Abstract
BackgroundOmeprazole 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.Methodology/Principal FindingsDose-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.ConclusionsWe 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.
Highlights
Despite relevant progression in diagnosis, resection and chemotherapy, pancreatic cancer is associated with a short survival [1]
A modulation of the lysosomal transport pathway and autophagy is caused in pancreatic cancer cells leading to programmed cell death
Considering the high chemoresistance of pancreatic tumour cells, one of the main aims of our study was to determine whether OMP would be effective in pancreatic cancer cell lines
Summary
Despite relevant progression in diagnosis, resection and chemotherapy, pancreatic cancer is associated with a short survival [1]. Omeprazole (OMP), established as a world-wide standard drug for gastritis and duodenal ulcer since the 1980s, has been described as a potential antiproliferative agent and a resistance modulator both in vitro and in xenograft tumours of mice [9,10]. Pglycoprotein (Pgp) [14] and cytochrome P450 2C19 isoform [15] cause pharmacokinetic interactions of OMP with other drugs (i.e. antibiotics, barbiturates, cytostatics) which are of clinical relevance. These data so far point to complex mechanisms involving, among others, the lysosomal transport system. 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
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