Novel RNA polymerase I inhibitor CX-5461 suppresses imiquimod-induced experimental psoriasis.

Abstract

Clinical treatment of psoriasis remains challenging because of possible long-term drug toxicities and loss of therapeutic effects over time. CX-5461 is a novel selective inhibitor of RNA polymerase I. Our previous studies have shown that CX-5461 has potent anti-inflammatory effects. Here we investigated whether CX-5461 could inhibit the development of imiquimod-induced experimental psoriasis in mice. Adult male C57BL/6 mice were used, and psoriasis-like lesions were induced by topical imiquimod treatment. In vivo, we demonstrated that topical application of CX-5461 prevented the development of imiquimod-induced psoriasis, with decreases in keratinocyte proliferation, T-cell infiltration and pathological angiogenesis. CX-5461 also reversed existing skin inflammation induced imiquimod and retarded the development of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal hyperplasia and inflammation. In vitro, CX-5461 induced cell cycle arrest in keratinocytes, inhibited expressions of interleukin-17, interleukin-23 receptor and retinoic acid receptor-related orphan receptor-γt in activated T cells, and reduced angiogenic functions of endothelial cells. In conclusion, CX-5461 exhibits therapeutic effects on experimental psoriasis in mice, likely via multiple mechanisms including anti-proliferative, anti-inflammatory and anti-angiogenic activities.