The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion-infected cells from prions

• Published in: Scientific reports Vol. 7; no. 1; pp. 17565 - 12
• Main Authors: Abdulrahman, Basant A., Abdelaziz, Dalia, Thapa, Simrika, Lu, Li, Jain, Shubha, Gilch, Sabine, Proniuk, Stefan, Zukiwski, Alexander, Schatzl, Hermann M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.12.2017; Nature Publishing Group
• Subjects: 13/106; 14/19; 38/1; 38/44; 42/41; 631/154/555; 631/326/421; 631/378/1689/364; Animals; Autophagy; Autophagy - drug effects; Celecoxib; Celecoxib - analogs & derivatives; Cell Line, Tumor; Cell lines; Confocal microscopy; Humanities and Social Sciences; Immunoblotting; Mice; multidisciplinary; Neurodegenerative diseases; Neurons - drug effects; Neurons - pathology; Phagocytosis; Prion protein; Protein folding; PrPSc Proteins - metabolism; Pyrazoles - chemistry; Pyrazoles - pharmacology; Science; Science (multidisciplinary); Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-17770-8

Prion diseases are fatal infectious neurodegenerative disorders that affect both humans and animals. The autocatalytic conversion of the cellular prion protein (PrP C ) into the pathologic isoform PrP Sc is a key feature in prion pathogenesis. AR-12 is an IND-approved derivative of celecoxib that demonstrated preclinical activity against several microbial diseases. Recently, AR-12 has been shown to facilitate clearance of misfolded proteins. The latter proposes AR-12 to be a potential therapeutic agent for neurodegenerative disorders. In this study, we investigated the role of AR-12 and its derivatives in controlling prion infection. We tested AR-12 in prion infected neuronal and non-neuronal cell lines. Immunoblotting and confocal microscopy results showed that AR-12 and its analogue AR-14 reduced PrP Sc levels after only 72 hours of treatment. Furthermore, infected cells were cured of PrP Sc after exposure of AR-12 or AR-14 for only two weeks. We partially attribute the influence of the AR compounds on prion propagation to autophagy stimulation, in line with our previous findings that drug-induced stimulation of autophagy has anti-prion effects in vitro and in vivo . Taken together, this study demonstrates that AR-12 and the AR-14 analogue are potential new therapeutic agents for prion diseases and possibly protein misfolding disorders involving prion-like mechanisms.