Multiple ingredients of a Chinese medicine formula Sheng-Mai-San coordinately attenuate doxorubicin-induced cardiotoxicity

Abstract

Background: Doxorubicin (DOX) is one of the most widely used antitumor drugs. However, continuous DOX treatment would cause crucial cardiotoxicity side effect, accompanied with the accumulation of reactive oxygen species (ROS), impaired mitochondrial functions and increased cardiomyocyte death. Sheng-Mai-San (SMS), a traditional Chinese medicine widely used for cardiovascular diseases, has been clinically used to counteract cardiotoxicity of DOX, yet the underlying mechanism is largely unknown. Methods: We utilized JC-1 assay to examine the effects of SMS and its components under DOX treatment in rat cardiomyocytes (H9c2 cells), and further investigated the functional mechanisms of active components in SMS formula via transcriptome sequencing, bioinformatics analysis and molecular experiments. Results: We identified three functional components of SMS in protecting cardiomyocytes from DOX-induced damages and revealed the coordinated regulatory mechanisms of these components, namely ginsenoside Rh2 (Rh2), Ophiopogonin D (OpD) and Schisandrin B (SchB). We found that Rh2 mainly acts to restore mitochondrial functions and to decrease ROS generation by enhancing fatty acid metabolism and antioxidant activity, OpD has assistive roles in mitochondrial function repair, and SchB mainly functions by inhibiting cell death, as well as activating cytoskeleton and ECM organization. Conclusion: This study provides supporting evidence for the clinical application of SMS to reduce the cardiotoxicity effects of DOX treatment, and also sheds light for the mechanistic studies of traditional Chinese medicine.

Keywords

• Cardiotoxicity
• Doxorubicin
• Ginsenoside Rh2
• Ophiopogonin D
• Schisandrin B
• Sheng-Mai-San