The VR23 Antitumor Compound Also Shows Strong Anti-Inflammatory Effects in a Human Rheumatoid Arthritis Cell Model and Acute Lung Inflammation in Mice

Abstract

We previously found that the novel VR23 proteasome inhibitor not only possesses an effective antitumor activity without causing any ill effects to animals but also reduces side effects caused by a partner drug when used in combination. In this article, we report that VR23, unlike other proteasome inhibitors, exhibits potent anti-inflammatory activity. In the LPS-induced THP-1 monocyte model, VR23 downregulates proinflammatory cytokines IL-1β, TNF-α, IL-6, and IL-8 at a similar efficacy to dexamethasone. In contrast, two well-known proteasome inhibitors, bortezomib and carfilzomib, do not effectively downregulate these proinflammatory cytokines. Data from a study with SW982 synovial cell line and primary human synoviocytes showed that VR23 not only effectively downregulates IL-6 but also inhibits cell migration. Interestingly, the IL-6 downregulation by VR23 was significantly more pronounced in the primary synovial cells from rheumatoid arthritis patients than those from healthy donors, suggesting that VR23 can be selective against rheumatoid arthritis. Finally, VR23 effectively reduces neutrophil migration, TNF-α secretion, and tissue inflammation in mice (female BALB/c strain) with an LPS-induced acute lung injury. Thus, our current data indicate that VR23 can be effective on both acute and chronic inflammatory conditions. Taken together with our previous work, VR23 is not only effective on inflammatory conditions but also applicable to different aspects of cancer control, including the treatment and prevention of tumor development by chronic inflammatory responses.