Camptothecin and Topotecan, Inhibitors of Transcription Factor Fli‐1 and Topoisomerase, Markedly Ameliorate Lupus Nephritis in (NZB × NZW)F1 Mice and Reduce the Production of Inflammatory Mediators in Human Renal Cells

Abstract

Objective. To examine the therapeutic effects of camptothecin (CPT) and topotecan (TPT), inhibitors of transcription factor Fli-1 and topoisomerase, on lupus nephritis in (NZB × NZW)F1 (NZBWF1) mice, and to examine the effects of CPT and TPT on inflammatory mediators in human renal cells.Methods. Female NZBWF1 mice were treated with vehicle, cyclophosphamide (CYC), CPT (1 mg/kg or 2 mg/kg), or TPT (0.03 mg/kg, 0.1 mg/kg, or 0. 3 mg/kg) by intraperitoneal injection twice a week, beginning at the age of 25 weeks (n = 8-10 mice per group). Blood and urine were collected for monitoring autoantibodies and proteinuria. Mice were euthanized at 40 weeks, and renal pathology scores were assessed. Human renal endothelial and mesangial cells were treated with CPT or TPT, and cytokine expression was measured.Results. None of the NZBWF1 mice treated with 1 mg/kg or 2 mg/kg of CPT or 0.3 mg/kg of TPT had proteinuria >100 mg/dl at the age of 40 weeks. One of 8 mice treated with 0.1 mg/kg of TPT and 1 of 10 mice treated with CYC had proteinuria >300 mg/dl, whereas 90% of the mice treated with vehicle had proteinuria >300 mg/dl. Compared to vehicle control, mice treated with 1 mg/kg or 2 mg/kg of CPT, 0.1 mg/kg or 0.3 mg/kg of TPT, or CYC had significantly prolonged survival, attenuated renal injury, diminished splenomegaly, reduced anti-double-stranded DNA autoantibody levels, and reduced IgG and C3 deposits in the glomeruli (all P < 0.05). Human renal cells treated with CPT or TPT had reduced expression of Fli-1 and decreased monocyte chemotactic protein 1 production following stimulation with interferon-α (IFNα) or IFNγ. Conclusion.Our findings indicate that low-dose CPT and TPT could be repurposed to treat lupus nephritis.

The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease

“…S12 B-F). Overall, these results suggest that targeting Fli-1 using low-dose camptothecin, topotecan, or etoposide are effective methods to prevent and or reverse cGVHD, where these effects can be attributed, at least in part, due to Fli-1 inhibition on lymphocytes since these drugs have established Fli-1 inhibitory activity as shown here and by others (15,16).…”

“…6D). Topotecan or TPT, another drug with previously demonstrated Fli-1 inhibitory activity (16), was also able to reduce Fli-1 expression in human Jurkat cells (Fig. S12 A) and attenuate cGVHD (Fig.…”

“…Cancer chemotherapeutics including camptothecin (CPT), the CPT analog topotecan (TPT), and etoposide (ETO) were shown to be potent Fli-1 protein inhibitors ( 15 , 16 )). In these studies, CPT impaired tumor growth in multiple erythroleukemia cell lines in vitro and in Friend murine leukemia virus–induced (F-MuLV-induced) erythroleukemia in vivo ( 15 , 17 ), whereas TPT reduced lupus nephritis and inflammatory factors in human renal cells ( 16 ).…”

Topoisomerase 1 inhibition modulates pyroptosis to improve recovery after spinal cord injury

“…Topoisomerase 1 inhibition therapy protects against Severe Acute Respiratory Syndrome Coronavirus 2 induced exaggerated and overshooting inflammation and death in animal models 64 . Topoisomerase 1 inhibition by CPT alleviates lupus nephritis in F1 mice and decreases the levels of inflammatory factors in human renal cells 65 . Moreover, CPT regulates microglia polarization and provides neuroprotective effects through activating AKT/Nrf2/HO‐1 and inhibiting NF‐κB pathways in vivo and in vitro 66 .…”

“…64 Topoisomerase 1 inhibition by CPT alleviates lupus nephritis in F1 mice and decreases the levels of inflammatory factors in human renal cells. 65 Moreover, CPT regulates microglia polarization and provides neuroprotective effects through activating AKT/ Nrf2/HO-1 and inhibiting NF-κB pathways in vivo and in vitro. 66 CPT-bile acid conjugate alleviated sepsis-induced liver injury by suppressing the NF-κB signaling pathway.…”