2. Academic Validation
  3. Doxorubicin-Induced Platelet Activation and Clearance Relieved by Salvianolic Acid Compound: Novel Mechanism and Potential Therapy for Chemotherapy-Associated Thrombosis and Thrombocytopenia

Doxorubicin-Induced Platelet Activation and Clearance Relieved by Salvianolic Acid Compound: Novel Mechanism and Potential Therapy for Chemotherapy-Associated Thrombosis and Thrombocytopenia

  • Pharmaceuticals (Basel). 2022 Nov 22;15(12):1444. doi: 10.3390/ph15121444.
Wenjing Ma 1 2,  Zackary Rousseau 1 2,  Sladjana Slavkovic 1 2,  Chuanbin Shen 1 2 3,  George M Yousef 1 2 4,  Heyu Ni 1 2 4 5 6
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
  • 2 Department of Laboratory Medicine, LKSKI-Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto Platelet Immunobiology Group, Toronto, ON M5B 1W8, Canada.
  • 3 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 4 Department of Medicine, University of Toronto, Toronto, ON M5S 1A1, Canada.
  • 5 Canadian Blood Services Centre for Innovation, Toronto, ON M5G 2M1, Canada.
  • 6 Department of Physiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
PMID: 36558895 DOI: 10.3390/ph15121444
Abstract

Doxorubicin (Dox) is a widely utilized chemotherapeutic; however, it carries side effects, including drug-induced immune thrombocytopenia (DITP) and increased risk of venous thromboembolism (VTE). Currently, the mechanisms for Dox-associated DITP and VTE are poorly understood, and an effective inhibitor to relieve these complications remains to be developed. In this study, we found that Dox significantly induced platelet activation and enhanced platelet phagocytosis by macrophages and accelerated platelet clearance. Importantly, we determined that salvianolic acid C (SAC), a water-soluble compound derived from Danshen root traditionally used to treat cardiovascular diseases, inhibited Dox-induced platelet activation more effectively than current standard-of-care anti-platelet drugs aspirin and ticagrelor. Mechanism studies with tyrosine kinase inhibitors indicate contributions of Phospholipase C, spleen tyrosine kinase, and protein kinase C signaling pathways in Dox-induced platelet activation. We further demonstrated that Dox enhanced platelet-cancer cell interaction, which was ameliorated by SAC. Taken together, these findings suggest SAC may be a promising therapy to reduce the risk of Dox-induced DITP, VTE, and the repercussions of amplified platelet-cancer interaction in the tumor microenvironment.

Keywords

cancer-platelet crosstalk; doxorubicin; platelet activation; platelet clearance; salvianolic acid C; tyrosine phosphorylation.

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