Proton pump inhibitors and colorectal cancer: A systematic review

Table 1 Summary of basic research studies (animal models)

Author	Aim of study	PPI investigated	Species strain, gender	Methods of CRC induction	PPI treatment	Experimental/ control group	Outcome measure	Main findings	Mechanism studied	Role of PPI in CRC
Graffner et al[16] 1992	To determine the influence of PPI-induced endogenous hypergastrinemia on growth in CRC-implanted mice	OME	BALB/C mice, M	MC-26 tumor cells injected SC in epigastric region	Daily for 19 d, 400 μmol/kg, PO	18/18	Tumor size, survival	5-fold higher serum gastrin levels in OME-treated animals than controls. No differences in tumor size, tumor weight, survival and metastatic potential (61% vs 72%, P = NR) between tumor-bearing treated and control group	Trophic effect of gastrin	NE
Penman et al[20] 1993	To assess the influence of OME-induced hypergastrinemia on CRC development in animal models	OME	Sprague-Dawley rats, F	12 (weekly) SC azoxymethane (10 mg/kg/wk)	Daily for 27 wk, 40 μmol /kg, PO	19/20	Number of tumors, position, volume; metastatic disease	9-10-fold higher gastrin levels in OME-treated groups than control groups. Significantly fewer OME-treated rats developed tumors compared to control group (63% vs 95%, P < 0.02). Number of tumors were also significantly lower in OME-treated rats. Average tumor size and invasiveness of CRC was similar for both groups	Trophic effect of gastrin	PE
Hurwitz et al[18] 1995	To evaluate effect of omeprazole-induced hypergastrinemia on carcinogen-induced CRC in rats	OME	Sprague-Dawley rats, M	Six (weekly) IP methylazoxymethanol (30 mg/kg)	Daily for 10 wk, 40 mg/kg, gastric gavage	NR	Number of tumors, volume and total tumor burden, biochemical and histological analysis	Serum gastrin levels were elevated 6-fold in OME-treated animals vs controls. No differences in tumor number, tumor volume, and total tumor burden between treated and control group. No histological (crypt/mucosal height) or biochemical features in CRC-free regions of colon	Trophic effect of gastrin	NE
Pinson et al[17] 1995	To assess if hypergastrinemia enhances progression or invasiveness of CRC	OME	Sprague-Dawley rats, M	Six (weekly) IP methylazoxymethanol (30 mg/kg)	Daily for 10 wk, 14 or 40 mg/kg, gastric gavage	162/108	Number of tumors, volume and total tumor burden, histological analysis	Plasma gastrin levels in the treated groups (low-dose OME, high-dose OME, ranitidine) were 3–5-fold higher than controls. Crypt height/mucosal height ratio of CRC-free colonic mucosa was similar between all groups. No significant differences in tumor number, tumor burden and invasiveness between OME-treated and control groups.	Trophic effect of gastrin	NE
Chen et al[19] 1998	To examine trophic effects of endogenous hypergastrinemia colonic mucosa and transplanted colon adenocarcinoma in rats	OME	Sprague-Dawley rats, M	Injection of K-12 cell line (Established in syngeneic BDIX rats via induction using 1,2-dimethylhydrazine)	Daily for 10 d, 400 μmol/kg, PO	NR	Tumor weight and volume, histological analysis, labelling index	OME treatment and fundectomy raised serum gastrin levels by 4-5-fold. OME-treatment did not stimulate growth of transplanted tumor (K-12) cells, while fundectomy suppressed CRC growth (decreased labelling index, weight and volume of tumor) Sustained hypergastrinemia did not affect the thickness and labelling index of normal colon mucosa	Trophic effect of gastrin	NE
Kim et al[23] 2010	To evaluate chemo-preventive properties of omeprazole in a colitis-associated CRC mouse model	OME	C57BL/6 mice, F	Colitis induction - 15 cycles of 0.7% DSS in drinking water	NR, 10 mg/kg, IP	12/24	Tumor burden, biochemical and histological analysis	OME-treated group developed significantly lower number of colon tumors than control groups. OME administration also resulted in decreased inflammatory markers (TNF-α, serum NO, and colon TBA-RS levels), attenuated expression of MMP, COX-2, NO synthase, and β-catenin, and greater apoptotic index	Cytostatic properties	PE
Patlolla et al[22] 2012	To assess chemo-preventive effects of omeprazole	OME	F344 rats, M	Two (weekly) SC azoxymethane (15 mg/kg)	9 wk, 200/400 ppm, PO	30/18	Aberrant crypt foci incidence	Omeprazole inhibited the AOM-induced colonic foci formation in a dose-dependent manner	Cytostatic properties	PE
Han et al[24] 2014	To study the effects of PPI on colitis-associated carcinogenesis	PAN	APCMin/+ mice, M	Genetically engineered mutation in APC gene	Thrice weekly for 10 wk, 8 mg/kg, IP	NR/8	Number and size of intestinal polyps	Gastrin + PPI exerted significant anti-polyposis effect through β-catenin inactivation, increased apoptosis, anti-angiogenic, and MAPK inactivation relevant to decreased levels of pro-inflammatory mediators	Cytostatic properties	PE
Zeng et al[26] 2016	To evaluate the effect of pantoprazole as TOPK inhibitor in vivo and in vitro	PAN	Non-obese diabetic-SCID mice	HCT 116 cells inoculated SC into left flank	Every 2 d for 19 d, 100 mg/kg, IP	8/8	Tumor volume, immunohistochemical analysis	Tumors treated with PAN grew significantly more slowly, and the size of tumors was smaller compared with the control group. PAN-treated group had lower average tumor volume per mouse compared to controls (111 mm3 vs 285 mm3, P < 0.05). Average body weight was similar throughout the study indicating no toxic effects of PAN in the mice IMHC for phosphorylated histone H3 revealed substantially decreased expression in PAN-treated group compared to control	TOPK inhibition	PE
Zheng et al[27] 2017	To evaluate the effect of PPI as a TOPK inhibitor in vivo and in vitro	ILA	CB-17/Icr-scid mice	HCT 116 cells inoculated SC into left flank	Daily for 19 d, 150 mg/kg, PO	8/8	Tumor volume, immunohistochemical analysis	Estimated tumor volumes of treatment groups were less than that of the control group. No toxicity or differences in body weight were observed. Expression levels of phosphorylated histone H3 were substantially decreased in ilaprazole-treated groups compared with the control group	TOPK inhibition	PE
Wang et al[25] 2017	To investigate the chemosensitizing potential of PPI in CRC	PAN	BALB/C mine, F	HT29 cells injected SC	Weekly for 4 wk, 30 mg/kg, IP	NR	Tumor burden	PAN combined with 5-FU demonstrated greater inhibition of tumor growth and smaller tumor sizes compared to 5-FU alone	Chemosensitizing properties	PE

AOM: Azoxymethane; CRC: Colorectal cancer; COX-2: Cyclooxygenase-2; F: Female; 5-FU: 5-Fluorouracil; ILA: Ilaprazole; IMHC: Immunohistochemistry; IP: Intraperitoneal; M: Male; MAPK: Mitogen-activated protein kinase; MMP: Matrix metalloproteinase; NO: Nitric oxide; NE: No effect; NR: Not reported; OME: Omeprazole; PAN: Pantoprazole; PO: Per os; PPI: Proton pump inhibitors; PE: Protective effect; SC: Subcutaneous; TOPK: T lymphokine-activated killer cell-originated protein kinase; TNF-α: Tumor necrosis factor-alpha; TBA-RS: Thiobarbituric acid-reactive substance.