Ciclopirox Olamine Induces Ferritinophagy and Ameliorates Disease Progression in Polycystic Kidney Disease

Abstract

Despite the recent launch of Tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox, as the free acid (CPX) and its olamine salt (CPX-O) , are contained in number of commercially available topical antifungal agents. CPX is reported in the literature to possess anticancer activity in number of solid tumor cancers and hematological malignancy by several proposed mechanisms of action including chelation of iron and inhibition of iron dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human cyst epithelial cells cultured in 3D collagen matrix. To determine if CPX-O inhibits PKD progression, we treated PKD mice with a low dose of 10 mg/kg CPX-O by daily intraperitoneal injections from day 21 to day 49 post- partum. CPX-O reduced the kidney to body weight ratio of the PKD mice. This was associated with decreased cell proliferation decrease cystic area and improved renal function. We found that ferritin levels were significantly elevated in cystic kidneys of PKD mice, and that CPX-O treatment reduced renal ferritin levels and increased ferritinophagy marker, NCOA4. Our data suggest that CPX-O dose dependently induces ferritin degradation via ferritinophagy which is associated with decreased cyst growth and disease progression in PKD mice. Most importantly these data indicate that CPX-O, a drug used to treat skin infections and currently in clinical trials for cancer, has the potential to treat ADPKD.