• ATP6V1D
• CRISPR-Cas9 knockout screen
• V-ATPase
• autophagy
• cancer stem cell
• hepatocellular carcinoma

• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/genetics
• Humans
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• Liver Neoplasms/genetics
• Vacuolar Proton-Translocating ATPases/metabolism
• Lysosomes/metabolism
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Animals
• Disease Progression
• Autophagy/physiology
• Cell Line, Tumor
• Mice
• Mice, Nude
• Endosomal Sorting Complexes Required for Transport/metabolism

• Cancer treatment monitoring
• Cisplatin
• Fluorescence lifetime nanoprobe
• Intracellular pH
• Volasertib

• Autophagy
• Chemo-resistance
• Chemotherapy
• OSCC
• Oral cancer
• V-ATPase

• Humans
• Carcinoma, Squamous Cell/drug therapy
• Squamous Cell Carcinoma of Head and Neck
• Vacuolar Proton-Translocating ATPases
• Mouth Neoplasms/drug therapy
• Autophagy
• Head and Neck Neoplasms
• Tumor Microenvironment

• Warburg effect
• acidosis
• pH regulation
• resistance to acidity
• temozolomide

• None French National Centre for Scientific Research

• Autophagy
• Chemotherapy
• Drug delivery system
• Drug resistance
• Nanoparticle
• Neoplasm
• Unfolded protein response

• Humans
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Drug Delivery Systems/methods
• Neoplasms/pathology
• Nanoparticles
• Molecular Targeted Therapy

• Gut-brain interaction
• kidney transplantation
• patient-reported outcome measures
• quality of life
• side effects
• tiredness

• drug development

This review article outlines six molecular pathways that confer resistance of cancer cells to ionizing radiation, and describes how proton pump inhibitors (PPIs) may be used to overcome radioresistance induced by alteration of one or more of these signaling pathways. The inflammatory, adaptive, hypoxia, DNA damage repair, cell adhesion, and developmental pathways have all been linked to the resistance of cancer cells to ionizing radiation. Here we describe the molecular link between alteration of these pathways in cancer cells and development of resistance to ionizing radiation, and discuss emerging data on the use of PPIs to favorably modify one or more components of these pathways to sensitize cancer cells to ionizing radiation. Understanding the relationship between altered signaling pathways, radioresistance, and biological activity of PPIs may serve as a basis to repurpose PPIs to restore key biological processes that are involved in cancer progression and to sensitize cancer cells to radiation therapy.

• breast cancer
• cisplatin
• combo therapies
• immune response
• proton exchanger inhibitors

• Amiloride/analogs & derivatives
• Amiloride/therapeutic use
• Animals
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• CD8-Positive T-Lymphocytes/metabolism
• Cell Line, Tumor
• Cell Proliferation
• Cisplatin/therapeutic use
• Esomeprazole/therapeutic use
• Female
• Humans
• Hydrogen-Ion Concentration
• Mice, Inbred BALB C
• Proton Pump Inhibitors/therapeutic use
• Sodium-Hydrogen Exchanger 1/metabolism
• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/metabolism
• Tumor-Associated Macrophages/metabolism
• Vacuolar Proton-Translocating ATPases/metabolism
• Mice

The use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal cancer (CRC) risk.

To summarize current knowledge on the relationship between PPI and CRC from basic research, epidemiological and clinical studies.

This systematic review was based on the patients, interventions, comparisons, outcome models and performed according to PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from inception until May 17, 2021. The initial search returned 2591 articles, of which, 28 studies met the inclusion criteria for this review. The studies were categorized as basic research studies (n = 12), epidemiological studies (n = 11), and CRC treatment studies (n = 5). The quality of the included studies was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool depending on the study design.

Data from basic research indicates that PPI do not stimulate CRC development via the trophic effect of gastrin but instead may paradoxically inhibit it. These studies also suggest that PPI may have properties beneficial for CRC treatment. PPI appear to have anti-tumor properties (omeprazole, pantoprazole), and are potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole), and chemosensitizing agents (pantoprazole). However, these mechanisms have not been confirmed in human trials. Current epidemiological studies suggest that there is no causal association between PPI use and increased CRC risk. Treatment studies show that concomitant PPI and capecitabine use may reduce the efficacy of chemotherapy resulting in poorer oncological outcomes, while also suggesting that pantoprazole may have a chemosensitizing effect with the fluorouracil, leucovorin, oxaliplatin (FOLFOX) regimen.

An unexpected inhibitory effect of PPI on CRC carcinogenesis by way of several potential mechanisms is noted. This review identifies that different PPI agents may have differential effects on CRC treatment, with practical implications. Prospective studies are warranted to delineate this relationship and assess the role of individual PPI agents.

• Colorectal cancer
• Proton pump inhibitor
• Carcinogenesis
• Cancer epidemiology
• Capecitabine
• Translational medicine

• Capecitabine
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/epidemiology
• Fluorouracil
• Humans
• Leucovorin
• Proton Pump Inhibitors/adverse effects

• ATP
• RNA
• biomolecular condensate
• lipid raft
• liquid–liquid phase separation
• m6A
• melatonin
• neurodegenerative disorder
• post-translational modification

• caspase reporter
• failed apoptosis
• invasion
• melanoma
• metastasis
• migration

• Apoptosis/genetics
• Cell Death/genetics
• Cell Proliferation
• Humans
• Melanoma/genetics
• Signal Transduction

• chemoresistance
• chemotherapy
• extracellular vesicles
• oral cancer
• oral squamous cell carcinoma

• H+-related therapeutics of breast cancer
• breast cancer etiopathogenesis
• breast cancer treatment
• hydrogen ion dynamics of cancer
• pH-related paradigm

• Animals
• Antineoplastic Agents
• Biomarkers, Tumor
• Breast Neoplasms/diagnosis
• Breast Neoplasms/drug therapy
• Breast Neoplasms/etiology
• Breast Neoplasms/metabolism
• Cation Transport Proteins/antagonists & inhibitors
• Cation Transport Proteins/metabolism
• Cell Respiration/drug effects
• Clinical Studies as Topic
• Combined Modality Therapy
• Disease Management
• Drug Resistance, Neoplasm
• Female
• Humans
• Hydrogen/metabolism
• Hydrogen-Ion Concentration
• Intracellular Space
• Molecular Targeted Therapy
• Proton Pump Inhibitors/pharmacology
• Proton Pump Inhibitors/therapeutic use
• Proton Pumps/metabolism
• Protons
• Sodium-Hydrogen Exchangers/metabolism
• Translational Research, Biomedical
• Treatment Outcome
• Tumor Microenvironment

• 2020/3 The Mercedes Castresana Foundation (Vitoria, Spain) (SH), and the Association for Proton Cancer Research and Treatment (APCRT), Madrid, Spain (JPO, SH).

Resistance to chemotherapeutics and targeted drugs is one of the main problems in successful cancer therapy. Various mechanisms have been identified to contribute to drug resistance. One of those mechanisms is lysosome-mediated drug resistance. Lysosomes have been shown to trap certain hydrophobic weak base chemotherapeutics, as well as some tyrosine kinase inhibitors, thereby being sequestered away from their intracellular target site. Lysosomal sequestration is in most cases followed by the release of their content from the cell by exocytosis. Lysosomal accumulation of anticancer drugs is caused mainly by ion-trapping, but active transport of certain drugs into lysosomes was also described. Lysosomal low pH, which is necessary for ion-trapping is achieved by the activity of the V-ATPase. This sequestration can be successfully inhibited by lysosomotropic agents and V-ATPase inhibitors in experimental conditions. Clinical trials have been performed only with lysosomotropic drug chloroquine and their results were less successful. The aim of this review is to give an overview of lysosomal sequestration and expression of acidifying enzymes as yet not well known mechanism of cancer cell chemoresistance and about possibilities how to overcome this form of resistance.

• V-ATPase
• V-ATPase inhibitors
• chemoresistance of cancer cells
• lysosomal sequestration
• lysosomotropic agents
• metallothioneins

• Antineoplastic Agents/pharmacology
• Cell Line, Tumor
• Drug Resistance, Neoplasm/drug effects
• Exocytosis
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Hydrogen-Ion Concentration
• Lysosomes/drug effects
• Lysosomes/enzymology
• Neoplasms/drug therapy
• Neoplasms/enzymology
• Vacuolar Proton-Translocating ATPases/antagonists & inhibitors

• cancers
• chemoresistance
• ion channels
• membrane transporters
• pumps

• (Pro) renin receptor
• Biomarker
• Cancer
• Cancer targeted therapy
• RAS
• Wnt/β-catenin signaling pathway

• breast cancer etiology
• breast cancer pathogenesis
• breast cancer treatment
• cancer proton reversal
• hydrogen ion dynamics of cancer
• multiple drug resistance (MDR) integral approach
• pH and breast cancer
• pH-centric anticancer paradigm

• Animals
• Antineoplastic Agents/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/metabolism
• Drug Resistance, Neoplasm
• Female
• Humans
• Proton Pump Inhibitors/therapeutic use
• Proton Pumps/metabolism
• Protons
• Tumor Microenvironment

• 2019 Mercedes Castresana Foundation. 2019-b. Association for Proton Research and Treatment

• cisplatin
• cybrids
• drug resistance
• mitochondria
• mtDNA haplogroups

Ovarian cancer (OVCA) patients often develop tolerance to standard platinum therapy that accounts for extensive treatment failures. Cisplatin resistant OVCA cells (cis-R) display enhanced survival mechanisms to cope with therapeutic stress. In these cells, increased autophagy process assists in chemoresistance by boosting the nutrient pool under stress. To improve the treatment response, both protective autophagy inhibition and its overactivation are showing efficacy in chemosensitization. Autophagy requires a tightly regulated intracellular pH. Vacuolar ATPases (V-ATPases) are proton extruding nanomotors present on cellular/vesicular membranes where they act as primary pH regulators. V-ATPase ‘a2' isoform (V0a2), the major pH sensing unit, is markedly overexpressed on the plasma membrane and the early endosomes of OVCA cells. Previously, V0a2 inhibition sensitized cis-R cells to platinum drugs by acidifying cytosolic pH that elevated DNA damage. Here, we examined how V0a2 inhibition affected endosomal function and the autophagy process as a possible factor for cisplatin sensitization. Clinically, V0a2 expression was significantly higher in tissues from drug nonresponder OVCA patients compared to treatment responders. In vitro V0a2 knockdown in cis-R cells (sh-V0a2-cisR) significantly reduced the tumor sphere-forming ability and caused complete disintegration of the spheres upon cisplatin treatment. The apoptotic capacity of sh-V0a2-cisR improved substantially with potentiation of both intrinsic and extrinsic apoptotic pathway when treated with cisplatin. Unlike the chemical V-ATPase inhibitors that acutely induce autophagy, here, the stable V0a2 inhibition dampened the protective autophagy process in sh-V0a2-cisR cells with downregulated expression of proteins beclin-1, ATG-7, and LC3B and low autophagosome numbers compared to control cis-R cells. These cells showed downregulated ERK/MEK pathway that is known to repress autophagy. Interestingly, upon cisplatin treatment of sh-V0a2-cisR, the autophagy initiation proteins (LC3B, ATG7, and Beclin 1) were found upregulated as a stress response compared to the untreated cells. However, there was a concomitant downstream autophagosome accumulation and an enhanced P62 protein levels indicating the overall block in autophagy flux. Mechanistically, V0a2 knockdown caused defects in early endosome function as the transferrin internalization was impaired. Taken together, this study provides a novel insight into the mechanism by which V-ATPase-isoform regulates autophagy that assists in chemoresistance in ovarian cancer. We conclude that V-ATPase-V0a2 is a potent target for developing an effective treatment to enhance patient survival rates in ovarian cancer.

• Mg-1Ag-1Y alloy
• antitumor properties
• orthopedic implant degradation
• osteosarcoma
• pulmonary metastasis

• Bicarbonate
• Breast cancer
• Immune system
• Metabolism
• Microenvironment
• Nanoparticle
• pH

Esophageal carcinoma (EC), consists of two histological types, esophageal squamous carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC accounted for 10% of EC for centuries; however, the prevalence of EAC has alarmingly risen 6 times and increased to about 50% of EC in recent 30 years in the western countries, while treatment options for EAC patients are still limited. Stratification of molecular subtypes by gene expression profiling methods had offered opportunities for targeted therapies. However, the molecular subtype in EAC has not been defined. Hence, Identification of EAC molecular subtypes is needed and will provide important insights for future new therapies.

We performed meta-analysis of gene expression profiling data on three independent EAC cohorts and showed that there are two common molecular subtypes in EAC. Each of the two EAC molecular subtypes has subtype specific expression patterns and mutation signatures. Genes which were over-expressed in subtype I EACs rather than subtype II EAC cases, were enriched in biological processes including epithelial cell differentiation, keratinocyte differentiation, and KEGG pathways including basal cell carcinoma. TP53 and CDKN2A are significantly mutated in both EAC subtypes. 24 genes including SMAD4 were found to be only significantly mutated in subtype I EAC cases, while 30 genes including ARID1A are only significantly mutated in subtype II EACs.

Two EAC molecular subtypes were defined and validated. This finding may offer new opportunities for targeted therapies.

The online version of this article (10.1186/s12864-018-5165-0) contains supplementary material, which is available to authorized users.

• Esophageal adenocarcinoma
• Gene expression
• Molecular subtype
• Mutation
• Therapy

• V-ATPase
• cancer
• drug resistance
• invasion
• metastasis
• novel therapy

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Humans
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/etiology
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Binding
• Structure-Activity Relationship
• Vacuolar Proton-Translocating ATPases/antagonists & inhibitors
• Vacuolar Proton-Translocating ATPases/chemistry
• Vacuolar Proton-Translocating ATPases/metabolism

• Cancer Research UK

The relationship between metabolism and methylation is considered to be an important aspect of cancer development and drug efficacy. However, it remains poorly defined how to apply this aspect to improve preclinical disease characterization and clinical treatment outcome. Using available molecular information from Kyoto Encyclopedia of Genes and Genomes (KEGG) and literature, we constructed a large-scale knowledge-based metabolic in silico model. For the purpose of model validation, we applied data from the Cancer Cell Line Encyclopedia (CCLE) to investigate computationally the impact of metabolism on chemotherapy efficacy. In our model, different metabolic components such as MAT2A, ATP6V0E1, NNMT involved in methionine cycle correlate with biologically measured chemotherapy outcome (IC50) that are in agreement with findings of independent studies. These proteins are potentially also involved in cellular methylation processes. In addition, several components such as 3,4-dihydoxymandelate, PAPSS2, UPP1 from metabolic pathways involved in the production of purine and pyrimidine correlate with IC50. This study clearly demonstrates that complex computational approaches can reflect findings of biological experiments. This demonstrates their high potential to grasp complex issues within systems medicine such as response prediction, biomarker identification using available data resources.

• chemotherapy
• metabolism
• methylation
• molecular modelling
• treatment prediction

• Autophagy
• Cancer
• Drug resistance
• Notch signaling
• TGF-β
• V-ATPase
• WNT
• Warburg effect
• mTOR

• Animals
• Biomarkers
• Disease Susceptibility
• Endosomes/metabolism
• Extracellular Space/metabolism
• Humans
• Hydrogen-Ion Concentration
• Intracellular Space/metabolism
• Lysosomes/metabolism
• Signal Transduction/drug effects
• Vacuolar Proton-Translocating ATPases/antagonists & inhibitors
• Vacuolar Proton-Translocating ATPases/metabolism
• Vacuoles/metabolism

• Acidic microenvironment
• Cancer
• Proton pump inhibitors (PPIs)
• V-ATPase

• CSC
• EMT
• Tumor immunoediting
• Tumor microenvironment

Vacuolar (H⁺)‐ATPases (V‐ATPases) have important roles in the supply of nutrients to tumors by mediating autophagy and the endocytic uptake of extracellular fluids. Accordingly, V‐ATPases are attractive therapeutic targets for cancer. However, the clinical use of V‐ATPase inhibitors as anticancer drugs has not been realized, possibly owing to their high toxicity in humans. Inhibition of V‐ATPase may be an appropriate strategy in highly susceptible cancers. In this study, we explored markers of V‐ATPase inhibitor sensitivity. V‐ATPase inhibitors led to pH impairment in acidic intracellular compartments, suppression of macropinocytosis, and decreased intracellular amino acid levels. The sensitivity of cells to V‐ATPase inhibitors was correlated with low cathepsin D expression, and cancer cells showed increased sensitivity to V‐ATPase inhibitors after pretreatment with a cathepsin D inhibitor and siRNA targeting the cathepsin D gene (CTSD). In addition, V‐ATPase inhibitor treatment led to the induction of the amino acid starvation response, upregulation of endoplasmic reticulum stress markers, and suppression of mammalian target of rapamycin (mTOR) signaling in cells expressing low levels of cathepsin D. Some colorectal cancer patients showed the downregulation of cathepsin D in tumor tissues compared with matched normal tissues. These findings indicate that V‐ATPase inhibitors are promising therapeutic options for cancers with downregulated cathepsin D.

• Cathepsin D
• V-ATPase
• colorectal cancer
• patient selection marker
• vulnerability

• Carbonic anhydrase 9
• Hypoxia
• Tumour
• acidic microenvironment
• pH regulation

• Disease Progression
• Humans
• Hydrogen-Ion Concentration
• Hypoxia/metabolism
• Hypoxia/pathology
• Neoplasms/metabolism
• Neoplasms/pathology
• Prognosis
• Tumor Microenvironment/physiology

• 16466 Cancer Research UK
• 18974 Cancer Research UK

• Cellular acidification in cancer treatment
• Cellular acidifiers
• Growth factors in cancer and neurodegenerative diseases
• Ion channels in cancer and neurodegeneration
• pH, NHE, cancer and neurodegenerative diseases

Recent evidence has reported that proton pump inhibitors (PPIs) can exert antineoplastic effects through the disruption of pH homeostasis by inhibiting vacuolar ATPase (H⁺-VATPase), a proton pump overexpressed in several tumor cells, but this aspect has not been deeply investigated in EAC yet. In the present study, the expression of H⁺-VATPase was assessed through the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's esophagus (BE) and the antineoplastic effects of PPIs and cellular mechanisms involved were evaluated in vitro. H⁺-VATPase expression was assessed by immunohistochemistry in paraffined-embedded samples or by immunofluorescence in cultured BE and EAC cell lines. Cells were treated with different concentrations of PPIs and parameters of citotoxicity, oxidative stress, and autophagy were evaluated. H⁺-VATPase expression was found in all biopsies and cell lines evaluated, showing differences in the location of the pump between the cell lines. Esomeprazole inhibited proliferation and cell invasion and induced apoptosis of EAC cells. Production of reactive oxygen species (ROS) seemed to be involved in the cytotoxic effects observed since the addition of N-acetylcysteine significantly reduced esomeprazole-induced apoptosis in EAC cells. Esomeprazole also reduced intracellular pH of tumor cells, whereas only disturbed the mitochondrial membrane potential in OE33 cells. Esomeprazole induced autophagy in both EAC cells, but also triggered a blockade in autophagic flux in the metastatic cell line. These data provide in vitro evidence supporting the potential use of PPIs as novel antineoplastic drugs for EAC and also shed some light on the mechanisms that trigger PPIs cytotoxic effects, which differ upon the cell line evaluated.

• Barrett's esophagus
• esophageal adenocarcinoma
• proton pump inhibitors
• reactive oxygen species
• vacuolar ATPase

Epi-reevesioside F, a new cardiac glycoside isolated from the root of Reevesia formosana, displayed potent activity against glioblastoma cells. Epi-reevesioside F was more potent than ouabain with IC₅₀ values of 27.3±1.7 vs. 48.7±1.8 nM (P < 0.001) and 45.0±3.4 vs. 81.3±4.3 nM (P < 0.001) in glioblastoma T98 and U87 cells, respectively. However, both Epi-reevesioside F and ouabain were ineffective in A172 cells, a glioblastoma cell line with low Na⁺/K⁺-ATPase α3 subunit expression. Epi-reevesioside F induced cell cycle arrest at S and G2 phases and apoptosis. It also induced an increase of intracellular concentration of Na⁺ but not Ca²⁺, cleavage and exposure of N-terminus of Bak, loss of mitochondrial membrane potential, inhibition of Akt activity and induction of caspase cascades. Potassium supplements significantly inhibited Epi-reevesioside F-induced effects. Notably, Epi-reevesioside F caused cytosolic acidification that was highly correlated with the anti-proliferative activity. In summary, the data suggest that Epi-reevesioside F inhibits Na⁺/K⁺-ATPase, leading to overload of intracellular Na⁺ and cytosolic acidification, Bak activation and loss of mitochondrial membrane potential. The PI3-kinase/Akt pathway is inhibited and caspase-dependent apoptosis is ultimately triggered in Epi-reevesioside F-treated glioblastoma cells.

• Epi-reevesioside F
• bak activation
• cytosolic acidification
• intracellular Na+ concentration
• mitochondrial dysfunction

• Cisplatin resistance
• Ovarian cancer
• Vacuolar ATPase
• a2 isoform

• proton pump inhibitor
• metastatic breast cancer
• chemotherapy
• time to progression (ttp)
• overall survival (os)

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/mortality
• Breast Neoplasms/pathology
• Drug Administration Schedule
• Esomeprazole/administration & dosage
• Female
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/mortality
• Lung Neoplasms/secondary
• Middle Aged
• Pilot Projects
• Proton Pump Inhibitors/administration & dosage
• Treatment Outcome

Mitochondria are important cellular organelles that function as control centers of the energy supply for highly proliferative cancer cells and regulate apoptosis after cancer chemotherapy. Cisplatin is one of the most important chemotherapeutic agents and a key drug in therapeutic regimens for a broad range of solid tumors. Cisplatin may directly interact with mitochondria, which can induce apoptosis. The direct interactions between cisplatin and mitochondria may account for our understanding of the clinical activity of cisplatin and development of resistance. However, the basis for the roles of mitochondria under treatment with chemotherapy is poorly understood. In this review, we present novel aspects regarding the unique characteristics of the mitochondrial genome in relation to the use of platinum-based chemotherapy and describe our recent work demonstrating the importance of the mitochondrial transcription factor A (mtTFA) expression in cancer cells.

• cancer chemotherapy
• cisplatin
• mtDNA
• mtTFA
• prognosis

Much effort is currently devoted to developing patient-specific cancer therapy based on molecular characterization of tumors. In particular, this approach seeks to identify driver mutations that can be blocked through small molecular inhibitors. However, this approach is limited by extensive intratumoral genetic heterogeneity, and, not surprisingly, even dramatic initial responses are typically of limited duration as resistant tumor clones rapidly emerge and proliferate. We propose an alternative approach based on observations that while tumor evolution produces genetic divergence, it is also associated with striking phenotypic convergence that loosely correspond to the well-known cancer “hallmarks”. These convergent properties can be described as driver phenotypes and may be more consistently and robustly expressed than genetic targets. To this purpose, it is necessary to identify strategies that are critical for cancer progression and metastases, and it is likely that these driver phenotypes will be closely related to cancer “hallmarks”. It appears that an antiacidic approach, by targetting a driver phenotype in tumors, may be thought as a future strategy against tumors in either preventing the occurrence of cancer or treating tumor patients with multiple aims, including the improvement of efficacy of existing therapies, possibly reducing their systemic side effects, and controlling tumor growth, progression, and metastasis. This may be achieved with existing molecules such as proton pump inhibitors (PPIs) and buffers such as sodium bicarbonate, citrate, or TRIS.

• Acidosis/complications
• Acidosis/drug therapy
• Acidosis/pathology
• Carcinogenesis/drug effects
• Carcinogenesis/genetics
• Carcinogenesis/metabolism
• Humans
• Neoplasm Metastasis
• Neoplasms/complications
• Neoplasms/drug therapy
• Neoplasms/pathology
• Proton Pump Inhibitors/therapeutic use
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/genetics

• Cell death
• Drug resistance
• Lysosomes
• Mitochondria
• Platinum compounds

Control of the extracellular environment of inner ear hair cells by ionic transporters is crucial for hair cell function. In addition to inner ear hair cells, aquatic vertebrates have hair cells on the surface of their body in the lateral line system. The ionic environment of these cells also appears to be regulated, although the mechanisms of this regulation are less understood than those of the mammalian inner ear. We identified the merovingian mutant through genetic screening in zebrafish for genes involved in drug-induced hair cell death. Mutants show complete resistance to neomycin-induced hair cell death and partial resistance to cisplatin-induced hair cell death. This resistance is probably due to impaired drug uptake as a result of reduced mechanotransduction ability, suggesting that the mutants have defects in hair cell function independent of drug treatment. Through genetic mapping we found that merovingian mutants contain a mutation in the transcription factor gcm2. This gene is important for the production of ionocytes, which are cells crucial for whole body pH regulation in fish. We found that merovingian mutants showed an acidified extracellular environment in the vicinity of both inner ear and lateral line hair cells. We believe that this acidified extracellular environment is responsible for the defects seen in hair cells of merovingian mutants, and that these mutants would serve as a valuable model for further study of the role of pH in hair cell function.

• Aminoglycosides
• Cisplatin
• H+-ATPase
• Hair cells
• Ototoxicity
• pH