The VR23 anticancer proteasome inhibitor also exhibits anti-inflammatory activity through the downregulation of the IL-6-JAK-STAT pathway

Abstract

Abstract We previously demonstrated that the novel proteasome inhibitor, VR23, possesses anti-tumor activity without causing any ill-effects to animals. We have now shown that the compound VR23 also possesses potent anti-inflammatory activity. Our data from a monocyte cell model shows that VR23 down-regulates pro-inflammatory cytokines IL-1β, TNF-α, IL-6, and IL-8 at similar efficacy as dexamethasone, a steroid widely used for the control of inflammatory conditions. Studies from a rheumatoid arthritis (RA) cell model show that VR23 can not only down-regulate IL-6 but also inhibit the cell migration. Importantly, the down-regulation of pro-inflammatory cytokines by VR23 is more pronounced in the primary synovial cells from RA patients than those from healthy donors. Since VR23 down-regulates not only STAT3 phosphorylation but also the expression of its downstream pathways, our data is consistent with the notion that VR23 exhibits its anti-inflammatory properties through the downregulation of the IL-6-JAK-STAT signaling pathway. The latter down-regulation is at the level of transcription of several important members of the IL-6-JAK-STAT family. Finally, VR23 effectively reduces neutrophil migration, TNF-α secretion, and tissue inflammation in mice with an LPS-induced acute lung injury. Our data thus suggest that VR23 is an agent with significant potential of controlling cancer as well as acute and chronic inflammatory conditions.