2. Academic Validation
  3. Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway

Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway

  • Biochem Pharmacol. 2019 Nov;169:113610. doi: 10.1016/j.bcp.2019.08.012.
Yongxia Zhu 1,  Weiqiong Zuo 2,  Lijuan Chen 3,  Shasha Bian 4,  Jiayu Jing 1,  Cailin Gan 2,  Xiuli Wu 2,  Hongyao Liu 2,  Xingping Su 2,  Wanglai Hu 5,  Yuqi Guo 1,  Yue Wang 6,  Tinghong Ye 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
  • 3 Department of Radiology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China.
  • 4 Medical Genetic Institute of Henan Province, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China.
  • 5 Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Science, Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China.
  • 6 Department of Obstetrics and Gynecology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: [email protected].
PMID: 31465777 DOI: 10.1016/j.bcp.2019.08.012
Abstract

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.

Keywords

Anti-helminthic drug; Melanoma; Niclosamide; Pulmonary metastasis; STAT3 signaling pathway.

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