Abstract
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.
Highlights
Gastric carcinoma (GC) is the second leading cause of cancer-related death in the world
Our laboratory and others have reported that combination of proteasome and histone deacetylase (HDAC) inhibitors can synergistically induce the killing of various types of cancer cell lines through the induction of apoptosis
We demonstrated that combination of a proteasome inhibitor, bortezomib, and a HDAC inhibitor, romidepsin, could potently induce the killing of GC cells through a mechanism involving the summative effect of the caspasedependent apoptosis and caspase-independent autophagy
Summary
Gastric carcinoma (GC) is the second leading cause of cancer-related death in the world. The mortality is especially high in Russia, Korea and Japan. Surgery is the only curative treatment for early stage of GC. GC remains asymptomatic for a long period of time and more than half of the cases are diagnosed clinically with distant metastasis. For such metastatic cases, the diseases are largely incurable and the 5-year survival rate is less than 10% [1]. Cisplatin and 5-fluorouracil are the most common types of chemotherapy for metastatic GC. There is a clear need to explore more potential therapeutic agents for the treatment of GC
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