Therapeutic Targets for DOX-Induced Cardiomyopathy: Role of Apoptosis vs. Ferroptosis

Hiroki Kitakata, Jin Endo, Hidehiko Ikura, Hidenori Moriyama, Kosuke Shirakawa, Yoshinori Katsumata, Motoaki Sano

Research output: Contribution to journalReview articlepeer-review

Abstract

Doxorubicin (DOX) is the most widely used anthracycline anticancer agent; however, its cardiotoxicity limits its clinical efficacy. Numerous studies have elucidated the mechanisms underlying DOX-induced cardiotoxicity, wherein apoptosis has been reported as the most common final step leading to cardiomyocyte death. However, in the past two years, the involvement of ferroptosis, a novel programmed cell death, has been proposed. The purpose of this review is to summarize the historical background that led to each form of cell death, focusing on DOX-induced cardiotoxicity and the molecular mechanisms that trigger each form of cell death. Furthermore, based on this un-derstanding, possible therapeutic strategies to prevent DOX cardiotoxicity are outlined. DNA dam-age, oxidative stress, intracellular signaling, transcription factors, epigenetic regulators, autophagy, and metabolic inflammation are important factors in the molecular mechanisms of DOX-induced cardiomyocyte apoptosis. Conversely, the accumulation of lipid peroxides, iron ion accumulation, and decreased expression of glutathione and glutathione peroxidase 4 are important in ferroptosis. In both cascades, the mitochondria are an important site of DOX cardiotoxicity. The last part of this review focuses on the significance of the disruption of mitochondrial homeostasis in DOX cardio-toxicity.

Original languageEnglish
Article number1414
JournalInternational journal of molecular sciences
Volume23
Issue number3
DOIs
Publication statusPublished - 2022 Feb 1

Keywords

  • Apoptosis
  • Cardiotoxicity
  • Doxorubicin
  • Doxorubicin-induced cardiomyopathy
  • Ferropto-sis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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