The anthelmintic drug niclosamide induces apoptosis, impairs metastasis and reduces immunosuppressive cells in breast cancer model

PLoS One. 2014 Jan 8;9(1):e85887. doi: 10.1371/journal.pone.0085887. eCollection 2014.

Abstract

Breast carcinoma is the most common female cancer with considerable metastatic potential. Discovery of new therapeutic approaches for treatment of metastatic breast cancer is still needed. Here, we reported our finding with niclosamide, an FDA approved anthelmintic drug. The potency of niclosamide on breast cancer was assessed in vitro and in vivo. In this investigation, we found that niclosamide showed a dramatic growth inhibition against breast cancer cell lines and induced apoptosis of 4T1 cells in a dose-dependent manner. Further, Western blot analysis demonstrated the occurrence of its apoptosis was associated with activation of Cleaved caspases-3, down-regulation of Bcl-2, Mcl-1 and Survivin. Moreover, niclosamide blocked breast cancer cells migration and invasion, and the reduction of phosphorylated STAT3(Tyr705), phosphorylated FAK(Tyr925) and phosphorylated Src(Tyr416) were also observed. Furthermore, in our animal experiments, intraperitoneal administration of 20 mg/kg/d niclosamide suppressed 4T1 tumor growth without detectable toxicity. Histological and immunohistochemical analyses revealed a decrease in Ki67-positive cells, VEGF-positive cells and microvessel density (MVD) and an increase in Cleaved caspase-3-positive cells upon niclosamide. Notably, niclosamide reduced the number of myeloid-derived suppressor cells (MDSCs) in tumor tissues and blocked formation of pulmonary metastases. Taken together, these results demonstrated that niclosamide may be a promising candidate for breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthelmintics / adverse effects
  • Anthelmintics / pharmacology
  • Anthelmintics / therapeutic use*
  • Antineoplastic Agents / pharmacology
  • Apoptosis* / drug effects
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Female
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / urine*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / secondary
  • Mice, Inbred BALB C
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / enzymology
  • Neovascularization, Pathologic / pathology
  • Niclosamide / adverse effects
  • Niclosamide / pharmacology
  • Niclosamide / therapeutic use*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Anthelmintics
  • Antineoplastic Agents
  • Immunosuppressive Agents
  • Niclosamide
  • Focal Adhesion Protein-Tyrosine Kinases

Grant support

This study was funded by the National Key Basic Research Program of China (2010 CB 529900) and the National Natural Science Foundation of China (81123003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.