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Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma
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Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma
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Journal Article
Valproic acid treatment response in vitro is determined by TP53 status in medulloblastoma
2018
Overview
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 IC
50
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.
Publisher
Springer Berlin Heidelberg,Springer Nature B.V
Subject
