Abstract
BackgroundThe proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Although bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood.MethodsProteasome activity, intracellular glutathione (GSH) and ROS levels, as well as activities of GSH synthesis enzymes were measured using spectrophotometric methods. Cell death was analyzed using flow cytometry and caspase activity assay. The expression level of GSH synthesis enzymes were measured using real-time RT-PCR.ResultsAt concentrations that effectively inhibited proteasome activity, bortezomib induced apoptosis in FRO cells, but not in ARO cells. Bortezomib elevated the amount of glutathione (GSH) and the treatment with bortezomib increased the level of mRNA for GCL, a rate-limiting enzyme in glutathione synthesis. Furthermore, depletion of GSH increases apoptosis induced by bortezomib, in contrast, repletion of GSH decreases bortezomib-mediated cell death.ConclusionGSH protects cells from proteasome inhibition-induced oxidative stress and glutathione-dependent redox system might play an important role in the sensitivity to proteasome inhibition-induced apoptosis.
Highlights
The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers
Effect of bortezomib on reactive oxygen species (ROS) generation in thyroid cancer cells In our recent studies, we had demonstrated that proteasome inhibitors exhibited significant cytotoxicity against human undifferentiated thyroid cancer cells [22]
The cell death effects of bortezomib in thyroid cancer cells were confirmed by caspase-3 activity assay (Figure 1C)
Summary
The proteasome inhibitor bortezomib has shown impressive clinical activity alone and in combination with conventional and other novel agents for the treatment of multiple myeloma (MM) and some solid cancers. Bortezomib is known to be a selective proteasome inhibitor, the downstream mechanisms of cytotoxicity and drug resistance are poorly understood. The ubiquitin-proteasome system (UPS) represents the major degradation pathway for proteins involved in the regulation of cell survival, proliferation, apoptosis and other critical cellular functions [1]. UPS has a critical role in the selective removal of mutant, damaged, and misfolded proteins. Based on these unique properties of the UPS, the proteasome pathway has recently emerged as an attractive target (page number not for citation purposes). Proteasome inhibitors represent a diverse group of agents that target the 20S proteasome, a component of the UPS that is responsible for the degradation of unwanted cellular proteins [2]. Experimental and clinical support for this therapeutic strategy has been provided by bortezomib [3,4]
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