Combination treatment with fasudil and clioquinol produces synergistic anti-tumor effects in U87 glioblastoma cells by activating apoptosis and autophagy

J Neurooncol. 2016 Apr;127(2):261-70. doi: 10.1007/s11060-015-2044-2. Epub 2016 Jan 2.

Abstract

Survival of patients with glioblastoma (GBM) remains poor, and novel treatment methods are urgently needed. In this study, we tested the effects of a combination of fasudil, a ROCK inhibitor, and clioquinol, an 8-hydroxyquinoline derivative with antimicrobial properties, on human GBM U87 cells. Combination treatment synergistically inhibited the viability of glioma cells but not mouse normal neuron HT22 cells and significantly induced mitochondria-mediated apoptosis. Moreover, the combination was also found to trigger macro-autophagy (henceforth referred to as autophagy) by increasing the expression levels of several proteins involved in the induction of autophagy. Further studies showed that 3-methyladenine (3-MA) or chloroquine (CQ), two autophagy inhibitors, abrogated the cytotoxic effects of the combination treatment as well as the autophagy. Overall, we demonstrated that fasudil and clioquinol show synergistic anti-cancer effects, providing evidence for the further development of combination therapy for GBM.

Keywords: Apoptosis; Autophagy; Clioquinol; Fasudil; Glioblastoma; Synergistic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Animals
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Blotting, Western
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Proliferation / drug effects
  • Clioquinol / pharmacology*
  • Drug Synergism*
  • Drug Therapy, Combination
  • Flow Cytometry
  • Glioblastoma
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Tumor Cells, Cultured

Substances

  • Protein Kinase Inhibitors
  • Clioquinol
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • fasudil