Department of Pediatric Neurosurgery, Xin Hua Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, People's Republic of China.
Key Laboratory of Cell Differentiation and Apoptosis of the National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Shanghai, 200025, People's Republic of China.
J Exp Clin Cancer Res. 2018 Oct 1;37(1):241. doi: 10.1186/s13046-018-0916-y.
Glioblastoma (GBM) is the most common and most malignant primary brain cancer in adults. Despite multimodality treatment, the prognosis is still poor. Therefore, further work is urgently required to discover novel therapeutic strategies for GBM treatment.
The synergistic effects of cotreatment with the histone deacetylase (HDAC) inhibitor panobinostat and bromodomain inhibitor JQ1 or OTX015 were validated using cell viability assays in GBM cell lines. Furthermore, the inhibitory mechanisms were investigated via an EdU proliferation assay, an apoptosis assay, qPCR, Western blot and RNAseq analyses.
We found that the cotreatment with panobinostat and JQ1 or OTX015 synergistically inhibited cell viability in GBM cells. The cotreatment with panobinostat and JQ1 or OTX015 markedly inhibited cell proliferation and induced apoptosis in GBM cells. Compared with treatment with each drug alone, the cotreatment with panobinostat and JQ1 induced more profound caspase 3/7 activation and cytotoxicity. Mechanistic investigation showed that combination of panobinostat with JQ1 or OTX015 results in stronger repression of GBM-associated oncogenic genes or pathways as well as higher induction of GBM-associated tumor-suppressive genes.
Our study demonstrated that HDAC inhibitor and bromodomain inhibitor had synergistical efficacy against GBM cells. The cotreatment with HDAC inhibitor and bromodomain inhibitor warrants further attention in GBM therapy.
胶质母细胞瘤（GBM）是成人中最常见和最恶性的原发性脑癌。尽管采用了多模式治疗，但预后仍然很差。因此，迫切需要进一步研究以发现治疗 GBM 的新治疗策略。
使用 GBM 细胞系中的细胞活力测定法验证组蛋白去乙酰化酶（HDAC）抑制剂帕比司他与溴结构域抑制剂 JQ1 或 OTX015 联合治疗的协同作用。此外，通过 EdU 增殖测定、凋亡测定、qPCR、Western blot 和 RNAseq 分析研究了抑制机制。
我们发现帕比司他与 JQ1 或 OTX015 的联合治疗可协同抑制 GBM 细胞的活力。帕比司他与 JQ1 或 OTX015 的联合治疗可显著抑制 GBM 细胞的增殖并诱导其凋亡。与单独使用每种药物相比，帕比司他与 JQ1 的联合治疗可诱导更强烈的 caspase 3/7 激活和细胞毒性。机制研究表明，帕比司他与 JQ1 或 OTX015 的联合使用可导致更强的抑制 GBM 相关致癌基因或途径，以及更高的诱导 GBM 相关肿瘤抑制基因。
我们的研究表明，HDAC 抑制剂和溴结构域抑制剂对 GBM 细胞具有协同作用。HDAC 抑制剂和溴结构域抑制剂的联合治疗值得进一步关注。
