Abrogation of skin disease in LUPUS‐prone MRL/FAS^lpr mice by means of a novel tylophorine analog

Abstract

Objective. To test the therapeutic effect of DCB-3503, a synthetic compound derived from a natural product that inhibits NF-B, on end-organ disease in the MRL-Fas lpr murine model of systemic lupus erythematosus (SLE).Methods. Eight-week-old female MRL/Fas lpr mice were treated intraperitoneally with a low (2 mg/kg) or high (6 mg/kg) dose of DCB-3503 for 10 weeks. Control groups were administered vehicle treatment alone (negative control) or 25 mg/kg cyclophosphamide (positive control). Mice were bled before (8 weeks) and during (13 weeks) treatment, and when they were killed (20 weeks), and serum samples were analyzed for total IgM and IgG levels and autoantibody titers. When the mice were killed, spleen and lymph nodes (axillary, brachial, and cervical) were examined by flow cytometric analysis. The presence of skin and renal disease was determined by histopathologic analysis.Results. DCB-3503 reduced anti-double-stranded DNA and antichromatin autoantibodies and nearly abrogated inflammatory skin disease in MRL/Fas lpr mice; however, it had little effect on histologic kidney disease. Treated mice did not have hematologic or hepatic toxicity. These data indicate that end-organ disease in MRL/Fas lpr mice responds differentially to NF-B inhibitor.Conclusion. DCB-3503 causes significant abrogation of skin disease in MRL/Fas lpr mice and may potentially be beneficial in the treatment of inflammatory skin disease in SLE.

NF-κB in Systemic Lupus Erythematosus and Antiphospholipid Syndrome

“…An attempt to treat MRL/lpr lupus mice with the NF-κB inhibitor DCB-3503, a tylophorine analog, resulted in almost complete abrogation of the inflammatory skin legions, but had little effect on renal histologic scores [26]. This may be because of the only partial reduction of anti-DNA antibodies achieved by the treatment.…”

A novel tylophorine analog NK-007 ameliorates colitis through inhibition of innate immune response

“…DCB-3503 (a tylophorine analog) has been commonly studied and showed antitumor activity [15,16] through mechanisms of inhibiting nucleic acid synthesis, RNA transcription, and protein synthesis [16][17][18]. Previously, DCB-3503 was reported to have anti-inflammatory effect in lupus and rheumatoid arthritis through suppressing innate immune response in our study [19,20]. In the current study, we synthesized (±)-tylophorine malate (NK-007), which had better water solubility (20 g/L at room temperature), whereas tylophorine (DCB-3503) could not be dissolved in water.…”

Targeting NF-κB: A Promising Molecular Therapy in Inflammatory Arthritis

“…These findings demonstrate that both NF-κB signaling pathways are important for development of lupuslike disease associated with BAFF overproduction [56]. Remarkably, another study has shown that administration of DCB3503, a NF-κB inhibitor, for 10 weeks nearly abrogated inflammatory skin disease with little effect on histologic kidney disease in MRL/Fas(lpr) mice [57]. …”