Thioredoxin Decreases Anthracycline Cardiotoxicity, But Sensitizes Cancer Cell Apoptosis

Cardiovasc Toxicol. 2021 Feb;21(2):142-151. doi: 10.1007/s12012-020-09605-2. Epub 2020 Sep 3.

Abstract

Cardiotoxicity is a major limitation for anthracycline chemotherapy although anthracyclines are potent antitumor agents. The precise mechanism underlying clinical heart failure due to anthracycline treatment is not fully understood, but is believed to be due, in part, to lipid peroxidation and the generation of free radicals by anthracycline-iron complexes. Thioredoxin (Trx) is a small redox-active antioxidant protein with potent disulfide reductase properties. Here, we present evidence that cancer cells overexpressing Trx undergo enhanced apoptosis in response to daunomycin. In contrast, cells overexpressing redox-inactive mutant Trx were not effectively killed. However, rat embryonic cardiomyocytes (H9c2 cells) overexpressing Trx were protected against daunomycin-mediated apoptosis, but H9c2 cells with decreased levels of active Trx showed enhanced apoptosis in response to daunomycin. We further demonstrate that increased level of Trx is specifically effective in anthracycline toxicity, but not with other topoisomerase II inhibitors such as etoposide. Collectively these data demonstrate that whereas high levels of Trx protect cardiomyocytes against anthracycline toxicity, it potentiates toxicity of anthracyclines in cancer cells.

Keywords: Anthracycline; Cardiomyocytes; Cardiotoxicity; Chemotherapy; Doxorubicin; Redox-cycling; Thioredoxin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity*
  • Apoptosis / drug effects*
  • Cardiotoxicity
  • Daunorubicin / toxicity*
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rats
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • U937 Cells

Substances

  • Antibiotics, Antineoplastic
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Thioredoxins
  • Poly(ADP-ribose) Polymerases
  • Daunorubicin