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. 2021 Nov 28;27(44):7716–7733. doi: 10.3748/wjg.v27.i44.7716

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.