The treatment of lupus nephritis is still an unmet medical need requiring new therapeutic approaches. We found by serendipity that irinotecan, an inhibitor of topoisomerase I (topo I), reversed proteinuria and prolonged survival in NZB/NZW mice with advanced lupus nephritis. It was known before that the highly conserved enzyme topo I mediates DNA relaxation by inducing single-stranded DNA breaks followed by its re-ligation to reconstitute double-stranded (ds) DNA. It was also established that topo I inhibitors stabilizes the complex of DNA and topo I. As a consequence irinotecan induces cell death (apoptosis) exclusively in rapidly dividing cells explaining why irinotecan is used for the treatment of metastatic cancer. In contrast to this we demonstrated that the dose of irinotecan necessary to suppress established lupus nephritis was more than 50 times lower than the dose used for chemotherapy. Moreover, irinotecan inhibited apoptosis in the kidneys of lupus-prone mice. Both results indicated that the molecular pathways targeted by irinotecan for chemotherapy and for the suppression of lupus nephritis are not similar. Also of importance, while currently unselective immunosuppressive drugs remain the central strategy to control lupus flares, we showed that irinotecan-induced amelioration of lupus nephritis was not accompanied by a relevant immunosuppression. Looking for the molecular mechanism we demonstrated that topo I-induced relaxation of supercoiled DNA enhanced the binding of lupus-derived anti-dsDNA antibodies; an effect which was prevented by inhibition of topo I. In conclusion, our data suggest that targeting DNA relaxation by topo I inhibitors may be a promising new treatment option for systemic lupus erythematosus.
Disclosure of Interest None declared