Induction of MAPK- and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib
| Autor: | Alan K. S. Chiang, Po Ling Yeung, Kwai Fung Hui |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Programmed cell death autophagy Blotting Western Mice Nude Apoptosis Biology Real-Time Polymerase Chain Reaction Romidepsin Bortezomib Immunoenzyme Techniques 03 medical and health sciences Mice Stomach Neoplasms Depsipeptides Antineoplastic Combined Chemotherapy Protocols medicine Tumor Cells Cultured Animals Humans romidepsin RNA Messenger gastric carcinoma Cell Proliferation Mitogen-Activated Protein Kinase 1 Mice Inbred BALB C Mitogen-Activated Protein Kinase 3 Reverse Transcriptase Polymerase Chain Reaction Intrinsic apoptosis Autophagy Xenograft Model Antitumor Assays 030104 developmental biology Oncology Proteasome Cancer cell Cancer research Proteasome inhibitor Female Reactive Oxygen Species medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Proteasome inhibitors and histone deacetylase (HDAC) inhibitors can synergistically induce apoptotic cell death in certain cancer cell types but their combinatorial effect on the induction of autophagy remains unknown. Here, we investigated the combinatorial effects of a proteasome inhibitor, bortezomib, and an HDAC inhibitor, romidepsin, on the induction of apoptotic and autophagic cell death in gastric carcinoma (GC) cells. Isobologram analysis showed that low nanomolar concentrations of bortezomib/romidepsin could synergistically induce killing of GC cells. The synergistic killing was due to the summative effect of caspase-dependent intrinsic apoptosis and caspase-independent autophagy. The autophagic cell death was dependent on the activation of MAPK family members (ERK1/2 and JNK), and generation of reactive oxygen species (ROS), but was independent of Epstein-Barr virus infection. In vivo, bortezomib/romidepsin also significantly induced apoptosis and autophagy in GC xenografts in nude mice. This is the first report demonstrating the potent effect of combination of HDAC and proteasome inhibitors on the induction of MAPK- and ROS-dependent autophagy in addition to caspase-dependent apoptosis in a cancer type. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|