Reciprocal crosstalk between platelets and
malignancies underscores the potential of antiplatelet
therapy in
cancer treatment. In this study, we found that human
chronic myeloid leukemia K562 cell-differentiated megakaryocytes and murine platelets produced bioactive substances and these are released into the extracellular space, partly in their exosomal form. High-mobility group box 1 (
HMGB1) is a type of exosomal cargo, and the
antiplatelet drugs aspirin and
dipyridamole interfered with its incorporation into the exosomes. Those released substances and exosomes, along with exogenous
HMGB1, promoted
cancer cell survival and protected cells from
doxorubicin cytotoxicity. In a
tumor-bearing model established using murine
Lewis lung carcinoma (LLC) cells and C57BL/6 mice, the
tumor suppressive effect of
dipyridamole correlated well with decreased circulating white blood cells, soluble
P-selectin, TGF-β1 (
Transforming Growth Factor-β1), exosomes, and exosomal
HMGB1, as well as
tumor platelet infiltration. Exosome release inhibitor
GW4869 exhibited suppressive effects as well. The suppressive effect of
dipyridamole on
cancer cell survival was paralleled by a reduction of
HMGB1/
receptor for advanced glycation end-products axis, and proliferation- and migration-related β-
catenin, Yes-associated
protein 1, Runt-related
transcription factor 2, and TGF- β1/Smad signals. Therefore, exosomes and exosomal
HMGB1 appear to have roles in platelet-driven
cancer malignancy and represent targets of
antiplatelet drugs in anticancer treatment.