Seratrodast platinum(iv) hybrids efficiently inhibit cancer-related thrombosis and metastasis phenotype in vitro and in vivo

Abstract

Venous thromboembolism caused by Pt(II)-based chemotherapy regimens increases the risk of colon cancer metastasis, recurrence, and treatment failure. Therefore, the reduction of tumor thrombosis during chemotherapy has received much attention. Herein, a series of Pt(IV) hybrids based on the TXA2R antagonist seratrodast (SRT) were synthesized and named Seratplatin. Bioactivity studies found that compounds 3 and 4 had stronger cytotoxicity and selectivity against cancer cells among four SRT-derived Pt(IV) complexes, especially compound 3, which demonstrated a nanomolar IC₅₀ value and 42-fold lower than that in CDDP. Studies on the mechanism indicated that the cisplatin-like prodrugs are accumulated more in cells, but only compound 3 with rapid reducing properties could induce severe DNA damage, ROS production, S-phase arrest, and cell apoptosis. Most strikingly, 3 had a higher binding affinity than SRT alone or the other three derivatives and effectively inhibited the expression of TXA2R at a dose of only 0.1 times that of free SRT, thereby preventing platelet aggregation and tumor thrombosis. Compound 3 exerted anti-metastasis, anti-invasion, and anti-angiogenesis via the down-regulation of vimentin, VEGFA, MMP-9, and up-regulation of E-cadherin. In in vivo tests, compound 3 displayed a high anti-tumor effect without significant weight changes or tissue damage in HCT-116 tumor-bearing mice. Overall, these findings shed light on the special therapeutic effects of SRT-derived Pt(IV) prodrugs for cancer therapy.