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J Cell Physiol. 2020 Jun;235(6):5270-5283. doi: 10.1002/jcp.29413. Epub 2019 Dec 17.

Repurposing an old drug for new use: Niclosamide in psoriasis-like skin inflammation.

Author information

1
Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India.

Abstract

Drug discovery is an onerous, extremely expensive, and time-consuming process. Instead, drug repurposing is an attractive strategy for exploiting novel indications for a drug beyond its original use. The untapped potential of drug repurposing compensates the barriers associated with the drug discovery pipeline. Psoriasis is an autoimmune skin disease, where hyperproliferation of keratinocytes and exaggerated immune responses are the important hallmarks of the disease. Extensive in vitro and preclinical research has demonstrated that niclosamide was found to exert potent anticancer and anti-inflammatory properties by targeting STAT3, p65 NF-κB, and NFATc-1 signaling paradigm with minimal host toxicity. From the disease perspective, the static intracellular molecular network in both cancer and psoriasis share overlapping pathological features in terms of hyperproliferation and chronic inflammation, which is mediated by the aforementioned signaling cascade. The plausible mechanistic relevance has prompted us to investigate the implementation of niclosamide for repositioning in psoriasis. Our in vitro and in vivo findings suggest that niclosamide inhibits keratinocytes hyperproliferation by reactive oxygen species-mediated apoptosis through the loss of mitochondrial membrane potential, cell cycle arrest at Sub G1 phase, and DNA fragmentation. Furthermore, niclosamide treatment resulted in abrogation of lipopolysaccharide-induced inflammatory cytokine levels in murine macrophages. Additionally, our results provided a preclinical rationale in imiquimod (IMQ)-induced BALB/c mouse model, where niclosamide diligently mitigated the IMQ-induced epidermal hyperplasia and inflammation by downregulating STAT3, p65 NF-κB, and NFATc-1 transcription factors along with Akt, Ki-67, and ICAM-1 protein expression.

KEYWORDS:

NFATc-1; STAT3; drug repurposing; niclosamide; p65 NF-κB; psoriasis

PMID:
31846070
DOI:
10.1002/jcp.29413

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