Blocking endoplasmic reticulum stress: attenuation of apatinib-induced hypertension in gastric cancer-bearing nude mice

Background and Purpose While hypertension is a well-established adverse effect of targeted anticancer therapies, the underlying mechanisms remain unclear. This study aimed to investigate whether apatinib induces hypertension by activating endoplasmic reticulum (ER) stress in the aortic tissues of gastric cancer-bearing nude mice, and whether the ER stress inhibitor 4-phenylbutyric acid (4-PBA) mitigates apatinib-associated hypertension. Methods Four-week-old SPF male Balb/c nude mice were randomized into four groups: Normal (NR, n≥3), Tumor-bearing (TB, n≥3), Tumor-bearing + Apatinib (TB+Apa, n≥3), and Tumor-bearing + Apatinib + 4-PBA (TB+Apa+4-PBA, n≥3). Human gastric cancer cells (MKN-45) were subcutaneously inoculated into the axillary region. After successful tumor engraftment, interventions were administered: apatinib mesylate (75 mg/kg/day) and 4-PBA (130 mg/kg/day) via oral gavage. Weekly measurements included blood pressure, body weight, and tumor volume. Following ethical euthanasia, aortic tissues were harvested for Western blot analysis of ER stress markers (GRP78, IRE1α). Statistical significance was defined as P < 0.05. Results Body weight: No significant intergroup differences were observed (Figure 1A);Tumor growth: TB+Apa and TB+Apa+4-PBA groups exhibited significantly suppressed tumor growth compared to TB from Week 3 (P < 0.05), with no significant difference between the two treatment groups (Figure 1B);Blood pressure: TB+Apa showed marked hypertension starting at Week 2 versus NR and TB (P < 0.05). Co-administration of 4-PBA significantly attenuated apatinib-induced hypertension (P < 0.05; Figure 1C-E);Tumor validation: Histopathology confirmed successful tumor establishment (Figure 2A-B);ER stress activation: Western blot confirmed upregulated ER stress markers in TB+Apa versus TB: GRP78 (P = 0.0329) and IRE1α (P < 0.001; Figure 2C-E). Conclusions Apatinib likely induces hypertension through ER stress activation in the aortic tissues of gastric cancer-bearing nude mice. Co-treatment with the ER stress inhibitor 4-PBA effectively mitigates this hypertensive effect while maintaining antitumor efficacy. Ongoing investigations aim to elucidate the specific signaling pathways involved.