Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells
Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells
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DOI：
10.1002/ddr.22013
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发表时间：
2022-12-09
影响因子：
3.8
通讯作者：
Ishizawa，Keisuke
中科院分区：
文献类型：
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作者：
Ando-Matsuoka，Rie;Yagi，Kenta;Ishizawa，Keisuke
质子泵抑制剂（PPI）是胃酸分泌的强效抑制剂，用作治疗消化性溃疡的一线药物。然而，我们之前曾报道PPI可能会降低抗血管内皮生长因子（VEGF）药物在癌症患者中的治疗效果。在本研究中，我们探索了沃诺拉赞（一种用于治疗消化性溃疡的新型胃酸分泌抑制剂）对癌细胞中VEGF分泌的影响，并尝试将其作为癌症化疗的替代PPI，通过真实的时间逆转录聚合酶链反应和ELISA比较了PPI和沃诺拉赞对癌细胞中VEGF表达的影响。通过对接模拟分析研究沃诺拉赞和PPI与转录调节因子的相互作用在各种癌细胞系中，包括人结直肠癌细胞系（LS 174 T），PPI可增加VEGF信使RNA表达和VEGF蛋白分泌，而沃诺拉赞未观察到这种作用。分子对接模拟分析表明，与PPI相比，沃诺拉赞与雌激素受体α（ER-α）（VEGF的转录调节因子之一）的结合亲和力较低。尽管PPI诱导的VEGF表达增加被药理学ER-α抑制抵消，但沃诺拉赞对VEGF表达的影响未发生变化。沃诺拉赞不影响癌细胞中的VEGF表达，这表明沃诺拉赞可能是PPI的替代药物，不干扰抗VEGF癌症化疗的治疗作用。
Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion, used as first‐line agents in treating peptic ulcers. However, we have previously reported that PPIs may diminish the therapeutic effect of anti‐vascular endothelial growth factor (VEGF) drugs in patients with cancer. In this study, we explored the effects of vonoprazan, a novel gastric acid secretion inhibitor used for the treatment of peptic ulcers, on the secretion of VEGF in cancer cells and attempted to propose it as an alternative PPI for cancer chemotherapy. The effects of PPI and vonoprazan on VEGF expression in cancer cells were compared by real‐time reverse transcription‐polymerase chain reaction and ELISA. The interaction of vonoprazan and PPIs with transcriptional regulators by docking simulation analysis. In various cancer cell lines, including the human colorectal cancer cell line (LS174T), PPI increased VEGF messenger RNA expression and VEGF protein secretion, while this effect was not observed with vonoprazan. Molecular docking simulation analysis showed that vonoprazan had a lower binding affinity for estrogen receptor alpha (ER‐α), one of the transcriptional regulators of VEGF, compared to PPI. Although the PPI‐induced increase in VEGF expression was counteracted by pharmacological ER‐α inhibition, the effect of vonoprazan on VEGF expression was unchanged. Vonoprazan does not affect VEGF expression in cancer cells, which suggests that vonoprazan might be an alternative to PPIs, with no interference with the therapeutic effects of anti‐VEGF cancer chemotherapy.