Tsai Hong-Chieh, Wei Kuo-Chen, Chen Pin-Yuan, Huang Chiung-Yin, Chen Ko-Ting, Lin Ya-Jui, Cheng Hsiao-Wei, Chen Yi-Rou, Wang Hsiang-Tsui
Department of Neurosurgery, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan.
Front Oncol. 2021 Oct 1;11:722754. doi: 10.3389/fonc.2021.722754. eCollection 2021.
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 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 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 may benefit from a combined TMZ+VPA treatment.
胶质母细胞瘤（GBM）是成人中最致命的脑肿瘤类型，具有显著的细胞异质性。GBM的标准辅助化疗药物替莫唑胺（TMZ）由于耐药性的产生，反应率适中。多项研究表明，丙戊酸（VPA）与TMZ联合使用时可增强GBM的肿瘤控制并延长生存期。然而，其有益效果存在差异。在本研究中，我们分析了VPA对GBM患者生存的影响及其与TMZ治疗和基因突变的可能相关性。此外，使用p53野生型和p53突变型人GBM细胞系研究了TMZ与VPA联合使用的分子机制。我们对临床数据的分析表明，GBM患者联合TMZ和VPA治疗的生存获益取决于其基因状态。在细胞实验中，我们的结果表明，VPA通过增强p53激活并促进其下游促凋亡蛋白PUMA的表达，增强了TMZ的抗肿瘤作用。我们的研究表明，野生型GBM患者可能从TMZ+VPA联合治疗中获益。
