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

Takumi Yokosawa, Mayuka Yamada, Takuya Noguchi, Saki Suzuki, Yusuke Hirata, Atsushi Matsuzawa

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)848-852
Number of pages5
JournalJournal of Antibiotics
Volume72
Issue number11
DOIs
Publication statusPublished - 2019 Nov 1

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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