Recombinant human interleukin-1 receptor antagonist protects mice against acute doxorubicin-induced cardiotoxicity

Eur J Pharmacol. 2010 Sep 25;643(2-3):247-53. doi: 10.1016/j.ejphar.2010.06.024. Epub 2010 Jun 30.

Abstract

Doxorubicin is a potent anticancer drug which is widely used in the treatments of a variety of solid and hematopoietic tumors, but its use is limited by its cardiotoxicity and dose-dependent congestive heart failure. After finding a close connection between Interleukin-1 family and doxorubicin-induced cardiotoxicity, we assumed that recombinant human interleukin-1 receptor antagonist (rhIL-1Ra), the natural antagonist of interleukin-1, might have a protective role in doxorubicin-induced cardiotoxicity. In this report, Balb/c mice were intraperitoneally injected with doxorubicin (18 mg/kg) followed by injections of 1mg/kg rhIL-1Ra 4h later, and consecutive daily injections of rhIL-1Ra on the following 4 days (1mg/kg/day). We found that rhIL-1Ra significantly decreased malondialdehyde in cardiac tissue and prevented doxorubicin-associated cardiac troponin I elevations in serum, especially at day 14 after doxorubicin treatment. Importantly, rhIL-1Ra diminished doxorubicin-induced microstructural damages of cardiac tissue and rescued doxorubicin-caused reduction of cardiac functions exemplified by ejection fraction and fraction shortening. Our results reveal a potential role of rhIL-1Ra in protecting mice against doxorubicin-induced cardiac injuries and lead to a conclusion that this protein may be a potential candidate agent that inhibits cardiomyocyte-toxicity in doxorubicin-exposed patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Cardiotonic Agents / therapeutic use*
  • Doxorubicin / toxicity*
  • Female
  • Heart Failure / chemically induced
  • Heart Failure / metabolism
  • Heart Failure / pathology
  • Heart Failure / prevention & control*
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / blood
  • Interleukin 1 Receptor Antagonist Protein / genetics
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interleukin 1 Receptor Antagonist Protein / therapeutic use*
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / genetics
  • Interleukin-1 / physiology*
  • Interleukin-1beta / blood
  • Lipid Peroxidation / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • RNA, Messenger / metabolism
  • Random Allocation
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism
  • Recombinant Proteins / therapeutic use
  • Specific Pathogen-Free Organisms
  • Stroke Volume / drug effects
  • Troponin I / blood

Substances

  • Antineoplastic Agents
  • Cardiotonic Agents
  • IL1RN protein, human
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Interleukin-1beta
  • RNA, Messenger
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • Troponin I
  • Doxorubicin