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©The Author(s) 2021.
World J Gastroenterol. Nov 28, 2021; 27(44): 7716-7733
Published online Nov 28, 2021. doi: 10.3748/wjg.v27.i44.7716
Published online Nov 28, 2021. 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 |
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 |
Table 3 Summary of epidemiological studies assessing the exposure of proton pump inhibitors in colorectal cancer patients
| Author, year, place | Accrual year | Study design | Grouping | Number | Exposed | Unexposed | OR (95%CI) | Adjustments | Risk of CRC |
| Robertson et al[28] 2007 (Denmark) | 1989-2005 | CC | CRC patients | 5589 | 295 | 5294 | 1.11 (0.97-1.27) | Age, sex, place of residence (matched), H2 blocker use, aspirin/NSAIDs, statins/diabetics use, history of cholecystectomy, alcohol | No increased risk |
| Non-CRC control | 55890 | 2692 | 53198 | ||||||
| Van Soest et al[29] 2008 (Netherland) | 1996-2005 | CC | CRC patients | 594 | 53 | 541 | 0.85 (0.63-1.16) | Age, sex, calendar time, follow-up duration (matched), comorbidities | No increased risk |
| Non-CRC control | 7790 | 725 | 7065 | ||||||
| Yang et al[30] 2007 (United Kingdom) | 1987-2002 | CC | CRC patients | 4432 | 769 | 3663 | 1.2 (0.8-1.9) | Age, sex, alcohol, smoking, BMI, H2 blocker use, aspirin/NSAID use, calendar time, follow-up, general practice site (matched), HRT use, history of colonoscopy/flexible sigmoidoscopy | No increased risk |
| Non-CRC control | 44292 | 5133 | 39159 | ||||||
| Lee et al[31] 2020 (San Francisco, United States) | 1996-2016 | CC | CRC patients | 18595 | 1406 | 17189 | NR | Age, sex, ethnicity, general practitioner site, enrolment duration, smoking, alcoholism, BMI, history of colonoscopy, family history of CRC, Crohn’s disease, Ulcerative colitis | No increased risk |
| Non-CRC control | 160122 | 10813 | 149309 | ||||||
| Chubak et al[32] 2009 (Washington State, United States) | 2000-2003 | CC | CRC patients | 641 | 16 | 482 | 1.7 (0.8-4.0) | Age, sex, calendar time, follow-up duration (matched) | No increased risk |
| Non-CRC control | 641 | 9 | 471 | ||||||
| Kuiper et al[33] 2020(Netherlands) | 2007-2014 | CC | CRC patients | 1978 | 1041 | 937 | 1.08 (0.97-1.21) | Age, sex, calendar time, H2 blocker use, aspirin, NSAIDs, statins, antidiabetics use | No increased risk |
| Non-CRC control | 7912 | 4161 | 3751 |
Table 4 Summary of epidemiological studies assessing the effect of proton pump inhibitors exposure on the risk of developing colorectal cancer
| Author, year, place | Accrual year | Study design | Grouping | Number of patients | Developed CRC | Did not develop CRC | HR (95%CI) | Adjustments | PPI use and CRC risk |
| Hwang et al 2017[34] (Korea) | 2007-2013 | P | PPI users | 49520 | Total cases (including PPI users and non-PPI users) 5304 | NR | NR | Sex, age, smoking, alcohol, BMI, consumption, physical activity, type 2 diabetes, CCI score, aspirin use, metformin use, stain use, socioeconomic status | No association |
| Non-PPI users | 401764 | ||||||||
| Babic et al 2020[35] (United States) | 1988-2015 | P | PPI users | 13205 | 83 | 13122 | 0.84 (0.67-1.04) | Age, physical activity, BMI, family history of CRC, alcohol, smoking, history of lower endoscopy, caloric intake, vitamin D, calcium intake, regular aspirin use, folate intake, menopausal hormone therapy use, and red meat | No association |
| Non-PPI users | 162654 | 1172 | 161482 | ||||||
| Lei et al 2020[36] (Taiwan) | 1999-2011 | R | PPI users | 45382 | 172 | 45210 | 2.03 (1.56-2.63) | Sex, age, year of index date, diabetes, coronary artery disease, HTN, dyslipidemia, COPD, cirrhosis, CCI, aspirin/NSAID use, statin use, antidiabetic use | Increased risk |
| Non-PPI users | 45382 | 93 | 45289 |
Table 5 Summary of treatment studies
| Author | Center | Study design | Cancer stage and type | Cancer treatment | PPI use (definition) | No. of patients | Results |
| Zhang et al[39] 2017 | Guangzhou, China | R | Stage II-III Rectal cancer | LCRT (46 Gy, Oxaliplatin + Capecitabine (2 cycles) | EOU = OME: 20 mg PO, min. OD for 6 d / 40 mg IVI, daily). EOG = total OME dose ≥ 200 mg1 | 125 | EOG vs non-EOG: 1DFS (3-year) = 77.1% vs 96.6%, P = 0.032, DFS (5-year) = 69.6% vs 46.7%, P = 0.032, OS (3-year) = 82.3% vs 96.6%, P = 0.092, OS (5-year) = 76.9% vs 89.5%, P = 0.092 EOU vs non-EOU: 1DFS (3-year) = 85.5% vs 77.8%, P = 0.658, DFS (5-year) = 75.6% vs 74.6%, P = 0.658, OS (3-year) = 90.3% vs 82.5%, P = 0.754, OS (5-year) = 82% vs 77.6%, P = 0.754 |
| Sun et al[40] 2016 | Edmonton, Canada | R | Stage I-III CRC | Adjuvant Capecitabine monotherapy | Any use during treatment (based on prescription data) | 298 | PPI-user vs non-users: RFS (5 years) = 74% vs 83%, P = 0.03; OS (5-year) = 81% vs 78%, P = 0.7. Multivariate RFS (5-year): HR (95%CI) = 1.65 (0.93-2.94), P = 0.09 |
| Wong et al[41] 2019 | Alberta, Canada | R | Stage II-III CRC | Adjuvant CapeOx or FOLFOX | Any use during treatment (based on prescription data) | 389 | PPI-users vs non-users, RFS (3-year): CapeOX = 69.5% vs 82.6%, P = 0.03; FOLFOX = 82.9% vs 61.7%, P = 0.7; Multivariate RFS: HR (95%CI) = 2.20 (1.14-4.25) P = 0.018; OS (3-year): CapeOX = 90.1% vs 91.2%, P = 0.345, FOLFOX = 77.4% vs 80.1%, P = 0.929 |
| Kichenadasse et al[42] 2021 | 6 clinical trials | Retrospective post-hoc analysis of RCT | Stage IV CRC | Fluoropyrimidine-based chemotherapy (± additional agents). Regimens differed across included trials | Minimum 7 d of use during study period | 5633 | OS: Significantly worse in PPI-users [HR (95%CI) = 1.20 (1.03-1.40)], P = 0.02; PFS: Significantly worse in PPI-users [HR (95%CI) = 1.20 (1.05-1.37)], P = 0.009 Various treatment subgroups did not influence OS and PFS |
| Kim et al[43] 2021 | China, Japan, South Korea (98 centers) | Retrospective post-hoc analysis of RCT | Stage IV CRC | mXELIRI or FOLFIRI (± Bevacizumab) | Use for ≥ 20% of study period | 620 | mXELIRI arm: No difference in OS or PFSFOLFIRI arm: Significantly better OS [HR (95%CI) = 0.5 (0.3-0.85), P = 0.11] and PFS [HR (95%CI) = 0.55 (0.33-0.91), P = 0.20] in PPI users |
- Citation: Patel A, Spychalski P, Antoszewska M, Regula J, Kobiela J. Proton pump inhibitors and colorectal cancer: A systematic review. World J Gastroenterol 2021; 27(44): 7716-7733
- URL: https://www.wjgnet.com/1007-9327/full/v27/i44/7716.htm
- DOI: https://dx.doi.org/10.3748/wjg.v27.i44.7716