Mefloquine binding to human acyl-CoA binding protein leads to redox stress-mediated apoptotic death of human neuroblastoma cells

Neurotoxicology. 2020 Mar;77:169-180. doi: 10.1016/j.neuro.2020.01.006. Epub 2020 Jan 24.

Abstract

Malaria is an infectious disease that is caused by different species of Plasmodium. Several antimalarial drugs are used to counter the spread and infectivity of Plasmodium species. However, humans are also vulnerable to many of the antimalarial drugs, including the quinoline-based drugs. In particular, the antimalarial mefloquine has been reported to show adverse neuropsychiatric effects in humans. Though mefloquine is known to be neurotoxic, the molecular mechanisms associated with this phenomenon are still obscure. In this study, we show that mefloquine binds to and inactivates the human acyl-CoA binding protein (hACBP), potentially inducing redox stress in human neuroblastoma cells (IMR-32). Mefloquine occupies the acyl-CoA binding pocket of hACBP by interacting with several of the critical acyl-CoA binding amino acids. This leads to the competitive inhibition of acyl-CoA(s) binding to hACBP and to the accumulation of lipid droplets inside the IMR-32 cells. The accumulation of cytosolic lipid globules and oxidative stress finally correlates with the apoptotic death of cells. Taken together, our study deciphers a mechanistic detail of how mefloquine leads to the death of human cells by perturbing the activity of hACBP and lipid homeostasis.

Keywords: Apoptosis; Human acyl-CoA binding protein; Lipid; Mefloquine; Redox stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / metabolism
  • Antimalarials / toxicity*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Diazepam Binding Inhibitor / metabolism*
  • Humans
  • Mefloquine / metabolism
  • Mefloquine / toxicity*
  • Oxidation-Reduction
  • Oxidative Stress / drug effects*

Substances

  • Antimalarials
  • Diazepam Binding Inhibitor
  • Mefloquine