Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer

Abstract

Hypertension is one of the main adverse effects of antiangiogenic tumor drugs and thus limits their application. The mechanism of hypertension caused by tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors is mainly related to inhibition of the nitric oxide (NO) pathway and activation of the endothelin pathway, as well as vascular rarefaction and increased salt sensitivity; consequently, prevention and treatment differ for this type of hypertension compared with primary hypertension. Apatinib is a highly selective TKI approved in China for the treatment of advanced or metastatic gastric cancer. The RhoA/ROCK pathway is involved in the pathogenesis of hypertension and mediates smooth muscle contraction, eNOS inhibition, endothelial dysfunction and vascular remodeling. In this study, in vivo experiments were performed to explore whether the RhoA/ROCK signaling pathway is part of a possible mechanism of apatinib in the treatment of gastric cancer-induced hypertension and the impairment of vascular remodeling and left ventricular function. Y27632, a selective small inhibitor of both ROCK1 and ROCK2, was combined with apatinib, and its efficacy was evaluated, wherein it can reduce hypertension induced by apatinib treatment in gastric cancer mice and weaken the activation of the RhoA/ROCK pathway by apatinib and a high-salt diet (HSD). Furthermore, Y-27632 improved aortic remodeling, fibrosis, endothelial dysfunction, superior mesenteric artery endothelial injury, left ventricular dysfunction and cardiac fibrosis in mice by weakening the activation of the RhoA/ROCK pathway. The expression of RhoA/ROCK pathway-related proteins and relative mRNA levels in mice after apatinib intervention were analyzed by various methods, and blood pressure and cardiac function indexes were compared. Endothelial and cardiac function and collagen levels in the aorta were also measured to assess vascular and cardiac fibrosis and to provide a basis for the prevention and treatment of this type of hypertension.

Efficacy and safety of apatinib combined with liposomal doxorubicin or paclitaxel versus liposomal doxorubicin or paclitaxel monotherapy in patients with recurrent platinum‐resistant ovarian cancer

“…18 The possible reason would be that apatinib might modulate vascular remodeling, nitric oxide production, endothelial dysfunction, and so on to induce hypertension in patients with recurrent PROC. 30,31 Apart from hypertension, the occurrence rate of other adverse events was not different between the two groups; which was in line with previous studies. 12,14,18 Moreover, this study discovered that the most frequent adverse events of apatinib plus chemotherapy were neutropenia (56.9%), leukopenia (47.1%), nausea and vomiting (37.3%), anorexia (35.3%), and fatigue (33.3%); meanwhile, grade 3-4 adverse events rarely occurred in patients with recurrent PROC receiving apatinib plus chemotherapy.…”

“…Furthermore, this study discovered that the incidence of hypertension was increased in patients with recurrent PROC receiving apatinib plus chemotherapy compared with patients receiving chemotherapy, which was in accordance with a previous study 18 . The possible reason would be that apatinib might modulate vascular remodeling, nitric oxide production, endothelial dysfunction, and so on to induce hypertension in patients with recurrent PROC 30,31 . Apart from hypertension, the occurrence rate of other adverse events was not different between the two groups; which was in line with previous studies 12,14,18 .…”

Microvascular rarefaction caused by the NOTCH signaling pathway is a key cause of TKI-apatinib-induced hypertension and cardiac damage

“…Similarly, in animal experiments, microvascular abnormalities occur early in the development of hypertension in SHRs (Antonios et al, 2003). In addition, the latest results from our research indicated that the administration of the ROCK inhibitor Y27632 can prevent microvascular rarefaction caused by apatinib and improve blood pressure (Wang et al, 2022a). Thus, microvascular growth disorders may have given rise to a new paradigm of hypertension treatment aimed at restoring microvascular development and branching, thereby further reducing peripheral resistance and improving the structural reduction of arterial blood pressure.…”

Apatinib induces zebrafish hepatotoxicity by inhibiting Wnt signaling and accumulation of oxidative stress

“…The typical serious adverse reaction is upper gastrointestinal bleeding 2,3 . Apatinib caused hypertension in a gastric cancer mouse model through the RhoA/ROCK signaling pathway 4 . It was reported that apatinib inhibits the proliferation of gastric cancer cells via the AKT/GSK signaling pathway in vivo 5 .…”

“…2,3 Apatinib caused hypertension in a gastric cancer mouse model through the RhoA/ROCK signaling pathway. 4 It was reported that apatinib inhibits the proliferation of gastric cancer cells via the AKT/GSK signaling pathway in vivo. 5 Moreover, apatinib induced apoptosis and autophagy via AKT/mTOR pathway in anaplastic thyroid carcinoma (ATC) cell lines.…”