Original ResearchSunitinib uptake inhibits platelet function in cancer patients
Introduction
Inhibition of protein tyrosine kinases has shown considerable anticancer activity in patients with malignancies [1]. The multitarget tyrosine kinase inhibitor (TKI) sunitinib has been approved for the treatment of advanced renal cell cancer (RCC) and for imatinib-resistant gastrointestinal and pancreatic neuroendocrine tumours [2]. The effect of sunitinib in the management of several other malignancies is currently being explored in several trials (ClinicalTrials.gov Identifiers: NCT02074878, NCT01396148, NCT02058901 and NCT00753727).
Although treatment with sunitinib has shown anticancer effects and improves progression-free survival, patients treated with this TKI may also encounter bleeding. Overall, bleeding occurs in approximately 19% of sunitinib-treated patients; about 3% of the bleeding incidents are life threatening [3]. The mechanism underlying this higher bleeding diathesis in patients treated with sunitinib is still poorly understood. Haemostasis upon vessel wall injury is an intricate process in which platelets play a major role; it involves activation of platelets by multiple exogenous and autocrine agonists and their receptors [4]. Exposed extracellular matrix proteins, including collagen and von Willebrand Factor (vWF), first mediate platelet adhesion and activation, as a prerequisite for ensuing aggregation and thrombus formation. A subpopulation of activated platelets exposes phosphatidylserine which promotes thrombin generation and fibrin formation [5], [6]. Platelets contain multiple active protein tyrosine kinases [4] that are essential for platelet functioning in haemostasis. Moreover, platelets also play an important role in tumour angiogenesis and cancer progression [7]. The role of platelets in sunitinib-induced toxicity has not been explored.
The current study examined the hypothesis that sunitinib treatment of cancer patients impairs platelet haemostatic function, explaining the higher occurrence of bleeding in patients undergoing this treatment. We investigated the effects of sunitinib on platelet activation, aggregation and thrombus formation both in vitro and in patients with RCC.
Section snippets
Patients
The study was approved by the medical ethics committee from Maastricht University Medical Centre+ (MUMC+, The Netherlands). Informed consent was obtained from all participants in accordance with the declaration of Helsinki. At the department of Medical Oncology of MUMC+, blood samples were obtained from eight patients diagnosed with metastatic RCC and eight healthy donors who were similar in age and gender to the RCC patients. The patients included were treated with sunitinib (Sutent®, Pfizer,
Sunitinib is sequestered by platelets and inhibits collagen-induced protein tyrosine phosphorylation
Visualisation by confocal microscopy of washed platelets from healthy individuals that were treated with 10 μM sunitinib showed that platelets accumulate sunitinib and sequester this fluorescent compound in granules (Fig. 1A). This uptake of sunitinib from the environment was observed within minutes after exposure. Platelets contain several tyrosine kinases implicated in platelet functioning, mostly acting in the collagen-induced signalling pathway [4]. Western blotting was used to investigate
Discussion
The present study shows that the multi-TKI sunitinib is taken up by platelets and inhibits collagen receptor-induced integrin activation, secretion, aggregation and thrombus formation. Protein tyrosine kinases are abundantly expressed in platelets and play important roles in platelet activation and haemostasis [9]. It has been shown that sunitinib also affects tyrosine kinases that are expressed in platelets [10]. This may explain that sunitinib treatment was accompanied by bleeding episodes in
Funding
This research is financially supported by the Netherlands Organization for Scientific Research (NWO) under project number 017.008.143, granted to Siamack Sabrkhany, and by the Cardiovascular Centre Maastricht (Thrombosis Expertise Centre) to Johan Heemskerk and Marijke Kuijpers.
Conflict of interest statement
None declared.
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2022, Biochemical PharmacologyCitation Excerpt :An example is provided by sunitinib malate (Sutent), a broad-spectrum TKI with antitumor activity. Platelets sequester sunitinib in vitro as well as in vivo in cancer patients and this uptake inhibits platelet function [178]. The inhibitory effect of sunitinib on thrombus formation was shown in vitro in human whole blood perfused over different surfaces and was associated with suppression of Syk- and Src-induced GPVI phosphorylation, inhibition of Ca+2 elevation, and impaired platelet activation, phosphatidylserine exposure and fibrin formation, effects magnified by aspirin [177].
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