The Vascular Endothelial Growth Factor Receptor Inhibitor Sunitinib Causes a Preeclampsia-Like Syndrome With Activation of the Endothelin System

Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, 's Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Hypertension (Impact Factor: 6.48). 06/2011; 58(2):295-302. DOI: 10.1161/HYPERTENSIONAHA.111.173559
Source: PubMed


Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension.

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Available from: Anton van den Meiracker, Jan 11, 2016
    • "The mechanisms involved 30 in the pathogenesis of these toxic effects are still unclear, although 31 several mechanisms have been proposed. Previous clinical and 32 experimental studies have shown that activation of the endothelin 33 (ET) system is involved in the Su-induced rise in blood pressure 34 (Banfor et al., 2009; Kappers et al., 2011). Besides inducing 35 vasoconstriction, ET-1 activates vascular NADPH oxidase, leading 36 to an increase in oxidative stress through enhanced reactive 37 oxygen species (ROS) production (An et al., 2007). "
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    ABSTRACT: Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of L-carnitine (LC). To this end, four groups of Wistar rats were used: 1) control; 2) rats treated with 400mg LC/kg/day; 3) rats treated with 25mg Su/kg/day; and 4) rats treated with LC + Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co- administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition.. Our results suggest that: i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; ii) these processes might be mediated by the transcription factor NF-κB; iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment.
    No preview · Article · Nov 2015 · Toxicology Letters
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    • "Patients receiving the anti-VEGF antibody therapy bevacizumab experience hypertension and proteinuria – side effects which are remarkably similar to preeclampsia patients (Zhu et al., 2007). Likewise, inhibition of the VEGF receptors by small molecule tyrosine kinase inhibitors increases blood pressure, at least partially mediated by increased endothelin-1 expression – a known final effector of hypertension in preeclampsia patients (Kappers et al., 2010, 2011, 2012; George and Granger, 2011). Finally, a plethora of studies have demonstrated that increasing circulating sFlt-1 levels through direct administration or viral overexpression induces a hypertensive, preeclampsia-like phenotype in animal models (Maynard et al., 2003; Li et al., 2007; Bridges et al., 2009; Suzuki et al., 2009; Gilbert et al., 2010; Murphy et al., 2010). "
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    ABSTRACT: The last several decades have seen intensive research into the molecular mechanisms underlying the symptoms of preeclampsia. While the underlying cause of preeclampsia is believed to be defective placental development and resulting placental ischemia, it is only recently that the links between the ischemic placenta and maternal symptomatic manifestation have been elucidated. Several different pathways have been implicated in the development of the disorder; most notably production of the anti-angiogenic protein sFlt-1, induction of auto-immunity and inflammation, and production of reactive oxygen species. While the molecular mechanisms are becoming clearer, translating that knowledge into effective therapeutics has proven elusive. Here we describe a number of peptide based therapies we have developed to target theses pathways, and which are currently being tested in preclinical models. These therapeutics are based on a synthetic polymeric carrier elastin-like polypeptide (ELP), which can be synthesized in various sequences and sizes to stabilize the therapeutic peptide and avoid crossing the placental interface. This prevents fetal exposure and potential developmental effects. The therapeutics designed will target known pathogenic pathways, and the ELP carrier could prove to be a versatile delivery system for administration of a variety of therapeutics during pregnancy.
    Full-text · Article · Sep 2014 · Frontiers in Pharmacology
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    • "Moreover, the rise in BP induced by VEGF inhibition can be fully reversed in animals by ET-1 receptor blockade with either a selective ETA antagonist (ABT-627) as well as with a dual ETA and ETB antagonist (ACT-064992).[14], [15] However, additional contractile mechanisms, predominantly elevated prostanoid signaling, may exacerbate the ET-1-induced BP elevation during VEGF inhibition as ET-1 stimulates production of the vasocontractile prostanoid thromboxane A2 (TXA2).[16], [17] Production of TXA2 is indeed elevated in pre-eclampsia and results in a decreased prostacyclin/TXA2 ratio [18], [19]. "
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    ABSTRACT: Scavenging of vascular endothelial growth factor (VEGF) elevates blood pressure (BP) in patients receiving anti-angiogenic therapy. Similarly, inhibition of circulation VEGF by its soluble receptor fms-like tyrosine kinase-1 (sFlt-1) underlies BP elevation in pre-eclampsia. Both phenotypes are characterized by augmented production of endothelin-1 (ET-1), suggesting a role for ET-1 in anti-angiogenic hypertension. We aimed to assess the effect of VEGF inhibition on ET-1-induced contractility and downstream ET-1 signaling. Male C57BL/6N mice were treated with either sFlt-1 or vehicle and BP was assessed via tail-cuff. Mean arterial pressure of sFlt-1-treated mice markedly increased compared to vehicle-treated controls (N = 11-12, p<0.05). After sacrifice, carotid and mesenteric arteries were isolated for isometric tension measurements. ET-1-induced contractions were similar in mesenteric arteries of vehicle and sFlt-1-treated mice, but augmented in carotid segments of sFlt-1-treated mice compared to controls (N = 9-10, p<0.05). The increased contraction in carotid segments could be completely abrogated by the cyclooxygenase (COX) inhibitor indomethacin (N = 9-10, p<0.05), indicating heightened prostaglandin-mediated vasoconstriction. This was associated with a shift towards procontractile ETB signaling in sFlt-1-treated mice, possibly explaining the increased ET-1-induced prostaglandin-mediated vasoconstriction. In line with the ex vivo findings, sFlt-1-induced BP elevation could be prevented in vivo by oral treatment with either a high-dose of the COX inhibitor aspirin (N = 7) or with picotamide (N = 9), a dual thromboxane A2 synthase inhibitor and receptor antagonist. VEGF inhibition augments the pressor response to ET-1. The cyclooxygenase-thromboxane signaling route downstream of ET-1 might be a possible target to prevent BP elevation during VEGF inhibition.
    Full-text · Article · Mar 2014 · PLoS ONE
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