Valproic Acid Enhanced Temozolomide-Induced Anticancer Activity in Human Glioma Through the p53-PUMA Apoptosis Pathway.

Hong-Chieh Tsai,Hsiao-Wei Cheng,Pin-Yuan Chen,Yi-Rou Chen,Hsiang-Tsui Wang,Ko-Ting Chen,Chiung-Yin Huang,Ya-Jui Lin,Kuo-Chen Wei

doi:10.3389/fonc.2021.722754

Abstract

Glioblastoma (GBM), the most lethal type of brain tumor in adults, has considerable cellular heterogeneity. The standard adjuvant chemotherapeutic agent for GBM, temozolomide (TMZ), has a modest response rate due to the development of drug resistance. Multiple studies have shown that valproic acid (VPA) can enhance GBM tumor control and prolong survival when given in conjunction with TMZ. However, the beneficial effect is variable. In this study, we analyzed the impact of VPA on GBM patient survival and its possible correlation with TMZ treatment and p53 gene mutation. In addition, the molecular mechanisms of TMZ in combination with VPA were examined using both p53 wild-type and p53 mutant human GBM cell lines. Our analysis of clinical data indicates that the survival benefit of a combined TMZ and VPA treatment in GBM patients is dependent on their p53 gene status. In cellular experiments, our results show that VPA enhanced the antineoplastic effect of TMZ by enhancing p53 activation and promoting the expression of its downstream pro-apoptotic protein, PUMA. Our study indicates that GBM patients with wild-type p53 may benefit from a combined TMZ+VPA treatment.

Highlights

Glioblastoma (GBM), the most common and most lethal type of brain tumor, accounts for 50% of malignancies in the intrinsic central nervous system and has the highest loss of potential life years compared to other cancers [1,2,3]
To evaluate the effect of valproic acid (VPA) on the survival of GBM patients, we retrospectively reviewed patients diagnosed with primary GBM from 2015 to 2017 who underwent curative excisional surgery
Our results indicate that VPA enhances TMZ cytotoxicity by promoting apoptosis through enhancing p53 pathway activation and increasing the expression of its downstream target gene, p53 upregulated modulator of apoptosis (PUMA)

Summary

Introduction

Glioblastoma (GBM), the most common and most lethal type of brain tumor, accounts for 50% of malignancies in the intrinsic central nervous system and has the highest loss of potential life years compared to other cancers [1,2,3]. The heterogeneous genetic background of GBM patients results in variable sensitivities of cancer cells to TMZ treatment and, differential clinical outcomes. Previous studies have shown that somatic alterations that deregulate p53 were found in 85%–90% of GBM tumors, including 27.9% of p53 gene mutations or deletions [16]. P53 mutation often co-occurs with IDH1 and ATRX mutations, which are critical markers defining GBM molecular classification [17, 18]. These molecular alterations have significant clinical implications in that they define radically different subgroups of GBM and significantly affect tumor susceptibility to treatment and, patient prognosis [19,20,21]

Methods

Results

Conclusion