Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway
Autor: | Yongxia Zhu, Lijuan Chen, Hongyao Liu, Wanglai Hu, Shasha Bian, Cailin Gan, Wang Yue, Xiuli Wu, Weiqiong Zuo, Xingping Su, Tinghong Ye, Jiayu Jing, Yuqi Guo |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
STAT3 Transcription Factor Lung Neoplasms Melanoma Experimental Apoptosis Biochemistry Stat3 Signaling Pathway 03 medical and health sciences Mice 0302 clinical medicine In vivo Cell Movement Cell Line Tumor medicine Animals Humans STAT3 Niclosamide Pharmacology Anthelmintics Membrane Potential Mitochondrial Mice Inbred BALB C biology Chemistry Melanoma Myeloid-Derived Suppressor Cells Drug Repositioning Cell migration medicine.disease In vitro 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Cancer research medicine.drug Signal Transduction |
Zdroj: | Biochemical pharmacology. 169 |
ISSN: | 1873-2968 |
Popis: | The incidence of melanoma is increasing rapidly worldwide. Additionally, new and effective candidates for treating melanoma are needed because of the increase in drug resistance and the high metastatic potential of this cancer. The STAT3 signaling pathway plays a pivotal role in pathogenesis of melanoma, making STAT3 a promising anticancer target for melanoma therapy. Niclosamide, an FDA-approved anti-helminthic drug, has been identified as a potent STAT3 inhibitor that suppresses STAT3 phosphorylation at Tyr705 and its transcript activity. In this study, we evaluated the biological activities of niclosamide in melanoma in vitro and in vivo. Niclosamide potently inhibited the growth of four melanoma cell lines and induced the apoptosis of melanoma cells via the mitochondrial apoptotic pathway. Further, western blot analysis indicated that cell apoptosis was correlated with activation of Bax and cleaved caspase-3 and decreased expression of Bcl-2. Moreover, niclosamide markedly impaired melanoma cell migration and invasion, reduced phosphorylated STAT3Tyr705 levels, and inhibited matrix metalloproteinase-2 and -9 expression. Additionally, in a xenograft model of A375, intraperitoneal administration of niclosamide inhibited tumor growth and tumor weight in a dose-dependent manner without obvious side effects. Histological and immunohistochemical analyses revealed a decrease in Ki-67-positive cells and p-STAT3Try705-positive cells and increase in cleaved caspase-3-positive cells. Notably, niclosamide significantly inhibited pulmonary metastasis in a B16-F10 melanoma lung metastasis model, including the number of lung metastatic nodules and lung/body coefficient. Importantly, a marked reduction in myeloid-derived suppressor cells (Gr1+CD11b+) infiltration in the pulmonary metastasis tissue was observed. Taken together, these results demonstrate that niclosamide is a promising candidate for treating melanoma. |
Databáze: | OpenAIRE |
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