Nitazoxanide, an antiprotozoal drug, inhibits late-stage autophagy and promotes ING1-induced cell cycle arrest in glioblastoma

Cell Death Dis. 2018 Oct 9;9(10):1032. doi: 10.1038/s41419-018-1058-z.

Abstract

Glioblastoma is the most common and aggressive primary brain tumor in adults. New drug design and development is still a major challenge for glioma treatment. Increasing evidence has shown that nitazoxanide, an antiprotozoal drug, has a novel antitumor role in various tumors and exhibits multiple molecular functions, especially autophagic regulation. However, whether nitazoxanide-associated autophagy has an antineoplastic effect in glioma remains unclear. Here, we aimed to explore the underlying molecular mechanism of nitazoxanide in glioblastoma. Our results showed that nitazoxanide suppressed cell growth and induced cell cycle arrest in glioblastoma by upregulating ING1 expression with a favorable toxicity profile. Nitazoxanide inhibited autophagy through blockage of late-stage lysosome acidification, resulting in decreased cleavage of ING1. A combination with chloroquine or Torin1 enhanced or impaired the chemotherapeutic effect of nitazoxanide in glioblastoma cells. Taken together, these findings indicate that nitazoxanide as an autophagy inhibitor induces cell cycle arrest in glioblastoma via upregulated ING1 due to increased transcription and decreased post-translational degradation by late-stage autophagic inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiprotozoal Agents / pharmacology*
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism
  • Cell Cycle Checkpoints / drug effects*
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chloroquine / pharmacology
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism*
  • Glioma / drug therapy
  • Glioma / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inhibitor of Growth Protein 1 / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Naphthyridines / pharmacology
  • Protein Processing, Post-Translational / drug effects
  • Thiazoles / pharmacology*
  • Transcription, Genetic / drug effects
  • Up-Regulation / drug effects

Substances

  • 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
  • Antiprotozoal Agents
  • ING1 protein, human
  • Inhibitor of Growth Protein 1
  • Naphthyridines
  • Thiazoles
  • Chloroquine
  • nitazoxanide