Pro-caspase-3 protects cells from polymyxin B-induced cytotoxicity by preventing ROS accumulation

J Antibiot (Tokyo). 2019 Nov;72(11):848-852. doi: 10.1038/s41429-019-0216-6. Epub 2019 Aug 2.


Polymyxin B (PMB), a last-line antibiotic used against antibiotic-resistant superbugs, causes undesirable cytotoxic side effects. However, its mechanisms remain unknown. In this study, we unexpectedly found that caspase-3, a main executor of apoptosis, plays a protective role in PMB-induced cytotoxicity. Caspase-3 knockout (KO) cells exhibited higher susceptibility to PMB-induced cytotoxicity compared with wild-type (WT) cells, accompanied by increased levels of reactive oxygen species (ROS). Interestingly, co-treatment with the antioxidant N-acetylcysteine (NAC) rescued cell viability to a similar extent as WT cells. Furthermore, PMB failed to facilitate the processing of inactive caspase-3 (pro-caspase-3) into active forms, suggesting that pro-caspase-3 nonenzymatically suppresses PMB-driven ROS accumulation and its cytotoxicity. Thus, our findings that demonstrate the potential ability of PMB to stimulate ROS generation, but which is normally masked by pro-caspase-3-dependent mechanisms, may provide novel insights into the mechanisms of PMB-induced side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / toxicity*
  • Caspase 3 / metabolism*
  • Cell Line
  • Cell Survival / drug effects
  • Fas Ligand Protein / pharmacology
  • Gene Deletion
  • Gene Expression Regulation / drug effects
  • Humans
  • Mice
  • Polymyxin B / pharmacology
  • Polymyxin B / toxicity*
  • Reactive Oxygen Species / metabolism*


  • Anti-Bacterial Agents
  • Fas Ligand Protein
  • Reactive Oxygen Species
  • Caspase 3
  • Polymyxin B
  • Acetylcysteine