Proton pump inhibitor: The dual role in gastric cancer

Table 1 Summary of clinical studies associating gastric cancer with long-term use of proton pump inhibitors

Author, year	Study design, country	Study period	Source of database	No. of case and control	Information of PPI	Adjustment	Main outcomes
Garcia-Rodriguez et al[24], 2006	Nested case-control, retrospective, United Kingdom	1994-2001	The general practitioners research database in the United Kingdom	522/10000	Duration, indication	Age, sex, calendar year, smoking, alcohol consumption, body mass index, gastro-esophageal reflux, hiatal hernia, peptic ulcer, and dyspepsia	OR for gastric cardia adenocarcinoma: 1.06 (0.57-2.00); gastric non-cardia adenocarcinoma: 1.75 (1.10-2.79)
Tamim et al[25], 2008	Case control, retrospective, Canada	1995-2003	Quebec health insurance plan	1598/12991	Type, dose, exposure time	Number of drug prescriptions, total length of hospitalizations, number of visits to GPs, specialists, and emergency rooms during the year before the diagnosis	Adjusted OR: 1.40 (1.08-1.51); 1st quartile: 1.66 (1.24-2.23); 2nd quartile: 1.37 (1.00-1.88); 3rd quartile: 1.57 (1.17-2.10); 4th quartile: 1.20 (0.85-1.70)
Poulsen et al[26], 2009	Population-based cohort, retrospective, Denmark	1990-2003	Danish National Health-care System	109/not reported	Type, year of follow-up, no. of prescription	Age, gender, calendar period, gastroscopy (≥ 1 yr before censoring events), use of NSAIDs and H. pylori eradication	IRR for gastric cancer: 1.2 (0.8-2.0) among PPI users with the largest number of prescriptions (15+) or the longest follow-up (5+)
Cheung et al[29], 2018	Population-based cohort study, retrospective, Hong Kong	2003-2012	Clinical Data Analysis and Reporting System of the Hong Kong Hospital Authority	153/63397	Frequency, duration	Age of receiving H. pylori eradication therapy, sex, smoking, alcohol use, comorbidities, concomitant medications	HR for gastric cancer: 2.44 (1.42-4.20); ≥ 1 yr: 5.04 (1.23-20.61); ≥ 2 yr: 6.65 (1.62-27.26); ≥ 3 yr: 8.34 (2.02-34.41). The adjusted absolute risk difference for PPIs vs nonPPIs use: 4.29 (1.25-9.54) per 10000 person-yr.
Brusselaers et al[33], 2017	Population-based cohort study, retrospective, Sweden	2005-2012	The Swedish Prescribed Drug Registry	2219/794848	Indication, cumulative defined daily dosages, estimated number of days	Age, sex, calendar period, indication of PPI, maintenance use (≥ 180 d) of aspirin or other NSAIDs	SIR: 3.38 (3.23-3.53) in both sexes, all age groups and all indication groups; < 1 yr: 12.82 (12.19-13.47); 1.0-2.9 yr: 2.19 (1.98 to 2.42); 3.0-4.9 yr: 1.10 (0.91-1.31); ≥ 2 yr: 0.61 (0.52-0.72)

PPI: Proton pump inhibitor; OR: Odds ratio; GP: General physician; NSAID: Nonsteroidal anti-inflammatory drug; H. pylori: Helicobacter pylori; IRR: Incidence rate ratio; HR: Hazard ratio; SIR: Standardized incidence ratio.

Table 2 Summary of clinical studies associating of gastric pre-malignant conditions with long-term use of proton pump inhibitors

Author, year	Study design, country	Source of database	No. of PPI and control group	Information of PPI	Aims	Main outcomes
Kuipers et al[34], 1996	Prospective cohort, Netherland/ Sweden	Reflux esophagitis cohort (fundoplication/ omeprazole)	105 (PPI)/ 72 (fundoplication)	Type (omeprazole only), dose (20 and 40mg), duration (5 years)	Corpus gastritis, atrophic gastritis	Atrophic gastritis: 0/31 (fundoplication group) vs 18/59 (omeprazole group) with H. pylori infection at baseline (P < 0.001); 0/41 (fundoplication group) vs 2/46 (omeprazole group) without H. pylori infection at baseline (P = 0.62)
Lundell et al[35], 1999	RCT, Sweden	RCT comparing the efficacy of omeprazole and ARS	155 (PPI)/155 (ARS)	Type (omeprazole only), duration (3 years)	Gastric corpus glandular atrophy, intestinal metaplasia of corpus mucosa	No difference in glandular atrophy between H. pylori-infected omeprazole and ARS group (P = 0.57); No difference in intestinal metaplasia between H. pylori-infected omeprazole and ARS group.
Lundell et al[36], 2006	RCT, Sweden	RCT comparing the efficacy of omeprazole and ARS	117 (PPI)/98 (surgical arm)	Type (omeprazole only), duration (7 years)	Gastric corpus glandular atrophy	No significant change of gastric atrophy between H. pylori-negative omeprazole and ARS group; Two patients developed severe atrophy from none at baseline in H. pylori-infected omeprazole group, three patients developed mild atrophy from none at baseline in H. pylori-infected ARS group, no statistical difference.
Gental et al[37], 2003	Two RCTs, United States	Maintenance trial (n = 519), Safety trial (n = 807)	Maintenance trial: 519 (PPI)/169 (placebo); Safety trial: 807/PPI	Type (esomeprazole only), duration (6 months: maintenance trial; 12 months: safety trial)	Atrophy (antrum and corpus), intestinal metaplasia (antrum and corpus)	In the maintenance studies, the majority of omeprazole group had no change in the extent of atrophy and intestinal metaplasia. In the safety study, > 98% of omeprazole had either no change or improved atrophy scores in antrum and corpus, and intestinal metaplasia scores remained unchanged or improved compared with those that worsened.

PPI: Proton pump inhibitor; RCT: Randomized controlled trial; ARS: Anti-reflux surgery; H. pylori: Helicobacter pylori.

Table 3 Summary of experimental studies investigating the effects of proton pump inhibitors in gastric cancer cells

Author, year	Study design	Type of PPI	Cell type	Main outcomes	Underlying hypothesis
Yeo et al[45], 2004	In vitro, in vivo	Pantoprazole	MKN 45, MKN 28, AGS, SNU 601, RGM-1 (normal gastric mucosa cell)	Apoptotic cell death in gastric cancer cells, but not in normal gastric mucosal cells, induced by pantoprazole	Modulation of heat-shock proteins (HSP 70, HSP 27)
Chen et al[46], 2009	In vitro	Pantoprazole	SGC7901	Inhibition of V-H+-ATPase expression in a dose-dependent manner; enhancement of efficacy of anti-tumor drug (cisplatin) and increased apoptosis rate	Change of pH gradient (decrease of intracellular pH and reverse of the transmembrane pH gradient)
Shen et al[47], 2013	In vitro	Pantoprazole	SGC7901	Anti-proliferation, anti-invasive and pro-apoptotic effects, decrease of V-H+-ATPase expression	Inhibition of LRP6 in Wnt/β-catenin signaling
Chen et al[48], 2018	In vitro, in vivo	Pantoprazole	SGC7901, SGC7901/MDR	Inhibition of V-H+-ATPase expression in, SGC7901/MDR cells	Inhibition of P-gp and MRP1, and downregulation of PI3K/Akt/mTOR/HIF-1α signaling pathway
Guan et al[49], 2017	In vitro, in vivo	Esomeprazole	SGC7901	Enhancement of efficacy of anti-tumor drugs (cisplatin, paclitaxel, 5-FU); Inhibition of transformation of CAF	Regulation of HIF-1α-FOXO1 axis and inhibition of release of exosome and exosome-related microRNAs (tumor invasion, metastasis and TGF-beta pathway)
Huang et al[73], 2013	In vitro	Pantoprazole	SGC7901, GBC823, AGS	Inhibition of cellular proliferation and increase in the number of apoptotic cells	Inhibition of STAT3
Koh et al[74], 2018	In vitro, in vivo	Pantoprazole	AGS, MKN-28	Inhibition of cellular invasion, migration and modulation of EMT markers	Induction of SHP-1 and inhibition of JAK2/STAT3
Zhang et al[79], 2015	In vitro	Pantoprazole	Adriamycin-resistant SGC7901 (SGC7901/ADR)	Inhibition of cellular migration/invasion and modulation of EMT markers in SGC7901/ADR cells	Inhibition of Akt/GSK-β/βcatenin signaling
Joo et al[80], 2018	In vitro, in vivo	Pantoprazole	AGS	Enhanced cellular migration/invasion and anti-tumor effect of docetaxel by combination with minimal dose pantoprazole	Induction of SHP-1 and inhibition of JAK2/STAT3

PPI: Proton pump inhibitor; V-H⁺-ATPase: Vacuolar-H⁺-ATPase; LRP6: Low-density lipoprotein receptor related protein 6; MDR: Multidrug resistance; MRP1: Multidrug resistance-associated protein 1; mTOR: Mammalian target of rapamycin; HIF-1α: Hypoxia-inducible factor 1alpha; CAF: Cancer associated fibroblast; FOXO1: Forkhead box protein O1; TGF-beta: Tumor growth factor-beta; EMT: Epithelial-mesenchymal transition; STAT3: Signal transducer and activator of transcription 3; JAK2: Janus kinase 2; ADR: Adriamycin; GSK-β: Glycogen synthetase kinase-3-β.