PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLS
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 th...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2016-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00452/full |
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| author | Eduardo Chueca Eduardo Chueca Nadezda Apostolova Nadezda Apostolova Juan Vicente Esplugues Juan Vicente Esplugues María Asunción García-González María Asunción García-González María Asunción García-González Angel Lanas Angel Lanas Angel Lanas Elena Piazuelo Elena Piazuelo Elena Piazuelo |
| author_facet | Eduardo Chueca Eduardo Chueca Nadezda Apostolova Nadezda Apostolova Juan Vicente Esplugues Juan Vicente Esplugues María Asunción García-González María Asunción García-González María Asunción García-González Angel Lanas Angel Lanas Angel Lanas Elena Piazuelo Elena Piazuelo Elena Piazuelo |
| author_sort | Eduardo Chueca |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T01:04:16Z |
| format | Article |
| id | doaj.art-f2f99574454c4b7ab2c97679bc00dbf0 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-11T01:04:16Z |
| publishDate | 2016-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-f2f99574454c4b7ab2c97679bc00dbf02022-12-22T01:26:14ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122016-11-01710.3389/fphar.2016.00452222425PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLSEduardo Chueca0Eduardo Chueca1Nadezda Apostolova2Nadezda Apostolova3Juan Vicente Esplugues4Juan Vicente Esplugues5María Asunción García-González6María Asunción García-González7María Asunción García-González8Angel Lanas9Angel Lanas10Angel Lanas11Elena Piazuelo12Elena Piazuelo13Elena Piazuelo14CIBERehdIIS AragónCIBERehdUniversity of ValenciaCIBERehdUniversity of ValenciaCIBERehdIIS AragónIACS AragónCIBERehdIIS AragónUniversity of ZaragozaCIBERehdIIS AragónIACS AragónRecent 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.http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00452/fullProton Pump InhibitorsReactive Oxygen SpeciesBarrett’s esophagusEsophageal adenocarcinomavacuolar ATPase |
| spellingShingle | Eduardo Chueca Eduardo Chueca Nadezda Apostolova Nadezda Apostolova Juan Vicente Esplugues Juan Vicente Esplugues María Asunción García-González María Asunción García-González María Asunción García-González Angel Lanas Angel Lanas Angel Lanas Elena Piazuelo Elena Piazuelo Elena Piazuelo PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLS Frontiers in Pharmacology Proton Pump Inhibitors Reactive Oxygen Species Barrett’s esophagus Esophageal adenocarcinoma vacuolar ATPase |
| title | PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLS |
| title_full | PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLS |
| title_fullStr | PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLS |
| title_full_unstemmed | PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLS |
| title_short | PROTON PUMP INHIBITORS DISPLAY ANTITUMOR EFFECTS IN BARRETT’S ADENOCARCINOMA CELLS |
| title_sort | proton pump inhibitors display antitumor effects in barrett s adenocarcinoma cells |
| topic | Proton Pump Inhibitors Reactive Oxygen Species Barrett’s esophagus Esophageal adenocarcinoma vacuolar ATPase |
| url | http://journal.frontiersin.org/Journal/10.3389/fphar.2016.00452/full |
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