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Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model.

Yang F, Hu M, Lei Q, Xia Y, Zhu Y, Song X, Li Y, Jie H, Liu C, Xiong Y, Zuo Z, Zeng A, Li Y, Yu L, Shen G, Wang D, Xie Y, Ye T, Wei Y - Cell Death Dis (2015)

Bottom Line: Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3.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.Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.

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-Stat3(Tyr705), 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.

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Effects of nifuroxazide on metastasis. (a) Lung metastatic nodules were visualized to show the inhibitory effects of nifuroxazide on 4T1 tumor 24 days after treatment. (b) The mean lung metastasis nodules of each group, the treatment with nifuroxazide at 10 mg/kg and 50 mg/kg resulted in significant inhibition of lung metastasis versus vehicle control. Bars showed mean±S.D. (n=6; **P<0.01; ***P<0.001). (c) Weight of lungs in each group. Bars showed mean±S.D. (n=6; *P<0.05; **P<0.01)
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fig5: Effects of nifuroxazide on metastasis. (a) Lung metastatic nodules were visualized to show the inhibitory effects of nifuroxazide on 4T1 tumor 24 days after treatment. (b) The mean lung metastasis nodules of each group, the treatment with nifuroxazide at 10 mg/kg and 50 mg/kg resulted in significant inhibition of lung metastasis versus vehicle control. Bars showed mean±S.D. (n=6; **P<0.01; ***P<0.001). (c) Weight of lungs in each group. Bars showed mean±S.D. (n=6; *P<0.05; **P<0.01)

Mentions: Previous studies have showed that 4T1 murine breast tumor have a high metastatic potential and spontaneously metastasize to lung as early as 2 weeks after inoculation.32, 33, 34 To analyze the effects of nifuroxazide on metastasis, lungs of 4T1 tumor-bearing mice killed on day 31 were removed and metastatic nodules were quantified. In vehicle-treated groups, multiple large nodules were evident, whereas the extent of lung metastasis was markedly reduced in nifuroxazide-treated mice (50 mg/kg groups; Figures 5a and b). Moreover, there was a remarkable decrease in lung weight after nifuroxazide treatment compared with the untreated control (Figure 5c). Importantly, histological analyses demonstrated that the number of micrometastatic nodules per field in the nifuroxazide-treated group at 50 mg/kg was also significant fewer than the other groups (Supplementary Figure S4). Overall, these results further indicated that nifuroxazide could inhibit lung metastasis in breast cancer.


Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model.

Yang F, Hu M, Lei Q, Xia Y, Zhu Y, Song X, Li Y, Jie H, Liu C, Xiong Y, Zuo Z, Zeng A, Li Y, Yu L, Shen G, Wang D, Xie Y, Ye T, Wei Y - Cell Death Dis (2015)

Effects of nifuroxazide on metastasis. (a) Lung metastatic nodules were visualized to show the inhibitory effects of nifuroxazide on 4T1 tumor 24 days after treatment. (b) The mean lung metastasis nodules of each group, the treatment with nifuroxazide at 10 mg/kg and 50 mg/kg resulted in significant inhibition of lung metastasis versus vehicle control. Bars showed mean±S.D. (n=6; **P<0.01; ***P<0.001). (c) Weight of lungs in each group. Bars showed mean±S.D. (n=6; *P<0.05; **P<0.01)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385941&req=5

fig5: Effects of nifuroxazide on metastasis. (a) Lung metastatic nodules were visualized to show the inhibitory effects of nifuroxazide on 4T1 tumor 24 days after treatment. (b) The mean lung metastasis nodules of each group, the treatment with nifuroxazide at 10 mg/kg and 50 mg/kg resulted in significant inhibition of lung metastasis versus vehicle control. Bars showed mean±S.D. (n=6; **P<0.01; ***P<0.001). (c) Weight of lungs in each group. Bars showed mean±S.D. (n=6; *P<0.05; **P<0.01)
Mentions: Previous studies have showed that 4T1 murine breast tumor have a high metastatic potential and spontaneously metastasize to lung as early as 2 weeks after inoculation.32, 33, 34 To analyze the effects of nifuroxazide on metastasis, lungs of 4T1 tumor-bearing mice killed on day 31 were removed and metastatic nodules were quantified. In vehicle-treated groups, multiple large nodules were evident, whereas the extent of lung metastasis was markedly reduced in nifuroxazide-treated mice (50 mg/kg groups; Figures 5a and b). Moreover, there was a remarkable decrease in lung weight after nifuroxazide treatment compared with the untreated control (Figure 5c). Importantly, histological analyses demonstrated that the number of micrometastatic nodules per field in the nifuroxazide-treated group at 50 mg/kg was also significant fewer than the other groups (Supplementary Figure S4). Overall, these results further indicated that nifuroxazide could inhibit lung metastasis in breast cancer.

Bottom Line: Here, we reported our finding with nifuroxazide, an antidiarrheal agent identified as a potent inhibitor of Stat3.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.Notably, nifuroxazide reduced the number of myeloid-derived suppressor cell in the lung.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.

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-Stat3(Tyr705), 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.

Show MeSH
Related in: MedlinePlus