Abstract
Antiangiogenic tyrosine kinases inhibitors induce hypertension, which may increase the incidents of cardiovascular complications and limit their use. However, the mechanisms by which usage of TKIs results in hypertension have not been fully understood. Here, we report the potential mechanisms of how sunitinib, a widely used TKI, induces hypertension. Male SD rats were randomly divided into control group and sunitinib-administrated group. We show that sunitinib administration for seven days caused a significant increase in artery blood pressure, along with glycerolipid metabolism abnormalities including decreased food intake and low body weight, hypoglycemia, hyperinsulinemia. Sunitinib administration also resulted in a significant increase in the levels of insulin autoantibody (IAA), cyclic adenosine monophosphate and free fatty acid in serum; whereas, sunitinib administration had no effects on serum glucagon levels. Sunitinib led to the decreased insulin sensitivity as determined by insulin tolerance test (ITT) and glucose tolerance test (GTT), reflecting insulin resistance occurred in sunitinib-treated rats. The results obtained from wire myograph assay in the mesenteric arteries show that endothelium-dependent relaxation, but not endothelium-independent relaxation, was impaired by sunitinib. Furthermore, western blot analysis revealed that the expressions levels of phosphorylated IRS-1, Pellino-1, AKT and eNOS were significantly attenuated by sunitinib in rat mesenteric artery tissues and in the sunitinib-treated primary cultured mesenteric artery endothelial cells. The levels of serum and endothelium-derived nitric oxide were also significantly decreased by sunitinib. Moreover, sunitinib-induced decrease in the expression levels of phosphorylated AKT and eNOS was further reduced by knocking down of Pellino-1 in MAECs. Our results suggest that sunitinib causes vascular dysfunction and hypertension, which are associated with insulin resistance- and Pellino-1-mediated inhibition of AKT/eNOS/NO signaling. Our results may provide a rational for preventing and/or treating sunitinib-induced endothelial dysfunction and hypertension.
Highlights
Sunitinib, as a member of small molecular tyrosine kinase inhibitor family, has been widely used to treat a variety types of cancer including gastrointestinal stromal tumors with secondary resistance to imatinib, advanced pancreatic neuroendocrine tumor and inoperable renal cell carcinoma (Demetri et al, 2006; Motzer et al, 2007; Raymond et al, 2011)
Our results show that there were no statistical differences in baseline systolic arterial blood pressure (sBP) between the control and sunitinib-treated groups
The major findings of the present study are: sunitinib administration led to an impairment of vascular function and hypertension in rats, via IRS-1- and Pellino-1-mediated inhibition of AKT/eNOS signaling and reduction of nitric oxide (NO) production
Summary
As a member of small molecular tyrosine kinase inhibitor family, has been widely used to treat a variety types of cancer including gastrointestinal stromal tumors with secondary resistance to imatinib, advanced pancreatic neuroendocrine tumor and inoperable renal cell carcinoma (Demetri et al, 2006; Motzer et al, 2007; Raymond et al, 2011). It has been reported that sunitinib often causes severe hypertension in the patients with a history of high BP (Bamias et al, 2011). Despite the occurrence of sunitinib induced hypertension has considered as a sign of drug response or expecting a longer tumor progression-free survival, proper management should be conducted to prevent cancer patients from developing severe cardiovascular complications secondary to sunitinib-induced hypertension (Donskov et al, 2015). Revealing the underlying mechanisms of sunitinib-induced hypertension is an important issue
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