Sodium thiosulfate prevents doxorubicin-induced DNA damage and apoptosis in cardiomyocytes in mice

  • Life Sci. 2020 Sep 15:257:118074. doi: 10.1016/j.lfs.2020.118074.
Yukie Mizuta  1 ,  Kentaro Tokuda  2 ,  Jie Guo  3 ,  Shuo Zhang  3 ,  Sayoko Narahara  4 ,  Takahito Kawano  4 ,  Masaharu Murata  4 ,  Ken Yamaura  5 ,  Sumio Hoka  5 ,  Makoto Hashizume  4 ,  Tomohiko Akahoshi  6
Affiliations
  • 1. Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 2. Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Intensive Care Unit, Kyushu University Hospital, Fukuoka, Japan. Electronic address: [email protected].
  • 3. Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 4. Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan.
  • 5. Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 6. Department of Disaster and Emergency Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Emergency and Critical Care Center, Kyushu University Hospital, Fukuoka, Japan.
PMID: 32673667 DOI: 10.1016/j.lfs.2020.118074
Abstract

Aim: Doxorubicin (DOX) induces dose-dependent cardiotoxicity due to Reactive Oxygen Species (ROS)-mediated oxidative stress and subsequent Apoptosis of cardiomyocytes. We aimed to assess whether sodium thiosulfate (STS), which has antioxidant and antiapoptotic properties, exerts cardioprotective effects on DOX-induced cardiomyopathy.

Main methods: Male C57BL/6N mice were divided into four groups, control, DOX, STS, and DOX + STS, and administered DOX (20 or 30 mg/kg) or normal saline intraperitoneally, followed by an injection of STS (2 g/kg) or normal saline 4 h later.

Key findings: The DOX group showed a poorer 6-day survival and decreased cardiac function than the DOX + STS group. The DOX group showed a marked increase in the plasma Creatine Kinase isoenzyme myocardial band (CK-MB) and Lactate Dehydrogenase (LDH) levels 10 h after DOX injection, while the DOX + STS group showed suppression of DOX-induced elevation of CK-MB and LDH levels. The DOX group showed increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the heart, whereas the DOX + STS group showed increased catalase and superoxide dismutase (SOD) activities and decreased 8-OHdG levels in the heart compared with DOX group, suggesting that STS reduces DOX-induced DNA damage by improving antioxidant Enzymes activities in cardiomyocytes. Additionally, the DOX + STS group showed attenuation of cleaved Caspase-3 and DNA fragmentation in cardiomyocytes compared with the DOX group, suggesting that STS suppresses DOX-induced Apoptosis in cardiomyocytes.

Significance: STS exerts cardioprotective effects against DOX-induced cardiac dysfunction partly by improving antioxidant defense and suppressing Apoptosis, indicating the therapeutic potential of STS against DOX-induced cardiomyopathy.

Keywords
Apoptosis; Cardiomyopathy; Doxorubicin; Oxidative stress; Sodium thiosulfate.
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