Tanshinone IIA suppresses cancer metastasis by modulating tumor cell-platelet-endothelial cell interactions.

Hematogenous metastasis is a major cause of cancer-related mortality and depends on coordinated interactions between circulating tumor cells, platelets and vascular endothelial cells. Targeting this metastatic microenvironment represents a promising strategy to limit tumor dissemination. Tanshinone IIA (Tan IIA), a bioactive compound derived from Salvia miltiorrhiza, has anti-tumor activity, however, its effects on tumor cell-platelet-endothelial interactions during metastasis remain incompletely understood. In the present study, Tan IIA was evaluated at low, non-cytotoxic concentrations to assess its influence on metastatic processes rather than direct tumor cell killing. In assessments of cell viability and the cell cycle, Tan IIA exhibited minimal effects on the viability of tumor and endothelial cells, while significantly suppressing tumor cell migration and invasion in vitro. Mechanistically, Tan IIA decreased CD29 expression on tumor cells, inhibited platelet activation, as indicated by decreased P-selectin expression, and attenuated tumor cell-platelet aggregate formation. Tan IIA diminished TNF-α-induced upregulation of endothelial adhesion molecules intercellular adhesion molecule-1 and E-selectin, resulting in decreased tumor cell adhesion to endothelial monolayers by inhibiting the NF-κB signaling pathway. These coordinated effects resulted in a significant reduction in pulmonary metastatic burden and prolonged survival in mouse models of hematogenous metastasis, without evidence of overt systemic toxicity. Collectively, these findings indicated that Tan IIA suppresses metastatic dissemination primarily by modulating interactions between tumor cells, platelets and endothelial cells, highlighting its potential as a pharmacological agent targeting the metastatic microenvironment.