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

Rie Ando-Matsuoka, Kenta Yagi, Mayu Takaoka, Yuko Sakajiri, Tomokazu Shibata, Ryusuke Sawada, Akinori Maruo, Koji Miyata, Fuka Aizawa, Hirofumi Hamano, Takahiro Niimura, Yuki Izawa-Ishizawa, Mitsuhiro Goda, Satoshi Sakaguchi, Yoshito Zamami, Yoshihiro Yamanishi, Keisuke Ishizawa

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalDrug Development Research
DOIs
Publication statusAccepted/In press - 2022

Keywords

  • fulvestrant
  • lansoprazole
  • Proton pump inhibitors
  • vascular endothelial growth factor
  • vonoprazan

ASJC Scopus subject areas

  • Drug Discovery

Fingerprint

Dive into the research topics of 'Differential effects of proton pump inhibitors and vonoprazan on vascular endothelial growth factor expression in cancer cells'. Together they form a unique fingerprint.

Cite this