Minireviews
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 7, 2019; 25(17): 2058-2070
Published online May 7, 2019. doi: 10.3748/wjg.v25.i17.2058
Proton pump inhibitor: The dual role in gastric cancer
Moon Kyung Joo, Jong-Jae Park, Hoon Jai Chun
Moon Kyung Joo, Jong-Jae Park, Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, Seoul 08308, South Korea
Hoon Jai Chun, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Digestive Disease and Nutrition, Korea University College of Medicine, Seoul 02841, South Korea
Author contributions: Joo MK, Park JJ and Chun HJ performed research; Joo MK wrote the paper; Park JJ and Chun HJ revised the manuscript for critical intellectual contents.
Supported by Basic Science Research Program through the National Research Foundation of Korea, No. NRF-2016R1D1A1A02936964.
Conflict-of-interest statement: None of the authors have potential conflicts (financial, professional, or personal) that are relevant to this publication.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Moon Kyung Joo, MD, PhD, Professor, Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, 148, Gurodong-ro, Guro-gu, Seoul 80548, South Korea. latyrx@korea.ac.kr
Telephone: +82-2-26263007 Fax: +82-2-26262024
Received: February 20, 2019
Peer-review started: February 20, 2019
First decision: March 5, 2019
Revised: March 17, 2019
Accepted: March 24, 2019
Article in press: March 25, 2019
Published online: May 7, 2019
Processing time: 74 Days and 22.5 Hours
Abstract

Proton pump inhibitors (PPIs) are one of the most frequently used medications for upper gastrointestinal diseases. However, a number of physicians have raised concern about the serious side effects of long-term use of PPIs, including the development of gastric cancer. Recent epidemiological studies have reported a significant association between long-term PPI intake and the risk of gastric cancer, even after successful Helicobacter pylori eradication. However, the effects of PPIs on the development of pre-malignant conditions such as atrophic gastritis or intestinal metaplasia are not fully known, suggesting the need for comprehensive and confirmative studies are needed in the future. Meanwhile, several experimental studies have demonstrated the effects of PPIs in reducing chemoresistance in gastric cancer cells by modulating the acidic microenvironment, cancer stemness and signal transducer and activator of transcription 3 (STAT3) signaling pathway. The inhibitory effects of PPIs on STAT3 activity may overcome drug resistance and enhance the efficacy of conventional or targeted chemotherapeutic agents. Taken together, PPIs may “play dual role” in gastric carcinogenesis and treatment of gastric cancer.

Keywords: Proton pump inhibitor; Gastric cancer; Drug resistance; Signal transducer and activator of transcription 3

Core tip: Recent epidemiological studies have demonstrated a significant increase in gastric cancer risk following the long-term use of proton pump inhibitors (PPIs). However, observational studies have fundamental limitations. PPIs may affect gastric cancer cells and the microenvironment by modifying the acidic conditions and inhibiting the cancer stemness via various signaling pathways including signal transducer and activator of transcription 3, which in turn, reduces drug resistance to chemotherapy. In this review, we briefly summarize the current clinical outcomes of the effects of long-term PPI use and the development of gastric cancer, as well as experimental studies showing enhanced chemosensitivity in gastric cancer.