Proton pump inhibitors and colorectal cancer: A systematic review

Agastya Patel, Piotr Spychalski, Magdalena Antoszewska, Jaroslaw Regula, Jarek Kobiela

Abstract

Key Words: Colorectal cancer; Proton pump inhibitor; Carcinogenesis; Cancer epidemiology; Capecitabine; Translational medicine

INTRODUCTION

Proton pump inhibitors (PPI) are among the most widely prescribed medications globally[1 ,2 ]. Since their development in the 1980 s, these drugs have been used for conditions such as peptic ulcer disease, gastroesophageal reflux disease, stress gastritis, and gastrinomas[3 ]. PPI are available by prescription, but are also sold overthe-counter resulting in frequent use without appropriate indication[4 ,5 ]. The mechanism of action of PPI involves irreversible, long-lasting binding to and inhibition of the hydrogen-potassium adenosine triphosphatase (ATPase) enzyme system on gastric parietal cells[6 ]. These ATPase pumps are responsible for secreting H+ions into the gastric lumen, resulting in the production of gastric acid. Suppression of gastric acid production by PPI lowers the acidity of gastric contents while causing feedback hypergastrinemia.

Gastrin, in turn, is a potent growth factor involved in several physiological and pathological processes, including neoplastic transformation[7 ]. One hypothesis suggests that gastrin may have pro-inflammatory properties and can stimulate the tumor microenvironmentviamacrophage activation and chemotaxis. It is therefore possible that PPI and the resultant hypergastrinemia have a cancer-promoting effect[8 ].

Some studies, however, suggest that PPI may also exert anti-tumor properties.These drugs might paradoxically inhibit the proliferative effects of hypergastrinemia while demonstrating anti-oxidant, anti-inflammatory, and pro-apoptotic activity[9 ].PPI could also have a potential chemotherapeutic role by reducing tumor resistance to chemotherapeutics. De Militoet al[10 ] reported that manipulating cancer pH may sensitize them to certain chemotherapeutics. In contrast, the TRIO-013 /LOGiC trial demonstrated that PPI may negatively affect the efficacy of some cytotoxic drugs,possibly due to alkalinization of the gastric environment[11 ].

Overall, concerns are increasing regarding the safety of PPI use because of induced hypergastrinemia and a possible association with gastrointestinal (GI) cancer risk,including colorectal cancer (CRC). Many current patients with CRC may have a history of PPI use, but precise epidemiological data are not available. Ahnet al[12 ] and Maet al[13 ] have summarized observational studies assessing the association of PPI use with the risk of developing CRC. Ahnet al[12 ] found no significant effect of PPI on CRC risk, whereas Maet al[13 ] found a weak association between long-term PPI use (>5 years) and increased CRC risk. However, there are no systematic reviews summarizing the evidence from basic research studies exploring mechanisms by which PPIs may affect CRC and from human epidemiological and clinical studies examining PPI use in the context of CRC survival and treatment. As a systematic review might identify important epidemiological and clinical findings, our aim was to provide a comprehensive report on the association of PPI use and CRC based on recent basic research and human studies.

MATERIALS AND METHODS

Literature search

This systematic review was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement using PICO(patients, interventions, comparisons, outcomes)-based questions. Following a predefined search strategy, we searched the MEDLINE, EMBASE, Web of Science, and Scopus online databases to identify suitable articles. No filters were applied during the search, and we also performed backward citation chaining of eligible full-text studies.

Evidence acquisition

On May 17 , 2021 , two independent researchers (AP, PS) performed a search of the target online databases for eligible studies. The search string was (“proton pump inhibitors”or “proton pump inhibitor”or “ppis”or“ppi”or “omeprazole”or “pantoprazole”or “esomeprazole”) and (“CRC”or “colorectal cancer”or “colon cancer”or “rectal cancer”).The preliminary search returned 2591 articles, which two independent researchers(AP, PS) screened. The entire protocol is presented in a PRISMA flowchart(Supplementary Figure 1 ).

Inclusion and exclusion criteria

We used PICO framework-based research questions for this review (Supplementary Table 1 ). If articles met predefined criteria, they were included and categorized as basic research (animal and cell studies), epidemiological (incidence and mortality studies), and treatment studies. Articles were excluded if the full text was not available or was not in English, were not original articles, or did not conform with PICO.

Evidence synthesis and Quality Assessment:

Two independent researchers (Patel A and Spychalski P) retrieved and summarized information from the eligible studies in tables. The authors (Patel A, Spychalski P,Antoszewska M and Kobiela J) discussed conflicts regarding inclusion of studies and resolved them by consensus. Two independent researchers (Patel A and Antoszewska M) assessed the quality of included case-control and cohort studies using the Newcastle-Ottawa scale (NOS)[14 ]. This scale awards a maximum of nine points for each of the following items: Selection (four stars), comparability (two stars) and outcomes (three stars). Studies were considered of high quality if they scored seven or more stars on NOS assessment. Additionally, the Cochrane Risk of Bias 2 .0 tool was used to assess bias in randomized controlled studies included in the retrospective post-hoc analysis reports[15 ]. The results of quality assessment are described in Supplementary Material along with Supplementary Table 2 .

RESULTS

A total of 28 studies were included in the review: Basic research studies (n = 12 )[animal models (n= 5 ), CRC cell lines (n = 1 ), or both (n = 6 )]; epidemiological studies (n= 11 ) [analyzing CRC risk (n = 9 ) and survival (n = 2 ) associated with PPI use]; and treatment studies (n= 5 ), examining the effects of PPI on CRC chemotherapy regimens.

Basic studies

The included basic studies examined two primary themes: (1 ) Trophic effects of PPIinduced hypergastrinemia; and (2 ) Potential chemotherapeutic role of PPI as cytostatic drugs, chemosensitizing drugs, or T lymphokine-activated killer cell-originated protein kinase (TOPK) inhibitors. The information from the basic studies is summarized in Tables 1 (animal models) and 2 (CRC cell lines).

Trophic studies:The trophic effects of PPI-induced hypergastrinemia were investigated in six studies[16 -21 ]. Four animal studies demonstrated that PPI-induced hypergastrinemia did not influence growth and invasiveness of CRC[16 -19 ]. These studies showed that omeprazole treatment resulted in significantly higher serum or plasma gastrin levels (4 - to 20 -fold across studies) in comparison to control groups.However, the treated and control groups were similar in terms of tumor burden and/or invasiveness of CRC. Graffneret al[16 ] found omeprazole-treated and control mice to be similar in terms of tumor size, survival and distant metastasis rate. Pinsonet al[17 ] compared low-dose and high-dose omeprazole, ranitidine (histamine-2 receptor antagonist), and control exposure in rats. They found that overall tumor burden and survival were similar among these groups but documented significantly lower mean tumor number, volume, and total mass in the ranitidine group (multiple comparisons,allP< 0 .05 ). Hurwitz et al[18 ] reported concordant findings in their study, additionally noting no significant differences in DNA, RNA or protein concentration in tumor-free colonic tissues of treatedversuscontrol rats. Chenet al[19 ] performed sham operation,colostomy and/or fundectomy, omeprazole treatment, or fasting with refeeding to assess the short-term and long-term effects of hypergastrinemia. None of the groups demonstrated growth of CRC tumors, but the fundectomy group showed suppressed tumor growth.

Two studies indicated that PPI treatment resulted in suppression of CRC growth[20 ,21 ]. Penman et al[20 ] found a significantly lower incidence of CRC tumors in omeprazole-treated rats than controls (63 % vs 95 %, P < 0 .02 ). They hypothesized that omeprazole possibly influenced metabolism of the carcinogen (azoxymethane) by affecting either intestinal microflora or P450 isoenzymes, therefore resulting in lower CRC growth. Working with the NCI-H719 human colon cancer cell line, Tobi et al[21 ]demonstrated a dose-dependent decrease in proliferation (cytostatic effect) with omeprazole, but noted no such effect in two other cell lines (DLD-1 and LCC-18 ).These researchers found that the cytostatic effect of omeprazole persisted even when omeprazole was combined with gastrin, suggesting a potential paradoxical inhibition of gastrin’s trophic influence on CRC.

Chemotherapeutic studies:Six studies addressed the potential chemotherapeutic role of PPI in CRC[22 -27 ]. Three studies assessed the cytotoxic effects – anti-proliferative,pro-apoptotic, and anti-inflammatory properties – of PPI on CRC and found that PPI(omeprazole, pantoprazole) dose-dependently inhibited proliferation and induced apoptosis in CRC models[22 -24 ]. Patlolla et al[22 ] reported that omeprazole resulted in upregulation of p21 waf1 /cip1 and downregulation of cyclin A, Bcl-2 , Bcl Xl, and survivin expression, leading to induction of cell apoptosis. Kimet al[23 ] reported on the anti-inflammatory activities of PPI, describing reduced tumor necrosis factor-alpha(TNF-α), nitric oxide (NO), colon thiobarbituric acid-reactive substance (TBA-RS), and expression of cyclooxygenase-2 (COX-2 ) and NO synthetase. These authors also suggested a potential anti-proteolytic and anti-mutagenic action of PPI, reporting decreased levels of matrix metalloproteinase (MMP)-9 , MMP-11 , and MT1 -MMP and decreased beta-catenin accumulation in omeprazole-treated mice as compared to controls.

Hanet al[24 ] reported similar findings on the pro-apoptotic, anti-inflammatory, and anti-proliferative properties of PPI, along with a potential anti-angiogenic effect. They found that PPI treatment reduced expression of angiogenic factors such as interleukin(IL)-8 , platelet-derived growth factor, vascular endothelial growth factor, and hypoxiainducible factor 1 -alpha. Moreover, Kim et al[23 ] and Han et al[24 ] demonstrated that PPI may paradoxically inhibit the trophic effect of gastrin on CRC cells. Kimet al[23 ]found cell proliferation to be significantly (P< 0 .05 ) reduced in cells treated with both omeprazole and gastrin compared to with gastrin only. Hanet al[24 ] reported similar findings and found that PPI antagonized gastrin’s binding to cholecystokinin B receptor (CCKBR), both alone and in combination with gastrin.

Table 1 Summary of basic research studies (animal models)

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.

Wanget al[25 ] found that PPI increased the chemosensitivity of human colon cancer cells (HT29 and RKO lines) as PPI combined with 5 -fluorouracil (5 -FU) resulted in significantly higher cell inhibition rates than 5 -FU alone (in vitro experiment: P = 0 .04 ;in vivoexperiment:P= 0 .03 ).

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

Zenget al[26 ] and Zheng et al[27 ] investigated pantoprazole and ilaprazole,respectively, as potential TOPK inhibitors. Both groups found that PPI inhibited CRC cell growthviaTOPK inhibitionin vitroandin vivo. Among the PPI, ilaprazole and pantoprazole showed the strongest affinity for TOPK. Zenget al[26 ] examining three colon cancer cell lines with different TOPK expression levels reported that pantoprazole had a growth-inhibiting effect through interaction with TOPK. Zhenget al[27 ] described similar results for ilaprazole, with PPI treatment resulting in decreased phosphorylation of histone, a TOPK-mediated process, suggesting that TOPK may be a direct target for these drugs. Furthermore, the authors found ilaprazole to be an inducer of apoptosisviaactivation of caspases and cleavage of poly-(ADP-ribose) polymerase.

Epidemiological studies

Six case-control studies[28 -33 ], two prospective studies[34 ,35 ], and one retrospective study[36 ] addressed the incidence of CRC in PPI-usersversusnon-users. Two retrospective cohort studies assessed the survival of CRC patients in relation to PPI use.

Incidence studies:The information from the six included case-control incidence studies is abstracted in Table 3 [28 -33 ]. The time definition of PPI use varied across studies. The included studies analyzed information from healthcare databases or registries of different regions – Denmark, the Netherlands, United Kingdom, San Francisco (United States), and Washington (United States). A total of 31829 CRC patients matched with 276647 controls were included in this review. After adjustment for confounders, none of the studies revealed an increased risk of CRC in current or ever PPI-users in comparison to non-users. Furthermore, most (5 /6 ) of the studies found that the duration of PPI use or average daily dose of PPI did not influence CRC risk[28 -30 ,32 ,33 ]. However, Lee et al[31 ] reported that the risk of CRC increased significantly with ≥ 10 years of PPI use compared to no use [odds ratio (OR) = 1 .28 ,95 % confidence interval (CI): 1 .15 -1 .44 ]. Robertson et al[28 ], Yang et al[30 ] and Kuiperet al[33 ] did not find any significant increase in risk in recent or former PPI-users.However, Kuiperet al[33 ] found that current PPI-users were at an increased risk of developing CRC (OR = 1 .30 , 95 %CI: 1 .16 -1 .47 ), especially with concomitant nonsteroidal anti-inflammatory drugs use (OR=1 .57 , 95 %CI: 1 .27 -1 .93 ).

Three cohort studies assessed the hazard of developing CRC in PPI-users and nonusers[34 -36 ] (Table 4 ). The review included a total of 108107 PPI-users and 609800 nonusers identified through healthcare databases in Korea, United States, and Taiwan.Hwanget al[34 ] and Babic et al[35 ] found no significant association between PPI exposure and CRC development, but Leiet al[36 ] reported a significantly increased risk of CRC among PPI-users [hazard ratio (HR) = 2 .03 , 95 %CI: 1 .56 -2 .63 , P < 0 .05 ].Hwanget al[34 ] reported that PPI use was associated with increased CRC risk in individuals at low risk for CRC (non-obese, non-diabetics, female, aged < 50 years, no history of alcoholism, receiving ≥ 180 daily defined dose of PPI) (HR = 12 .30 , 95 %CI:1 .71 -88 .23 , P < 0 .01 ). Babic et al[35 ] found that the period of PPI use had no effect on CRC risk but that current PPI use was associated with a decreased risk (HR = 0 .82 ,95 %CI: 0 .68 -0 .98 ). In contrast, Lei et al[36 ] reported a time-dependent and dosedependent relationship between PPI use and CRC development, with patients at higher risk if they were using PPI for ≥ 1 year and increasing doses of PPI. On further analysis, Leiet al[36 ] found that the risk of CRC was increased with esomeprazole,lansoprazole, and omeprazole, but no such association was seen with pantoprazole and rabeprazole.

Survival studies:Survival of CRC patients was assessed in two retrospective studies.Grahamet al[37 ] included 1304 CRC (117 PPI-users at diagnosis) patients with similar baseline characteristics, but greater cardiac comorbidities in PPI-users (P< 0 .05 ). The authors found similar overall survival (OS) rates at 1 -, 2 - and 5 -years between PPIusers and non-users, but the cumulative survival of PPI-users was significantly shorter than non-users (1775 vs 2279 d, P = 0 .048 ). Furthermore, after controlling for known risk factors, the risk of mortality was significantly higher in CRC patients using PPI(HR = 1 .34 , 95 %CI: 1 .01 -1 .78 , P = 0 .04 ). Tvingsholm et al[38 ] analyzed cancer-specific mortality for nine cancers in a cohort of 347919 patients, including 47188 CRC patients.They found that the risk of mortality in CRC patients was approximately 12 times higher in PPI-users as compared to non-users (HR = 11 .8 , 95 %CI: 11 .3 -12 .4 ).

Treatment studies

The effects of PPI use concurrently with chemotherapeutic treatment of CRC wasassessed in three retrospective studies, two post-hoc analyses of randomized controlled trials (RCTs)[39 -43 ]. These studies cumulatively examined 7065 patients and are summarized in Table 5 .

Table 3 Summary of epidemiological studies assessing the exposure of proton pump inhibitors in colorectal cancer patients

Zhanget al[39 ] examined 125 patients with stage II-III rectal cancer dichotomizing them as eligible omeprazole users (EOU, 20 mg per os at least once/day for 6 d and/or 40 mg IV infusion daily during adjuvant chemotherapy) or non-EOU, and an effective omeprazole group (EOG, OME ≥ 200 mg total during the study period), or a non-EOG.The authors found that 5 -year disease-free survival (DFS) was significantly decreased in the EOGvsnon-EOG group (P= 0 .032 ), but OS was similar among the groups (P=0 .092 ). Additionally, the recurrence of rectal cancer was more common in the non-EOG group than in the EOG group (31 .3 % vs 10 .3 %, P = 0 .025 ). A comparison of EOU and non-EOU patients revealed similar DFS and OS at 3 and 5 years.

In a cohort of 298 patients with stage I-III CRC, Sun et al[40 ] identified 77 patients who used PPIs concurrently during adjuvant capecitabine therapy. PPI-users were found to have significantly lower 5 -year recurrence-free survival (RFS) (74 % vs 83 %,P= 0 .03 ), but similar OS (81 % vs 78 %, P = 0 .7 ) compared to non-users. Multivariate analysis revealed similar RFS between the groups (HR = 1 .65 , 95 %CI: 0 .93 -2 .94 ,P=0 .09 ).

Table 4 Summary of epidemiological studies assessing the effect of proton pump inhibitors exposure on the risk of developing colorectal cancer

Wonget al[41 ] studied PPI use with adjuvant CapeOx (capecitabine, intravenous oxaliplatin), or adjuvant FOLFOX (intravenous 5 -FU, leucovorin, oxaliplatin) therapy.Of 389 patients with stage II-III CRC, 214 underwent CapeOx therapy and 175 had FOLFOX therapy. The proportions of patients taking PPI in both groups were similar(23 .4 % CapeOx vs 28 % FOLFOX, P = 0 .3 ). Comparing PPI-users and non-users, the authors found 3 -year RFS to be significantly lower in CapeOx-treated PPI-users (P=0 .029 ) but similar between the two groups in FOLFOX-treated patients (P = 0 .66 ).Multivariate analysis showed that PPI use was associated with increased risk of CRC recurrence in the CapeOx-treated group (HR = 2 .20 , 95 %CI: 1 .14 -4 .25 , P = 0 .018 ). The use of PPI in combination with either adjuvant treatment regimen did not affect 3 -year OS in this study (CapeOx,P= 0 .35 ; FOLFOX, P = 0 .929 ).

Kichenadasseet al[42 ] analyzing data from six RCTs including metastatic CRC patients reported that PPI-users had significantly poorer OS (HR = 1 .20 , 95 %CI: 1 .03 -1 .40 , P = 0 .02 ) and PFS (HR = 1 .20 , 95 %CI: 1 .05 -1 .37 , P = 0 .009 ). The subgroup analysis revealed that chemotherapy type, use of capecitabine or 5 -FU, line of therapy and VEGF inhibitor use, across studies, did not influence oncological outcomes between users and non-users. Kimet al[43 ] described post-hoc analysis of data relating to PPI use from the AXEPT trial. The authors reported that PPI users in the FOLFIRI(fluorouracil, leucovorin, irinotecan) arm had significantly better OS (HR = 0 .5 , 95 %CI:0 .30 -0 .85 ; P = 0 .011 ) and PFS (HR = 0 .55 , 95 %CI: 0 .33 -0 .91 , P = 0 .02 ) compared to nonusers, while there were no differences noted in the mXELIRI (capecitabine, irinotecan)arm.

DISCUSSION

This systematic review of 26 articles is the first in the literature to summarize the evidence on the association between PPI and CRC from basic research, epidemiological, and clinical treatment studies. Previously published meta-analyses by Ahnetal[12 ] and Ma et al[13 ] primarily focused on the epidemiological aspect, assessing the risk of CRC with PPI exposure. In this systematic review, we describe evidence from basic research studies on the potential pro-tumor (proliferative) and anti-tumor(therapeutic) effects of PPI, assess if these findings are translatable into human studies,and discuss future clinical and research aspects related to the use of PPI in patients with CRC.

Table 5 Summary of treatment studies

Although primarily responsible for gastric acid secretion, gastrin and its precursors are also potent growth factors for normal and malignant GI tissues[44 ]. Gastrin exerts its trophic effect through interaction with CCKBR, resulting in activation of growthpromoting downstream pathways[24 ,44 ]. As noted, long-term PPI use causes hypergastrinemia, raising concerns regarding the effects of PPI-induced hypergastrinemia on GI cancers. Recent reviews on the association of PPI use and various GI cancers such as pancreatic, hepatocellular, esophageal, and gastric cancer have yielded conflicting evidence[45 -47 ]. Previous reviews addressing PPI and CRC suggested that there may not be any causative association between them[12 -13 ]. However, Maet al[13 ] suggested that long-term PPI use (> 5 years) may increase CRC risk.

Of the six basic research studies on PPI-induced hypergastrinemia, four demonstrated that PPI did not influence CRC growth and progression, whereas two suggested that PPI may even have a protective effect against CRC[16 ,17 ,19 -21 ]. The two publications reporting a suggested protective effect, by Penmanet aland Tobiet al[21 ], demonstrated a lower CRC tumor burden in PPI-treated animal models and a dose-dependent decrease in CRC cell line (NCL-H716 ) proliferation, respectively.These findings may be suggestive of an anti-tumor effect of this drug class or may be explained by a possible interaction with the carcinogen (azoxymethane) used for tumor induction (as Penmanet al[20 ] hypothesized).

The included human epidemiological studies do not present compelling evidence of a causative relationship between PPI use and CRC. Seven of nine studies demonstrated no significant risk of CRC development in patients previously or currently using PPI[28 -35 ]. However, of these, Lee et al[31 ] reported an increased incidence with long-term use (≥ 10 years), whereas Hwang et al[34 ] found increased cases in a specific cohort of patients using PPI and at low risk of developing CRC. Of the remaining two studies, Lei and colleagues[36 ], found that the risk of CRC was significantly increased in PPI users while Kuiperet al[33 ] found significantly increased risk only in current PPI users, especially those using NSAIDs concomitantly. These results from human studies may be corroborative of the basic research findings that PPI do not have a growth-promoting effect on CRC. However, two included retrospective analyses examining survival among CRC patients, found that mortality risk was significantly higher in those using PPI compared to non-users[37 ,38 ]. In their cohort, Grahamet al[37 ] found any comorbidities, advanced tumor stage, and poor tumor differentiation to be significant predictors of mortality. Such data may depict a potential pro-tumor influence of PPI on the CRC microenvironment, in contrast to findings from basic research mentioned above. Another explanation for poorer survival seen in PPI-using patients with CRC could be drug-drug interactions between PPI and commonly used chemotherapeutics, such as capecitabine. However, neither study describes information on CRC treatment of their cohorts.

Capecitabine is rapidly and predominantly absorbed from the upper GI tract[48 ]. It is thought that the dissolution and absorption of capecitabine may be reduced with increasing gastric pH (an effect produced by PPI)[49 ]. Sunet aland Wonget alstudied the drug interaction between PPI and capecitabine in patients diagnosed with CRC.After adjustment for confounders, these authors found conflicting evidence: Sunet al[40 ] reported similar RFS, but Wong et al[41 ] found significantly lower 3 -year RFS in the cohort concomitantly treated with CapeOx and PPI. These studies did not account for several potential confounders, such as concomitant drug use (statins, aspirin, antidiabetics), serious comorbidities, and treatment modifications, making it difficult to draw firm conclusions. Furthermore, a recent study by Sekidoet al[50 ] concluded that rabeprazole does not influence the plasma concentration of capecitabine and its metabolites, and subsequently their inhibitory effect on CRC cell proliferation.

Several basic research studies have also focused on identifying potential anti-tumor mechanisms of PPIs in CRC. Three basic research studies revealed that PPI may exert anti-tumorigenic effects through several mechanisms: Reducing pro-inflammatory signaling molecules (TNF-α, COX-2 , and IL-6 ), oxidative stressors (NO and TBA-RS),and proteolytic enzymes (MMP-9 , MMP-11 , and MT1 -MMP); exerting anti-mitogenic effects (inhibition of MAPKs) and anti-angiogenic effects (hypoxia-inducible factor 1 -alpha, vascular endothelial growth factor, platelet-derived growth factor, IL-8 ); and inducing apoptosisviaupregulating pro-apoptotic molecules (p21 waf1 /cip1 ) and downregulating anti-apoptotic molecules (cyclin A, Bcl-2 , Bcl-xl and survivin)[23 ,24 ].Additionally, these studies also found that PPI could exert anti-tumor properties even when co-administered with gastrin. It seems that instead of enhancing the trophic effects of gastrin, PPI may paradoxically inhibit these effects by interfering with the interaction between gastrin and CCKBR[24 ].

These results may explain the earlier findings of Penmanet al[20 ] and Tobi et al[21 ],who also used omeprazole in their work and found a protective effect of PPI on CRC.Zenget al[26 ] and Zheng et al[27 ] identified another potential action of specific PPI agents (pantoprazole, ilaprazole), as inhibitors of TOPK, a kinase highly expressed in rapidly proliferating tissues of embryological and cancerous origin[51 ]. The overexpression of TOPK in cancers has been associated with aggressive tumor behavior and poor clinical outcomes. Therefore, this kinase has been speculated to be a viable target for inhibiting downstream growth-promoting pathways[51 ]. Considering that no specific TOPK-inhibiting drugs have been approved for clinical use and the reported findings, further examination of these properties of pantoprazole and ilaprazole may be worthwhile.

Figure 1 Figure outlining areas for future research to establish a better understanding of the relationship between proton pump inhibitors and colorectal cancer. CapeOx: Capecitabine plus oxaliplatin; CRC: Colorectal cancer; DFS: Disease free survival; FOLFOX: Fluorouracil, leucovorin, oxaliplatin; 5 -FU: 5 -flourouracil; MFS: Metastasis free survival; OME: Omeprazole; OS: Overall survival; PAN: Pantoprazole; PPI: Proton pump inhibitors; RCT: Randomized controlled trials; RFS: Recurrence free survival; TOPK: T lymphokine–activated killer cell-originated protein kinase.

It has also been suggested that PPIs have chemosensitizing ability. This was highlighted by Wanget al[25 ] demonstrating that pantoprazole enhanced the cytostatic effect of FOLFOX in CRC. Chemoresistance has been associated with an acidic tumor microenvironment, which results from the increased production of lactic acid(Warburg effect) and/or overexpression of vacuolar-ATPase pumps[52 ,53 ]. It is thought that this microenvironment neutralizes the effects of chemotherapeutic agents while decreasing their uptake into cancer cells. PPI appear to inhibit the activity of vacuolar-ATPase pumps, thereby increasing the pH of cancer cells and sensitizing them to chemotherapeutics[54 ]. This mechanism may suggest a potential role for PPI as adjuvants during chemotherapy, not only for the symptomatic treatment of side effects but also to improve oncological outcomes. Zhanget al[39 ] further provided evidence to support this rationale by demonstrating lower recurrence rates and better chemoradiotherapy efficacy in patients using omeprazole concomitantly during chemotherapy compared with those did not.

Various PPI agents have been developed on the basis of the prototype PPI,omeprazole. They all share structural similarities and are generally effective and safe in the treatment of acid-related disorders[6 ]. However, differences in pharmacokinetics and pharmacodynamics exist among them, with the newer agents offering several advantages[55 ]. Although these differences are primarily related to the onset of action and degree of acid suppression, they also include reduced potential for drug interaction and other potential mechanisms of action that could make them effective in the treatment of diseases other than acid-related disorders.

Finally, it is important to mention that long-term PPI use also results in intestinal dysbiosis, with reduced abundance and diversity of gut microbiota and an increase in pathogenic bacteria[56 ]. Pathogenic bacteria implicated in the carcinogenesis of CRC,such asFusobacterium nucleatum,Escherichia coli,Enterococcus faecalis etc.are more prevalent in PPI users[57 ]. These bacteria form a special microenvironment in the colorectal tissue that is conducive to neoplastic transformation and progression. They produce toxins that can damage the intestinal cell barrier, dysregulate immune cell function, induce a chronic inflammatory state, and cause DNA damage and genomic instability, all of which increase cell proliferation and contribute to the development of CRC[57 ,58 ]. One group has found that the abundance ofFusobacterium nucleatummay be associated with chemoresistance in CRC, resulting in poor response to 5 -FU and oxaliplatin and higher recurrence rates[59 ]. This review did not identify any studies assessing the effect on CRC of intestinal dysbiosis resulting from PPI use. Studies focusing on the interaction of PPI-induced dysbiosis in CRC are needed to resolve the inconsistencies between the basic research and human studies.

A major limitation of this review is the heterogeneity among the included studies.The basic research studies describe experiments with different animal models and cell lines, using different PPI doses and exposure periods, whereas the human (epidemiological and treatment) studies varied in accounting for potential confounding factors and inclusion criteria for PPI exposure. Additionally, most of the human studies used prescription databases to ascertain PPI use, which may fail to accurately determine PPI use because they do not account for prescription non-adherence and possible over-thecounter use. Moreover, stratification of epidemiological and treatment-related evidence based on the individual PPI agents was lacking in all but one included study.These limitations make it difficult to present conclusive evidence on the question of whether PPI are an adversary or an ally in relation to CRC. Nonetheless, this review is the first to systematize the entirety of current evidence on the topic, and summarize data from different levels and aspects of the relationship.

In light of the evidence, we suggest that PPI use should continue when appropriately indicated, while a cautious approach should be implemented when combining them with capecitabine-based chemotherapy. Patients must be educated regarding the potential adverse effects of long-term PPI use and advised to avoid over-the-counter use for improper indications, with physicians being more diligent not to overprescribe.There are several aspects of this relationship which require further, high-quality investigation as outlined in Figure 1 .

CONCLUSION

In conclusion, this review highlights an unexpected potential beneficial role of specific PPI agents in relation to CRC. First, PPI instead of promoting CRC growthviatrophic effects of hypergastrinemia, may paradoxically inhibit them. Second, current evidence suggests that individual PPI agents may affect CRC differently: Pantoprazole and ilaprazole as TOPK inhibitors; rabeprazole with lower drug interaction capability with capecitabine; and pantoprazole and rabeprazole with little impact on CRC incidence(as evidenced by Leiet al[36 ])[26 ,27 ,50 ]. These findings warrant further studies to better understand these mechanisms and possibly facilitate use of PPI differently in clinical practice.

ARTICLE HIGHLIGHTS