Abstract
Breast carcinoma is the most common female cancer with considerable metastatic potential. Signal transducers and activators of the transcription 3 (Stat3) signaling pathway is constitutively activated in many cancers including breast cancer and has been validated as a novel potential anticancer target. Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3. The potency of nifuroxazide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that nifuroxazide decreased the viability of three breast cancer cell lines and induced apoptosis of cancer cells in a dose-dependent manner. In addition, western blot analysis demonstrated that the occurrence of its apoptosis was associated with activation of cleaved caspases-3 and Bax, downregulation of Bcl-2. Moreover, nifuroxazide markedly blocked cancer cell migration and invasion, and the reduction of phosphorylated-Stat3Tyr705, matrix metalloproteinase (MMP) MMP-2 and MMP-9 expression were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 50 mg/kg/day nifuroxazide suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without detectable toxicity. Meanwhile, histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells, MMP-9-positive cells and an increase in cleaved caspase-3-positive cells upon nifuroxazide. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung. Our data indicated that nifuroxazide may potentially be a therapeutic agent for growth and metastasis of breast cancer.
Highlights
There is currently no effective therapy to control the recurrence and metastasis of breast cancer, and the development of new therapies is essential
Stat[3] is a key negative regulator of tumor immune surveillance and is critically involved in tumor accumulation of myeloid-derived suppressor cells (MDSCs), which has an important role in suppressing antitumor immune responses (S100A9).[15,16,17]
Because Stat[3] is constitutively activated in ~ 70% of breast tumors, we determined the level of phospho-Stat[3] (Tyr705) in three breast cancer cell lines by western blot analysis
Summary
There is currently no effective therapy to control the recurrence and metastasis of breast cancer, and the development of new therapies is essential. Our data showed that nifuroxazide may be a potential candidate for treating breast cancer
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