Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells

Background. 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. Methods. The effects of PPI and vonoprazan on VEGF expression in cancer cells were compared by real-time rt-PCR and ELISA. The interaction of vonoprazan and PPIs with transcriptional regulators by docking simulation analysis. Results. In various cancer cell lines, including the human colorectal cancer cell line (LS174T), PPI increased VEGF mRNA 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. Conclusions. 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.

内容要旨・審査要旨・論文本文の公開
本論文は，著者Rie Ando-Matsuokaの学位論文として提出され，学位審査・授与の対象となっている。

This is the peer reviewed version of the following article: Ando-Matsuoka, R., Yagi, K., Takaoka, M., Sakajiri, Y., Shibata, T., Sawada, R., Maruo, A., Miyata, K., Aizawa, F., Hamano, H., Niimura, T., Izawa-Ishizawa, Y., Goda, M., Sakaguchi, S., Zamami, Y., Yamanishi, Y., & Ishizawa, K. (2023). Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells. Drug Development Research, 84, 75– 83., which has been published in final form at https://doi.org/10.1002/ddr.22013. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.