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.