title: Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells.
abstract: BACKGROUND
  Omeprazole has recently been described as a modulator of tumour chemoresistance, although its underlying molecular mechanisms remain controversial. Since pancreatic tumours are highly chemoresistant, a logical step would be to investigate the pharmacodynamic, morphological and biochemical effects of omeprazole on pancreatic cancer cell lines.
  
  
  RESULTS
  Dose-effect curves of omeprazole, pantoprazole, gemcitabine, 5-fluorouracil and the combinations of omeprazole and 5-fluorouracil or gemcitabine were generated for the pancreatic cancer cell lines MiaPaCa-2, ASPC-1, Colo357, PancTu-1, Panc1 and Panc89. They revealed that omeprazole inhibited proliferation at probably non-toxic concentrations and reversed the hormesis phenomena of 5-fluorouracil. Electron microscopy showed that omeprazole led to accumulation of phagophores and early autophagosomes in ASPC-1 and MiaPaCa-2 cells. Signal changes indicating inhibited proliferation and programmed cell death were found by proton NMR spectroscopy of both cell lines when treated with omeprazole which was identified intracellularly. Omeprazole modulates the lysosomal transport pathway as shown by Western blot analysis of the expression of LAMP-1, Cathepsin-D and β-COP in lysosome- and Golgi complex containing cell fractions. Acridine orange staining revealed that the pump function of the vATPase was not specifically inhibited by omeprazole. Gene expression of the autophagy-related LC3 gene as well as of Bad, Mdr-1, Atg12 and the vATPase was analysed after treatment of cells with 5-fluorouracil and omeprazole and confirmed the above mentioned results.
  
  
  CONCLUSIONS
  We hypothesise that omeprazole interacts with the regulatory functions of the vATPase without inhibiting its pump function. A modulation of the lysosomal transport pathway and autophagy is caused in pancreatic cancer cells leading to programmed cell death. This may circumvent common resistance mechanisms of pancreatic cancer. Since omeprazole use has already been established in clinical practice these results could lead to new clinical applications.
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital of Ulm, Ulm, Germany.
authors.forename: Andrej
authors.initials: A
authors.lastname: Udelnow
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreyes
authors.forename: Stefan
authors.initials: S
authors.lastname: Ellinger
authors.forename: Katharina
authors.initials: K
authors.lastname: Landfester
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.forename: Thomas
authors.initials: T
authors.lastname: Klapperstueck
authors.forename: Johannes
authors.initials: J
authors.lastname: Wohlrab
authors.forename: Doris
authors.initials: D
authors.lastname: Henne-Bruns
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
authors.forename: Peter
authors.initials: P
authors.lastname: Würl
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020756:Coatomer Protein / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009853:Omeprazole / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D014461:Ultracentrifugation; D000093542:Gemcitabine; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000970:Antineoplastic Agents; D002402:Cathepsin D; D020756:Coatomer Protein; D003841:Deoxycytidine; D005472:Fluorouracil; D051907:Lysosomal Membrane Proteins; D009853:Omeprazole; D000093542:Gemcitabine; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1