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New therapeutic target for pediatric anaplastic ependymoma control: study of anti-tumor activity by a Kunitz-type molecule, Amblyomin-X

2019; Nature Portfolio; Volume: 9; Issue: 1 Linguagem: Inglês

10.1038/s41598-019-45799-4

2045-2322

Lorena Favaro Pavon, David Capper, Tatiana Taís Sibov, Sílvia Regina Caminada de Toledo, Ulrich-W. Thomale, Jean Gabriel de Souza, Francisco Romero Cabral, Carolina Maria Berra, Marcos Devanir Silva da Costa, Jardel Mendonça Nicácio, Patrícia Alessandra Dastoli, Daniela Mara de Oliveira, Suzana Mária Fleury Malheiros, Edgar Ferreira da Cruz, Jackeline Moraes Malheiros, Sérgio Mascarenhas de Oliveira, Nasjla Saba Silva, Antônio Sérgio Petrilli, Andréa Cappellano, Milena Karina Coló Brunialti, Reinaldo Salomão, Manoel Antônio de Paiva Neto, Ana Marisa Chudzinski‐Tavassi, Sérgio Cavalheiro,

Ubiquitin and proteasome pathways

EPNs comprise a heterogeneous group of neuroepithelial tumors, accounting for about 10% of all intracranial tumors in children and up to 30% of brain tumors in those younger than 3 years. Actually, the pattern therapy for low-grade EPNs includes complete surgical resection followed by radiation therapy. Total surgical excision is often not possible due to tumor location. The aim of this study was to evaluate, for the first time, the anti-tumor activity of Amblyomin-X in 4 primary cultures derived from pediatric anaplastic posterior fossa EPN, Group A (anaplastic, WHO grade III) and one primary culture of a high grade neuroepithelial tumor with MN1 alteration, which was initially misdiagnosed as EPN: i) by in vitro assays: comparisons of temozolomide and cisplatin; ii) by intracranial xenograft model. Amblyomin-X was able to induce cell death in EPN cells in a more significant percentage compared to cisplatin. The cytotoxic effects of Amblyomin-X were not detected on hFSCs used as control, as opposed to cisplatin-treatment, which promoted a substantial effect in the hAFSCs viability. TEM analysis showed ultrastructural alterations related to the process of cell death: mitochondrial degeneration, autophagosomes and aggregate-like structures. MRI and histopathological analyzes demonstrated significant tumor mass regression. Our results suggest that Amblyomin-X has a selective effect on tumor cells by inducing apoptotic cell death and may be a therapeutic option for Group AEPNs.