Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma.

Yongxia Zhu,Xi Yu,Yuquan Wei,Li Liu,Yong Xia,Yongmei Xie,Lifeng Zhao,Tinghong Ye,Tiantao Gao,Ying Xiong,Hongxia Deng,Xuejiao Song,Luoting Yu,Lidan Zhang,Fangfang Yang,Cuiting Peng,Ningyu Wang,Weiqiong Zuo,Qian Lei

doi:10.1038/srep20253

Abstract

Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma.

Highlights

Melanoma invasiveness and is required for active melanogenesis by regulating tyrosinase gene expression and enzyme activity[23]
Our data provided evidence that nifuroxazide could inhibit the proliferation of melanoma cells by inducing cell cycle arrest via inhibition of CDK1 and cyclin B1, and by inducing apoptosis via the reactive oxygen species (ROS)-mitochondria apoptotic pathway
The results indicated that most melanoma cancer cells had constitutively activated Stat[3] as assessed by its phosphorylation status at Tyr[705], while the HEK293 cells almost no expression of p-Stat[3] (Supplementary Fig. S1a)

Summary

Introduction

Melanoma invasiveness and is required for active melanogenesis by regulating tyrosinase gene expression and enzyme activity[23]. Increasing evidences demonstrated that blockade of Stat[3] by inhibitors could inhibit angiogenesis and trigger apoptosis in melanoma cells[24,25], and inhibit cellular growth in melanoma cells with acquired resistance to vemurefenib[26]. These data all suggest that Stat[3] inhibition provides a rational approach to therapy for melanoma. We evaluated the antitumor activity of nifuroxazide in A375 tumor-bearing xenograft mice model and B16-F10 melanoma metastasis model These data suggested that nifuroxazide could be a new agent for the treatment of melanoma

Methods

Results

Conclusion