Enhanced efficacy of histone deacetylase inhibitor combined with bromodomain inhibitor in glioblastoma.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Wei Meng, Baocheng Wang, Weiwei Mao, Jiajia Wang, Yang Zhao, Qifeng Li, Chenran Zhang, Yujie Tang, Jie Ma
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 37 Issue 1 Pg. 241 (Oct 01 2018) ISSN: 1756-9966 [Electronic] England
• PMID: 30285808 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BRD4 protein, human
• Cell Cycle Proteins
• Histone Deacetylase Inhibitors
• Nuclear Proteins
• Transcription Factors

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Brain Neoplasms (drug therapy, pathology)
• Cell Cycle Proteins
• Cell Line, Tumor
• Glioblastoma (drug therapy, pathology)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Humans
• Nuclear Proteins (antagonists & inhibitors)
• Transcription Factors (antagonists & inhibitors)