Proton pump inhibitor: The dual role in gastric cancer

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.