Induction of MAPK- and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib

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.

Reactive Oxygen Species–Mediated Synergism of Fenretinide and Romidepsin in Preclinical Models of T-cell Lymphoid Malignancies

“…Vitamins C and E are two naturally occurring antioxidants, capable of entering mitochondria, ER, and other compartments (52,53), while the thiol antioxidants STS and NAC aid in the replenishment of glutathione in the cytoplasm (25,51,54,55), and may be excluded from cellular compartments involved in the generation and/or action of fenretinide-induced ROS, likely mitochondria and/or ER. HDAC inhibitors were shown to synergize with tyrosine kinase and proteasome inhibitors via ROS-mediated activation of MAP kinase pathways, but in those experiments addition of NAC abrogated the ROS, MAPK activation, and synergistic cytotoxicity (56,57). Our observation that thiol antioxidants did not prevent 4-HPR induced ROS from synergistically enhancing ROM activity suggests that the mechanism we determined is distinct from that reported for HDAC inhibitors mediated synergy with other agents via ROS and MAP kinase pathway activation.…”

Signaling Diversity Enabled by Rap1-Regulated Plasma Membrane ERK with Distinct Temporal Dynamics

“…This pathway is utilized by a host of different extracellular cues to regulate cellular processes such as proliferation, differentiation, and survival (3,4). However, studies have shown that ERK is also critically involved in regulating many other cellular processes, such as cell migration (5,6), cell cycle progression (7,8), autophagy (9,10), metabolism (11,12), insulin secretion (13), or even apoptosis (14,15). The variety of processes induced through the ERK pathway presents a conundrum: how do extracellular cues specifically regulate the ERK pathway to induce the proper cellular response?…”

Respiratory Syncytial Virus Replication Is Promoted by Autophagy-Mediated Inhibition of Apoptosis

“…Cellular stress responses, such as endoplasmic reticulum (ER) stress and oxidative stress, may be induced by viral infection and may trigger autophagy. Accumulating evidence on tumors has highlighted the role of reactive oxygen species (ROS), a key molecule to induce oxidative stress, in autophagy induction (15)(16)(17)(18). However, to the best of our knowledge, the relationship between ROS and autophagy regulation during virus infection is not fully understood.…”