Abstract
Pazopanib is an angiostatic tyrosine kinase inhibitor (TKI) presently used for cancer treatment, particularly in patients with renal cell carcinoma (RCC). This treatment can be accompanied by mild bleeding as an adverse effect. Given the role of protein tyrosine kinases in platelet activation processes, we investigated whether and how pazopanib can affect platelet functions in purified systems and during treatment of advanced RCC patients. In isolated platelets from healthy volunteers, pazopanib dose-dependently reduced collagen-induced integrin activation and secretion, as well as platelet aggregation. Pazopanib addition diminished glycoprotein (GP) VI-dependent tyrosine phosphorylation of multiple platelet proteins, including the tyrosine kinase Syk. Furthermore, pazopanib inhibited GPVI-induced Ca2+ elevation, resulting in reduced exposure of the procoagulant phospholipid phosphatidylserine (PS). Upon perfusion of control blood over a collagen surface, pazopanib inhibited thrombus size as well as PS exposure. Blood samples from 10 RCC patients were also analyzed before and after 14 days of pazopanib treatment as monotherapy. This treatment caused an overall lowering in platelet count, with 3 out of 10 patients experiencing mild bleeding. Platelets isolated from pazopanib-treated patients showed a significant lowering of PS exposure upon activation. In addition, platelet procoagulant activity was inhibited in thrombi formed under flow conditions. Control experiments indicated that higher pazopanib concentrations were required to inhibit GPVI-mediated PS exposure in the presence of plasma. Together, these results indicated that pazopanib suppresses GPVI-induced platelet activation responses in a way partly antagonized by the presence of plasma. In treated cancer patients, pazopanib effects were confined to a reduction in GPVI-dependent PS exposure. Together with the reduced platelet count, this may explain the mild bleeding tendency observed in pazopanib-treated patients.
Highlights
Tyrosine kinase inhibitors (TKIs) are widely approved drugs, aiming to target tyrosine kinase signaling pathways that regulate uncontrolled cellular growth and proliferation
Since effects of pazopanib on platelet function have not been reported, we aimed to investigate this in vitro and ex vivo, using blood from renal cell carcinoma (RCC) patients and control subjects
Fluorescein isothiocyanate (FITC)-labeled PAC-1 monoclonal antibody against activated human integrin αIIbβ3 was from BD Bioscience (Franklin Lakes NJ, USA; nr. 340507), while FITC-labeled anti-human CD62 mAb was from Beckman Coulter (Sydney, Australia; nr. 65050)
Summary
Tyrosine kinase inhibitors (TKIs) are widely approved drugs, aiming to target tyrosine kinase signaling pathways that regulate uncontrolled cellular growth and proliferation. Several TKIs are in clinical use for the treatment of malignancies, such as lung, breast, kidney, and neuro-endocrine pancreatic cancers as well as gastro-intestinal stromal tumors and chronic myeloid leukemia [1,2,3]. Their common way of action is by competition with adenosine triphosphate (ATP) in the conserved catalytic binding site in the protein tyrosine kinase superfamily. The expected effects are to reduce tumor lesions, delay disease development, and prolong the progression-free survival of patients [7]
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