title: Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs.
abstract: BACKGROUND
  Resistance to antitumor agents is a major cause of treatment failure in patients with cancer. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents.
  
  
  METHODS
  We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice.
  
  
  RESULTS
  PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic drugs, with clear targeting to the nucleus in the case of doxorubicin. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin.
  
  
  CONCLUSIONS
  Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.
authors.affiliation: Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Luciani
authors.forename: Massimo
authors.initials: M
authors.lastname: Spada
authors.forename: Angelo
authors.initials: A
authors.lastname: De Milito
authors.forename: Agnese
authors.initials: A
authors.lastname: Molinari
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Montinaro
authors.forename: Manuela
authors.initials: M
authors.lastname: Marra
authors.forename: Luana
authors.initials: L
authors.lastname: Lugini
authors.forename: Mariantonia
authors.initials: M
authors.lastname: Logozzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Lozupone
authors.forename: Cristina
authors.initials: C
authors.lastname: Federici
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Iessi
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Arancia
authors.forename: Filippo
authors.initials: F
authors.lastname: Belardelli
authors.forename: Stefano
authors.initials: S
authors.lastname: Fais
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D064098:Esomeprazole; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D020128:Inhibitory Concentration 50; D008223:Lymphoma / Q000188:drug therapy*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors; D013454:Sulfoxides / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D054328:Proton Pump Inhibitors; D013454:Sulfoxides; D014747:Vinblastine; D000077402:Pantoprazole; D009853:Omeprazole; D064098:Esomeprazole; D002945:Cisplatin; D005472:Fluorouracil