Isoquercetin and Zafirlukast Cooperatively Suppress Tumor Growth and Thromboinflammatory Signaling in a Xenograft Model of Ovarian Cancer

Cancer-associated thrombosis (CAT), encompassing both venous thromboembolism and arterial thrombosis, contributes to up to 14% of cancer-related mortality and remains difficult to treat due to the bleeding risks of conventional anticoagulants. Protein disulfide isomerase (PDI) and its family member ERp57 (PDIA3) are thiol isomerases that regulate both arterial and venous thrombosis and are also upregulated in tumors, where they promote growth, metastasis, and immune evasion. Here, we evaluated the therapeutic potential of two thiol isomerase inhibitors-isoquercetin (ISOQ), a selective PDI inhibitor, and zafirlukast (ZAF), a broad-spectrum inhibitor of thiol isomerases such as PDI and ERp57-individually and in combination, in a xenograft model of ovarian cancer. ISOQ inhibited both platelet aggregation and Factor Xa generation induced by tumor cells and significantly suppressed tumor growth, thromboinflammatory markers, and expression of tissue factor, VEGF, TMEM176B, and PD-L1. ISOQ also potentiated standard cisplatin/gemcitabine chemotherapy. Notably, the combination of low-dose ISOQ plus ZAF achieved ≥ 80% inhibition of key tumor-associated markers at one-third the monotherapy dose and outperformed either agent alone. These findings support ISOQ and ZAF as promising agents for the treatment of cancer and CAT and establish thiol isomerase inhibition as a strategy to simultaneously target thrombosis, tumor progression, and immune escape.