Abstract
Purpose To investigate the effects of anthelminthic drug niclosamide in renal cell carcinoma (RCC) and the underlying mechanisms of its action.MethodsThe effects of niclosamide on the proliferation and apoptosis of RCC cells were examined in vitro and in vivo by using MTS, colony formation assay, flow cytometry and xenograft cancer mouse model. Mechanism studies were performed by analyzing Wnt/β-catenin signaling and mitochondrial functions in a panel of RCC cell lines.ResultsWe show that niclosamide effectively targets two RCC cell lines through inhibiting proliferation and anchorage-independent colony formation, and inducing apoptosis. It also enhances the inhibitory effects of chemotherapeutic drug cisplatin in two independent in vivo RCC xenograft mouse models. Mechanistically, niclosamide decreases β-catenin levels and therefore suppresses Wnt/β-catenin activities. Overexpression of β-catenin partially reverses the inhibitory effects of niclosamide in RCC cells, demonstrating that besides β-catenin, other mechanisms are involved in niclosamide’s anti-cancer activity. Indeed, we further show that niclosamide induces mitochondrial dysfunctions as shown by the decreased level of mitochondrial membrane potential and respiration, resulting in decreased ATP levels and increased reactive oxygen species (ROS) levels.ConclusionsOur findings support the inhibitory effects of niclosamide in cancer and provide better understanding on its underlying mechanism. Our data suggests that niclosamide is a useful addition to the treatment armamentarium for RCC.
Highlights
Renal cell carcinoma (RCC) is an epithelial tumour derived from the proximal tubules of nephrons (Thoenes et al 1986)
We investigated the effects of niclosamide and its underlying mechanisms in RCC cells using in vitro cellular culture system and in vivo xenograft mouse tumor model
Niclosamide is active against renal carcinoma cells Two human RCC cell lines, A-498 and SW-839, were used in this study
Summary
Renal cell carcinoma (RCC) is an epithelial tumour derived from the proximal tubules of nephrons (Thoenes et al 1986). It is the most aggressive type of genitourinary cancer and resistant to chemotherapy, radiotherapy and targeted therapy (Bukowski 1997; Kanesvaran and Tan 2014). Niclosamide is an anthelmintic drug especially used for the treatment of cestodes infection (Tanowitz et al 1993). Niclosamide has been recently identified as a novel type of anti-cancer drug It suppresses growth of several tumor cell lines (Arend et al 2014; Osada et al 2011; Lu et al 2011; Khanim et al 2011).
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