Mdivi-1 reduces blood pressure in gastric cancer-bearing nude mice by ameliorating apatinib-induced Drp1-mediated excessive mitochondrial fission
F Si, X Ma, Y D Wang, J Ma, C Y Feng, J YuAbstract
Objective
Hypertension induced by apatinib, a VEGFR-2 inhibitor used in gastric cancer treatment, often compromises its anti-cancer efficacy. This study aims to evaluate the effects of Mdivi-1 on blood pressure and the anti-tumor efficacy of apatinib in gastric cancer-bearing nude mice by inhibiting excessive mitochondrial fission in endothelial cells during apatinib treatment.
Methods
Gastric cancer models were established in 5-week-old SPF male nude mice using MKN45 cells. Mice received either 100 mg/kg/d apatinib via oral gavage alone or in combination with intraperitoneal injections of Mdivi-1 at 2 mg/kg/d for 4 weeks. Systolic blood pressure and diastolic blood pressure were monitored. Western blotting was performed to measure the aortic levels of Drp1, Fis1, ET-1and p-eNOS/eNOS. Transmission electron microscopywas used to observe and assess mitochondrial morphology in aortic endothelial cells. Tissue immunofluorescence was employed to detect the co-localization of high Drp1 expression with endothelial cells. Tumor volume was measured using a high-precision vernier caliper. Results were expressed as mean ± SD, with P < 0.05 considered statistically significant.
Results
Mdivi-1 significantly inhibited the apatinib-induced upregulation of Drp1 and Fis1 and increased the p-eNOS/eNOS ratio. The fluorescence intensity of Drp1 localized in the thoracic aortic endothelial cells was markedly reduced following Mdivi-1 treatment. Administration of Mdivi-1 decreased the apatinib-induced increase in mitochondrial fragmentation, significantly increased mitochondrial area, and reduced the mitochondrial roundness index. The elevated systolic and diastolic blood pressure observed in the apatinib-treated nude mice were significantly lowered after Mdivi-1 treatment. Although the tumor growth rate in the apatinib plus Mdivi-1 group was lower than that in the apatinib alone group, the difference in final tumor volume between the two groups was not statistically significant.
Conclusion
Mdivi-1 can ameliorate hypertension without compromising the anti-tumor efficacy of apatinib. Drp1 represents a common intervention target for balancing hypertension management and anti-cancer therapy in the context of tumor vascular targeting.