Proton pump inhibitors and colorectal cancer: A systematic review

Table 2 Summary of basic research studies (colorectal cancer cell lines)

Author	Aim of study	PPI investigated	Cell lines studied	Outcome measure	Main finding	Mechanisms	Role of PPI in CRC
Tobi et al[21] 1995	To assess the direct effects of gastrin and OME on growth of CRC origin cells separately and in combination	OME	NCI-H716, LCC-18, DLD-1	Proliferation of cell lines	OME treatment resulted in cytostatic effect on 1 of the 3 cell (NCI-H716) lines tested. Dose-dependent decrease in cell proliferation noted compared to controls (P < 0.05). Effect seen with gastrin (low concentration), OME, or both in combination. Gastrin increased proliferation of NCI-H716 cells only at high concentrations	Trophic effect of gastrin	PE
Kim et al[23] 2010	To evaluate chemo-preventive properties of omeprazole in a colitis-associated CRC mouse model	OME	HT29	Cell viability and growth	Significant cleavage of capsase-3 in presence of 500 μmol/L omeprazole, but effect attenuated with gastrin pre-treatment, signifying that gastrin could attenuate the cytotoxicity of PPI by decreasing apoptosis. Compared with the gastrin-treated group, cell proliferation was significantly attenuated in the presence of omeprazole (P < 0.05), suggesting that PPI could offset the trophic action of gastrin on colon cells	Cytostatic properties	PE
Patlolla et al[22] 2012	To assess chemo-preventive effects of OME	OME	HCA-7, HCT-116	Cell viability, cytotoxicity assays, apoptotic assays	Dose-dependent suppression of cell growth and induction of apoptosis seen in both cell lines	Cytostatic properties	PE
Han et al[24] 2014	To study the effects of PPI on colitis-associated carcinogenesis	PAN	HCT116	Proliferation rate, apoptosis, and molecular analysis	PPI antagonizes trophic actions of gastrin, causes dose-dependent suppression of cellular viability. Combination of PPI and gastrin had higher cytotoxic activity than PPI alone. PPI alone or in combination with gastrin induces apoptosis and blocks gastrin-CCKBR binding. PPI may possess anti-angiogenic activity, which inhibits the expression of angiogenic factors induced by gastrin	Cytostatic properties	PE
Zeng et al[26] 2016	To evaluate the effect of pantoprazole as TOPK inhibitor in vivo and in vitro	PAN	HCT116, SW480, WiDr	Cell viability, TOPK assay analysis, cytotoxicity assays	Pantoprazole had different cytotoxicity toward different colon cancer cells. It inhibits anchorage-independent growth of colon cancer cells. Cell line with high TOPK activity (HCT116) was more sensitive to pantoprazole. The study suggests that TOPK is a direct target for pantoprazole to suppress colon cancer cell growth	TOPK inhibition	PE
Zheng et al[27] 2017	To evaluate the effect of PPI as TOPK inhibitor in vivo and in vitro	ILA	HCT116	Cell viability, TOPK assay analysis, cytotoxicity assays	Ilaprazole exhibited potent inhibitory effect on growth and induced apoptosis in HCT116 cells in a dose-dependent manner. The study suggests that TOPK was a direct target for ilaprazole to suppress cancer cell growth and its anticancer activities were dependent on the TOPK expression. Inhibition of TOPK by ilaprazole is dependent on TOPK abundance in cancer cells	TOPK inhibition	PE
Wang et al[25] 2017	To investigate the chemosensitizing potential of PPI in CRC	PAN	HT29, RKO	Cell inhibition rate	PPI in combination with 5-FU had a higher inhibitory effect on CRC cell line growth compared to controls. The study suggests that PPI may increase sensitivity of CRC tumors to 5-FU in vitro	Chemosensitizing properties	PE

CCKBR: Cholecystokinin-B receptor; CRC: Colorectal cancer; ILA: Ilaprazole; OME: Omeprazole; PAN: Pantoprazole; PPI: Proton pump inhibitors; PE: Protective effect; TOPK: T lymphokine–activated killer cell–originated protein kinase.