Sunitinib Combined with Angiotensin-2 Type-1 Receptor Antagonists Induces More Necrosis: A Murine Xenograft Model of Renal Cell Carcinoma

Abstract

Background. Angiotensin-2 type-1 receptor antagonists not are only antihypertensive drugs but also can inhibit VEGF production. We hypothesised that adding telmisartan to sunitinib could potentiate the antiangiogenic effects. Material and Methods. 786-O cell lines were injected in nude mice. After tumor development, mice were divided into 4 groups: the first was the control group (DMSO), the second group was treated with sunitinib alone, the third group was treated with telmisartan alone, and the fourth group was treated with the combination. Drugs were orally administered every day for four weeks. Animals were sacrificed after treatment. Blood and tumor tissues were collected for analysis by immunohistochemistry, Western Blot, and ELISA methods. Results. All animals developed a ccRCC and ten in each group were treated. Using a kinetic model, tumors tended to grow slower in the combination group compared to others (P = 0.06). Compared to sunitinib alone, the addition of telmisartan significantly increased tissue necrosis (P = 0.038). Central microvascular density decreased (P = 0.0038) as well as circulating VEGF (P = 0.003). There was no significant variation in proliferation or apoptosis markers. Conclusion. The combination of sunitinib and telmisartan revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis.

Angiotensin System Inhibitors and Survival Outcomes in Patients with Metastatic Renal Cell Carcinoma

“…(29, 30) Physiologic concentrations of sunitinib are near 10 μM. The combination of sunitinib with captopril decreased cell viability to 59.3%, 48.1%, and 36.8% at 10, 100 and 1000 μM concentrations in A-498 RCC cells (Figure 3A).…”

“…(4) Recently, Verhoest and colleagues reported that combination therapy with sunitinib and telmisartan, an ARB, resulted in slower tumor growth, increased tumor necrosis, decreased central microvascular density, and decreased circulating VEGF levels in a murine xenograft model of RCC. (30)…”

Treatment of Hypertension and Renal Injury Induced by the Angiogenesis Inhibitor Sunitinib

“…In addition, it has been shown that an anti-RAS agent can enhance the effect of sunitinib in a murine xenograft tumor model. 35 Although NO donors such as nitrates or phosphodiesterase 5 inhibitors may also be beneficial, it has been suggested that these agents may potentially compromise the antiangiogenic effect and therefore they can best be avoided. 22 The knowledge that activation of the endothelin-axis is involved in the hypertension induced by angiogenesis inhibition may also favor the use of endothelin receptor blockers in angiogenesis inhibitioninduced hypertension.…”

Hypertension and angiotensin system inhibitors in patients with metastatic renal cell carcinoma

“…In a murine xenograft model of RCC, the combination of sunitinib and telmisartan, compared to sunitinib alone, revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis. 53 Recent clinical evidences suggest that use of ASI and ARB may be associated with improved outcomes in kidney cancer patients particularly when they are used with VEGF therapies. Three prior studies have reported on a significant association of ASI use (at baseline or within first 30 days of VEGF-targeted therapy) and survival for patients with mRCC using a VEGF-targeted therapy.…”