Niclosamide nanocrystal for enhanced in-vivo efficacy against gastrointestinal stromal tumor via regulating EGFR/STAT-3/DR-4 axis

Abstract

Currently, available gastrointestinal stromal tumor therapy is marred with limited efficacy and resistance. Considering the involvement of epidermal growth factor receptor- Signal transducer and activator of transcription 3 mediated signaling in gastrointestinal stromal tumors progression, we hypothesized that the signal transducer and activator of transcription 3 inhibitor, niclosamide could be repurposed to treat gastrointestinal stromal tumors. Niclosamide nanocrystal was developed to enhance solubility and bioavailability. Cytotoxicity and the nature of cell death were accessed by various in vitro assays. Niclosamide showed dose-dependent cytotoxicity, mitochondrial damage, and apoptotic-like cell death in the gastrointestinal stromal tumor cell line. Niclosamide nanocrystal displayed a 2-fold enhancement in in-vitro anticancer activity. Immunoblotting and immuno-flow-cytometry confirmed that epidermal growth factor stimulation had increased phosphorylation Signal transducer and activator of transcription 3 via epidermal growth factor receptor and downregulated Death receptor 4 mediated apoptosis which was reversed by niclosamide treatment. Moreover, niclosamide nanocrystal (50 mg/kg) showed better tumor suppression than pure niclosamide (50 mg/kg), indicating that niclosamide nanocrystal has more bioavailability than niclosamide. This study demonstrated that nanocrystals might become a promising delivery strategy for delivering niclosamide to treat the gastrointestinal stromal tumor.