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22.05.2018 | Original Paper

Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma

verfasst von: Bruna Mascaro-Cordeiro, Indhira Dias Oliveira, Francine Tesser-Gamba, Lorena Favaro Pavon, Nasjla Saba-Silva, Sergio Cavalheiro, Patrícia Dastoli, Silvia Regina Caminada Toledo

Erschienen in: Child's Nervous System | Ausgabe 8/2018

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Abstract

Purpose

Histone deacetylate inhibitors (HDACi), as valproic acid (VA), have been reported to enhance efficacy and to prevent drug resistance in some tumors, including medulloblastoma (MB). In the present study, we investigated VA role, combined to cisplatin (CDDP) in cell viability and gene expression of MB cell lines.

Methods

Dose-response curve determined IC₅₀ values for each treatment: (1) VA single, (2) CDDP single, and (3) VA and CDDP combined. Cytotoxicity and flow cytometry evaluated cell viability after exposure to treatments. Quantitative PCR evaluated gene expression levels of AKT, CTNNB1, GLI1, KDM6A, KDM6B, NOTCH2, PTCH1, and TERT, before and after treatment. Besides, we performed next-generation sequencing (NGS) for PTCH1, TERT, and TP53 genes.

Results

The most effective treatment to reduce viability was combined for D283MED and ONS-76; and CDDP single for DAOY cells (p < 0.0001). TERT, GLI1, and AKT genes were overexpressed after treatments with VA. D283MED and ONS-76 cells presented variants in TERT and PTCH1, respectively and DAOY cell line presented a TP53 mutation.

Conclusions

MB tumors belonging to SHH molecular subgroup, with TP53^MUT, would be the ones that present high risk in relation to VA use during the treatment, while TP53^WT MBs can benefit from VA therapy, both SHH and groups 3 and 4. Our study shows a new perspective about VA action in medulloblastoma cells, raising the possibility that VA may act in different patterns. According to the genetic background of MB cell, VA can stimulate cell cycle arrest and apoptosis or induce resistance to treatment via signaling pathways activation.

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Titel: Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma
verfasst von: Bruna Mascaro-Cordeiro
Indhira Dias Oliveira
Francine Tesser-Gamba
Lorena Favaro Pavon
Nasjla Saba-Silva
Sergio Cavalheiro
Patrícia Dastoli
Silvia Regina Caminada Toledo
Publikationsdatum: 22.05.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Child's Nervous System / Ausgabe 8/2018
Print ISSN: 0256-7040
Elektronische ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-018-3817-7

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