A dual role of proton pump inhibition on cancer: a critical review

P-ATPase

H⁺/K⁺ ATPase, secreted from parietal cells, regulate the exchange of cytoplasmic H⁺ with extracellular K⁺. Hydrochloric acid (HCl) is formed by the combination of the H ion secreted into the gastric lumen with the luminal Cl ion. Tight regulation of parietal cells ensures proper secretion of HCl. Inhibition of H⁺/K⁺ ATPase is the most effective way for the prevention of gastric acid secretion [1].

V-ATPase

V-ATPases are ATP-dependent proton pumps that have a variety of functions including providing energy for membrane transport processes and the regulation of acidity of the cells and organelles. Dysfunction of ATPase is seen in many diseases such as osteopetrosis and renal acidosis [2, 3].

V-ATPases play major roles in many physiological and pathophysiological conditions. V-ATPase generates an electrochemical gradient across the cell membranes and this gradient provides energy for cellular processes. Acidification of intracellular vesicles and organelles following activation of V-ATPase results in the formation of the necessary environment for many biological events.

The relationship between V-ATPase activity and carcinogenesis is well established. Increased activity of V-ATPase induces cancer invasiveness and metastasis, whereas the decreased activity of V-ATPase, e.g., following the use of V-ATPase inhibitors, inhibits cancer progression [4].

Tumor cells express V-ATPase which results in an acidic microenvironment and induces cancer growth and infiltration. The acidic tumor microenvironment is necessary for cancer progression and metastasis.

Lysosomal enzymes secreted by the tumor cells play a major role in the degradation of the extracellular matrix. These enzymes are more active at low pH. Acidification of the tumor microenvironment is provided by the V-ATPases. Low pH may cause extracellular matrix (ECM) degradation and remodel through the activation of proteolytic enzymes which contribute to invasion and cancer metastas.

V-ATPase inhibitors were classified as plecomacrolide antibiotics (concanamycin and bafilomycin), benzolactone enamides (salicylamide, apicularens, lobatamides, oximidines, cruentaren), archazolid, indoyls and late-generation V-ATPase inhibitors [5].

V-ATPase inhibition has also been shown to induce apoptosis in many tumor types through caspase-dependent and independent mechanisms [6].

Bafilomycin A1 and concanamycin A inhibit growth and induce apoptosis in different human cell lines. Bafilomycin A1 was assessed as a potential anticancer agent because it inhibits cell proliferation and tumor growth.

Specific VATPase inhibitors for mammals belonging to the benzolactone enamide class have also shown promise as anticancer agents. Proton secretion by the tumor cells leads to acidification of the extracellular medium and keeps the cytoplasm more alkaline. Acidic medium facilitates extracellular matrix (ECM) degradation through the activation of the proteolytic enzymes (especially matrix metalloproteinases) which is mandatory for cancer invasion as well as metastasis development. Studies with V-ATPase inhibitors had also revealed that these agents have the potential to suppress the incidence of metastasis development. Treatment with V-ATPase inhibitors lowers H+ extrusion, both in vitro and in vivo [5].

V-ATPase functions to increase lysosomal pH and impairs autophagy. On the other hand, V-ATPase inhibition induces autophagy and leads to the accumulation of autophagosomes [3, 6]. Carcinogenesis depends on autophagy, especially during development of metastasis. Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis during stress conditions. Dysregulated autophagy has implications in both health and disease. Specifically, in cancer, autophagy plays a dichotomous role by inhibiting tumor initiation but supporting tumor progression. There is evidence that autophagy has reduced the effectiveness of chemotherapeutics [7]. V-ATPase has a similar effect on chemotherapeutics as well. Therefore, the use of V-ATPase inhibitors has an indirect effect on chemotherapeutic drug effectiveness [8].

V-ATPases have also a role in chemoresistance to antineoplastic agents and V-ATPase inhibitors may be used to manage drug resistance in cancer treatment. V-ATPase inhibition alters the acidity of the tumor microenvironment and increases the chemosensitivity of the cancer cells to antineoplastic agents. Specific V-ATPase inhibition has also the potential to decrease the toxicity to normal cells [9]. The solid tumor microenvironment is more acidic than normal tissue [10, 11] due to V-ATPase dysregulation [12]. More precisely, the dysregulation of V-ATPase causes to increase of the rate of uptaken glucose and, therefore, to accumulate the lactate. The described process, which is also known as Warburg Effect, is demonstrated schematically in Figure 1. This process also leads to aggresivity of the tumor cells for attempting survival [10, 13], [14], [15], [16].

Figure 1:

The basic scheme of the construction of acidic environment by the V-ATPase protein.

Effects of PPIs on cancer

This section provides the possible relations between the use of proton pump inhibitors and cancer. The key aspects of the relationship can be divided into positive and negative. Prior to presenting the literature, some clues from the databases have been given to make this study much more powerful and meaningful.

The positive effect of the use of PPIs: “the relation with the tumor microenvironment”

By the consensus of the authors V-ATPase and cancer-related publications have been focused on. To enrich a deep understanding of cancer disease, research on the tumor microenvironment has become popular in recent years [18], [19], [20], [21], [22], [23], [24]. The main aim of the current section is to present the literature knowledge on the relationship of proton pump inhibitors (PPI) on the tumor microenvironment.

A general search was conducted on two databases (Scopus and PubMed) to review relevant articles published until December 31, 2021. To do so, the algorithmic query has been developed as follows: (“tumor microenvironment” or “cancer”) and (“V-ATPase” or “vacuolar H⁺ ATPase” or “H⁺ ATPase” or “ H⁺/K⁺ ATPase ” or “ATP4A” or “ATP4B”). With the help of the developed query all possible combinations coupling with tumor microenvironment/cancer and one of the ATPase proteins have been searched.

After data is extracted from the databases, Pandas libraries in Python language has been used as a tool for data preprocessing. Duplication of articles has been checked on the ‘doi’ of the articles. Thus, the articles whose doi number are no accessible are removed. All above-mentioned instructions have been implemented, 524 studies were recorded. A further exclusion has been done to preserve the consistency of the study. Due to the fact that the nature of the use of PPIs is to neutralize of the acidity of the medium, we have focused on the studies which contain at least one of the following keys: “Proton Pump”, “Acidity”, “vacuolar ATPase” “vacuolar H⁺ ATPase”, “V-ATPase”, “proton pump inhibitor” (all case sensitivies has been taken into account). By doing so, the recorded articles have been reduced to 177 studies. Finally, the remaining 177 articles have been reduced to 33 articles by making an abstract review by the authors. Figure 3 illustrates the flow diagram of the review.

Figure 3:

Flow diagram for selection of studies.

According the present review, the sample studies revealing the relationship between V-ATPase proton pump and cancer are as follows: V-ATPase is overexpressed in non-small cell lung cancer, and drug resistance of this cancer type is probably related to V-ATPase overexpression [25]. Kulshrestha et al. referred to the team’s previous work, which inferred that the V-ATPase a2 isoform is overexpressed in cisplatin-resistant cells of ovarian cancer cells, targeting V-ATPase-V0a2 makes chemoresistance-resistant ovarian cancer cells susceptible to cisplatin treatment [26]. Moreover, there has not been a demonstrated correlational relationship between clinical drug resistance and V-ATPase expression [26]. In a study, which is mainly on ovarian cancer, that PPI could be, hopefully, a promising strategy to increase the efficacy of therapy in anti-epithelial ovarian carcinoma, despite drug resistance developed by vacuolar H + -ATPase overexpression [27]. Additionally, various studies have reported that V-ATPase expression is associated with glioma aggressiveness [28], [29], [30]. The authors have examined the proton pump expression of V-ATPase in gliomas. In that research paper, the authors have tested their in-silico findings on a small cohort of related brain tumors. Additionally, V-ATPase G1 (ATP6V1G1) expression is very high in glioblastomas and this expression is highly correlated to short-term rental survival [30]. Therefore, it was pointed out that inhibition of V-ATPase would be a new therapeutic approach for glioblastoma [31]. In addition to the aforementioned cancer types, it has been stated that the V-ATPase proton pump increases the invasive nature of the cancers such as pancreatic, breast, and esophagus [15, 32], [33], [34], [35]. Furthermore, in colorectal cancer, it has been highlighted that ATP6L, which is a subunit of V-ATPase, triggers metastasis and is a potential target in tumor therapy [36].

Although there are various studies in the literature that long-term use of PPIs may pose a cancer risk [37], [38], [39], [40], [41], to the best knowledge of the authors there is no clear evidence yet. Nevertheless, a remarkable study conducted by Luciani et al. shows that PPIs (Omeprazole, esomeprazole, and pantoprazole) have proven through in vitro experiments that pretreatment with antitumor drugs can reduce acidification around the tumor [42]. The study has also demonstrated in vivo experiments that omeprazole can induce sensitivity to oral pretreatment cisplatin. In addition to the mentioned study, more recent studies have provided evidence that V-ATPase/H⁺/K⁺ ATPase pump inhibitors will contribute to the therapeutic strategy and increase chemosensitivity [10, 14, 34, 43, 44].

The negative effect of the use of PPIs: “long-term PPI” use on pre-cancerous lesions

Hypergastrinemia develops in response to deep acid-suppressing therapy. Hyperplasia of ECL cells may occur with prolonged hypergastrinemia, especially in individuals with H. pylori infection or more markedly increased gastrin levels [43]. It has been reported that ECL-like cell hyperplasia can lead to dysplasia and eventually into gastric carcinoid formation in both rats and humans [44]. Scarpignato et al. reported that two individuals using PPIs for more than 10 years developed well-differentiated neuroendocrine tumors [45]. However, other long-term studies of people using PPIs have not shown an increased risk of carcinoids [46]. Based on a systematic review by meta-analysis, long-term use of PPIs (≥12 months) was associated with an increased risk of fundic gastric metaplasia [47]. In animal models, the carcinogenicity of PPIs has been widely studied, particularly in rodents where PPIs cause cancer and other rare gastrointestinal (GI) tumors, whereas in humans this association is less clear. However, there is great concern with the long-term use of PPIs and the development of GI cancers, particularly gastric, colon cancer and carcinoid tumor.

It was concluded that PPI therapy is one of the strongest risk factors for the development of fundic gastric polyps (FGPs), and their high prevalence is probably due to increased prescription in recent years, but no evidence of dysplasia or sporadic cancer was observed. Evidence of malignant transformation was not found by Genta et al. using data from more than 6,000 FGP patients. Therefore, the evolution of FGPs towards dysplasia appears to be an extremely rare event and endoscopic follow-up for these polyps is not currently recommended [48].

In addition to being a well-known risk factor for gastric cancer, H. pylori infection is known to cause loss of parietal cells and thus decreased gastric secretion. The resulting hypochlorhydria may increase the risk of bacterial overgrowth responsible for worsening gastritis observed in H. pylori-infected patients treated with PPIs. Moreover, gastric atrophy and hypochlorhydria can lead to non-helicobacter microbiota overgrowth, which may increase the risk of gastric cancer in patients infected with H. pylori [49]. A subgroup analysis by Tran‐Duy and coworkers added information about the duration of PPI therapy, reporting that after long-term treatment with PPI (>36 months), the interaction between H. pylori infection and PPI use may cause more disease. Compared to shorter treatment times, severe gastritis results in an increased risk of atrophic gastritis [47].

Another area of major concern is the effect of long-term PPI therapy and associated hypergastrinemia on ECL cells and the possible development of preneoplastic and carcinoid lesions. Similarly, Lundell and colleagues noted that long-term use of PPIs was associated with only moderate hypergastrinemia resulting in an increased prevalence of ECL cell hyperplasia, however, none of the patients included in the study developed a neuroendocrine tumor (NET) [50]. Neuroendocrine tumor development in patients using long-term therapy with PPI is an uncertain and rare event and therefore these findings may be incidental. Progression to dysplasia has only been reported in rare cases of Zollinger-Ellison syndrome and multiple endocrine neoplasia type I, but this is due to the presence of marked hypergastrinemia and chronic atrophic gastritis rather than PPI therapy.

Increased gastrin level, as a result of PPI inhibition, has been found to play a role in tumorigenesis in the GI tract, and high gastrin levels have also been shown to have a trophic effect on colon cancer cells in vitro. Therefore, theoretically, hypergastrinemia may lead to the development of colonic adenoma and colorectal cancer.