(365) Investigating Pranlukast’s Role in Thiol Isomerase Inhibition and Application in Cancer Induced Thrombosis

Objective : Cancer patients, particularly those receiving systemic chemotherapy, have a significantly increased risk of developing both arterial and venous thrombosis. Thiol isomerase inhibitors such as zafirlukast and, to a lesser extent, montelukast, have both anti-thrombotic and anti-neoplastic activity, which is ideal for targeting cancer-induced thrombosis. The goal of this study was to examine the potential of another -lukast compound, pranlukast, to affect thiol isomerase activity.

Methods: The ability of pranlukast to inhibit the activity of protein disulfide isomerase (PDI), as well as the related thiol isomerase ERp57 in an enzymatic assay, was determined by the insulin turbidometry assay. Cellular cytotoxicity of OVCAR8 ovarian cancer cells after pranlukast treatment was measured using the PrestoBlue assay from ThermoFisher. Finally, washed platelets were treated with pranlukast, and alterations in aggregation were examined using standard platelet aggregometry.

Results: Pranlukast inhibited both PDI and ERp57 in a concentration-dependent manner in the insulin turbidity assay with an IC50 of about 30 µM, demonstrating the compound is a broad-spectrum thiol isomerase inhibitor. Cell viability decreased as pranlukast concentration increased from concentrations ranging from 1-100 µM, with a similar IC50. Overall, pranlukast seemed to have similar efficacy to zafirlukast.

Conclusions: Pranlukast has similar effects to zafirlukast and was stronger than montelukast at inhibiting thiol isomerase activity and inducing cancer cell cytotoxicity. These data indicate the pranlukast may be another option in the -lukast family to explore for the treatment of cancer-induced thrombosis.