Evidences for the mechanism of Shenmai injection antagonizing doxorubicin-induced cardiotoxicity

Phytomedicine. 2021 Jul 15:88:153597. doi: 10.1016/j.phymed.2021.153597. Epub 2021 May 21.

Abstract

Background: Doxorubicin (DOX) is a widely used antitumor drug. However, its clinical application is limited for its serious cardiotoxicity. The mechanism of DOX-induced cardiotoxicity is attributed to the increasing of cell stress in cardiomyocytes, then following autophagic and apoptotic responses. Our previous studies have demonstrated the protective effect of Shenmai injection (SMI) on DOX-induced cardiotoxicity via regulation of inflammatory mediators for releasing cell stress.

Purpose: To further investigate whether SMI attenuates the DOX-induced cell stress in cardiomyocytes, we explored the mechanism underlying cell stress as related to Jun N-terminal kinase (JNK) activity and the regulation of autophagic flux to determine the mechanism by which SMI antagonizes DOX-induced cardiotoxicity.

Study design: The DOX-induced cardiotoxicity model of autophagic cell death was established in vitro to disclose the protected effects of SMI on oxidative stress, autophagic flux and JNK signaling pathway. Then the autophagic mechanism of SMI antagonizing DOX cardiotoxicity was validated in vivo.

Results: SMI was able to reduce the DOX-induced cardiomyocyte apoptosis associated with inhibition of activation of the JNK pathway and the accumulation of reactive oxygen species (ROS). Besides, SMI antagonized DOX cardiotoxicity, regulated cardiomyocytes homeostasis by restoring DOX-induced cardiomyocytes autophagy. Under specific circumstances, SMI depressed autophagic process by reducing the Beclin 1-Bcl-2 complex dissociation which was activated by DOX via stimulating the JNK signaling pathway. At the same time, SMI regulated lysosomal pH to restore the autophagic flux which was blocked by DOX in cardiomyocytes.

Conclusion: SMI regulates cardiomyocytes apoptosis and autophagy by controlling JNK signaling pathway, blocking DOX-induced apoptotic pathway and autophagy formation. SMI was also found to play a key role in restoring autophagic flux for counteracting DOX-damaged cardiomyocyte homeostasis.

Keywords: Autophagic flux; Cardiotoxicity; Doxorubicin; JNK pathway; Shenmai injection.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / adverse effects
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Beclin-1 / metabolism
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / pharmacology*
  • Cardiotoxicity / drug therapy*
  • Cardiotoxicity / metabolism
  • Cell Line
  • Doxorubicin / adverse effects*
  • Drug Combinations
  • Drugs, Chinese Herbal / administration & dosage
  • Drugs, Chinese Herbal / pharmacology*
  • Humans
  • Injections
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Oxidative Stress / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Beclin-1
  • Cardiotonic Agents
  • Drug Combinations
  • Drugs, Chinese Herbal
  • Reactive Oxygen Species
  • fructus schizandrae, radix ginseng, radix ophiopogonis drug combination
  • Doxorubicin
  • JNK Mitogen-Activated Protein Kinases