Abstract 580: Lung Cancer Chemotherapy Agents Increase Procoagulant Activity via Protein Disulfide Isomerase-Dependent Tissue Factor Decryption
Background: Lung cancer patients undergoing chemotherapy have an elevated risk for thrombosis. However, the mechanisms by which chemotherapy agents increase the risk for thrombosis remains unclear.
Objectives: To determine the mechanism(s) by which lung cancer chemotherapy agents cisplatin, carboplatin, gemcitabine, and paclitaxel elicit increased tissue factor (TF) activity on endothelial cells, A549 cells, and monocytes.
Methods: TF activity, TF antigen, and phosphatidylserine exposure were measured on chemotherapy-treated human umbilical vein endothelial cells (HUVEC), A549 cells, and monocytes. Cell surface protein disulfide isomerase (PDI) and cell surface free-thiol levels were measured on HUVEC and A549 non-small cell lung carcinoma cells.
Results: Treatment of HUVECs, A549 cells, and monocytes with lung cancer chemotherapy significantly increased cell surface TF activity. However, elevated TF antigen levels were observed only on cisplatin- and gemcitabine-treated monocytes. Cell surface levels of phosphatidylserine were increased on HUVEC and monocytes treated with cisplatin/gemcitabine combination therapy. Chemotherapy also resulted in increased cell surface levels of PDI and reduced cell surface free thiol levels. Glutathione treatment and PDI inhibition, but not phosphatidylserine inhibition attenuated TF activity. Furthermore, increased TF activity was reversed by reducing cysteines with dithiothreitol.
Conclusions: These studies are the first to demonstrate that lung cancer chemotherapy agents increase procoagulant activity on endothelial cells, blood monocytes, and A549 cells by TF decryption through a disulfide bond formation in a PDI-dependent mechanism.
Author Disclosures: Z. Lysov: None. L. Swystun: None. S. Kuruvilla: None. A. Arnold: None. P. Liaw: None.
- © 2014 by American Heart Association, Inc.