Niclosamide enhances the cytotoxic effect of cisplatin in cisplatin-resistant human lung cancer cells via suppression of lung resistance-related protein and c-myc

Mol Med Rep. 2018 Mar;17(3):3497-3502. doi: 10.3892/mmr.2017.8301. Epub 2017 Dec 18.

Abstract

Lung cancer is a leading cause of cancer-associated mortality worldwide. The cisplatin (DDP)‑based chemotherapy remains the foundation of treatment for the majority of patients affected by advanced non‑small cell lung cancer (NSCLC). However, DDP‑resistance limits the clinical utility of this drug in patients with advanced NSCLC. The aim of the present study was to investigate the inhibitory effect of niclosamide on human lung cancer cell growth and to investigate the possible underlying mechanism. The effects of niclosamide on the proliferation of human lung adenocarcinoma (A549) and DDP‑resistant (CR) human lung adenocarcinoma (A549/DDP) cells were examined by Cell Counting kit‑8 assay. The impact of niclosamide on the apoptosis of A549/DDP cells was detected by Annexin V‑fluorescein isothiocyanate/propidium iodide assay. The expression levels of cisplatin‑resistant‑associated molecules (lung resistance‑related protein and c‑myc) following niclosamide treatment in A549/DDP cells were evaluated by western blot analysis. The results indicated that niclosamide in combination with DDP demonstrated a synergistic effect in A549/DDP cells and directly induced apoptosis, which may be associated with caspase‑3 activation. Furthermore, niclosamide decreased the expression level of c‑myc protein, which may influence DDP sensitivity of A549/DDP cells. Thus, the present study indicates that niclosamide combined with DDP exerts a synergistic effect in cisplatin‑resistant lung cancer cells and may present as a promising drug candidate in lung cancer therapy.

Keywords: niclosamide; non-small cell lung cancer; cisplatin-resistant lung cancer; lung resistance-related protein; c-myc.

MeSH terms

  • A549 Cells
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Caspase 3 / metabolism
  • Cisplatin / pharmacology*
  • Cisplatin / therapeutic use
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Niclosamide / pharmacology*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Vault Ribonucleoprotein Particles / metabolism*

Substances

  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-myc
  • Vault Ribonucleoprotein Particles
  • major vault protein
  • Niclosamide
  • Caspase 3
  • Cisplatin