC-mediated long-term retention of nab-paclitaxel in pediatric sarcomas
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2023-02-06T10:19:35Z
dc.journal.volume
342
dc.journal.pagination
81-92
dc.journal.pais
Países Bajos
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dc.journal.ciudad
Amsterdam
dc.description.fil
Fil: Pascual Pasto G.. Institut de Recerca Sant Joan de Déu; España
dc.description.fil
Fil: Castillo Ecija, Helena. Institut de Recerca Sant Joan de Déu; España
dc.description.fil
Fil: Unceta, Nora. Institut de Recerca Sant Joan de Déu; España
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Fil: Aschero, Rosario. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Resa Pares, Claudia. Institut de Recerca Sant Joan de Déu; España
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Fil: Gómez Caballero, Alberto. Institut de Recerca Sant Joan de Déu; España
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Fil: Vila Ubach, Monica. Technion - Israel Institute of Technology; Israel
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Fil: Muñoz Aznar, Oscar. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
dc.description.fil
Fil: Suñol, Mariona. Universidad de la República; Uruguay
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Fil: Burgueño, Victor. Hospital Sant Joan de Déu; España
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Fil: Gomez Gonzalez, Soledad. Institut de Recerca Sant Joan de Déu; España
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Fil: Sosnik, Alejandro. Institut de Recerca Sant Joan de Déu; España
dc.description.fil
Fil: Ibarra, Manuel. Universidad de la República; Uruguay
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Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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Fil: de Álava, Enrique. Universidad de Sevilla; España
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Fil: Tirado, Oscar M.. No especifíca;
dc.description.fil
Fil: Mora, Jaume. Institut de Recerca Sant Joan de Déu; España
dc.description.fil
Fil: Carcaboso, Angel M.. Institut de Recerca Sant Joan de Déu; España
dc.journal.title
Journal of Controlled Release
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S016836592100688X
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1016/j.jconrel.2021.12.035
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