Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells

被引:82
作者
Udelnow, Andrej [1 ]
Kreyes, Andreas [2 ]
Ellinger, Stefan [2 ]
Landfester, Katharina [3 ]
Walther, Paul [4 ]
Klapperstueck, Thomas [5 ]
Wohlrab, Johannes [5 ]
Henne-Bruns, Doris [1 ]
Knippschild, Uwe [1 ]
Wuerl, Peter [1 ]
机构
[1] Univ Hosp Ulm, Dept Gen Visceral & Transplantat Surg, Ulm, Germany
[2] Univ Ulm, Inst Organ Chem Macromol Chem & Organ Mat, Ulm, Germany
[3] Max Planck Inst Polymer Res, D-55128 Mainz, Germany
[4] Univ Ulm, Dept Elect Microscopy, Ulm, Germany
[5] Univ Halle Wittenberg, Dept Dermatol & Venereol, Halle, Germany
来源
PLOS ONE | 2011年 / 6卷 / 05期
关键词
PROTON PUMP INHIBITORS; CHOLINE PHOSPHOLIPID-METABOLISM; MAGNETIC-RESONANCE-SPECTROSCOPY; BREAST-CANCER; IN-VITRO; MALIGNANT-TRANSFORMATION; EPITHELIAL-CELLS; TUMOR RESISTANCE; APOPTOTIC DEATH; DOSE-RESPONSES;
D O I
10.1371/journal.pone.0020143
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. Methodology/Principal Findings: 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 nontoxic 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 beta-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.
引用
收藏
页数:17
相关论文
共 71 条
  • [1] Autophagy delays apoptotic death in breast cancer cells following DNA damage
    Abedin, M. J.
    Wang, D.
    McDonnell, M. A.
    Lehmann, U.
    Kelekar, A.
    [J]. CELL DEATH AND DIFFERENTIATION, 2007, 14 (03) : 500 - 510
  • [2] Aboagye EO, 1999, CANCER RES, V59, P80
  • [3] Ackerstaff E, 2001, CANCER RES, V61, P3599
  • [4] An endosomal beta COP is involved in the pH-dependent formation of transport vesicles destined for late endosomes
    Aniento, F
    Gu, F
    Parton, RG
    Gruenberg, J
    [J]. JOURNAL OF CELL BIOLOGY, 1996, 133 (01) : 29 - 41
  • [5] Autophagy: assays and artifacts
    Barth, Sandra
    Glick, Danielle
    Macleod, Kay F.
    [J]. JOURNAL OF PATHOLOGY, 2010, 221 (02) : 117 - 124
  • [6] Gemcitabine-induced programmed cell death (apoptosis) of human pancreatic carcinoma is determined by Bcl-2 content
    Bold, RJ
    Chandra, J
    McConkey, DJ
    [J]. ANNALS OF SURGICAL ONCOLOGY, 1999, 6 (03) : 279 - 285
  • [7] AN EQUATION TO DESCRIBE DOSE RESPONSES WHERE THERE IS STIMULATION OF GROWTH AT LOW-DOSES
    BRAIN, P
    COUSENS, R
    [J]. WEED RESEARCH, 1989, 29 (02) : 93 - 96
  • [8] Mechanism of the pharmacokinetic interaction between methotrexate and benzimidazoles:: Potential role for breast cancer resistance protein in clinical drug-drug interactions
    Breedveld, P
    Zelcer, N
    Pluim, D
    Sönmezer, Ö
    Tibben, MM
    Beijnen, JH
    Schinkel, AH
    van Tellingen, O
    Borst, P
    Schellens, JHM
    [J]. CANCER RESEARCH, 2004, 64 (16) : 5804 - 5811
  • [9] Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo
    Brockschmidt, C.
    Hirner, H.
    Huber, N.
    Eismann, T.
    Hillenbrand, A.
    Giamas, G.
    Radunsky, B.
    Ammerpohl, O.
    Bohm, B.
    Henne-Bruns, D.
    Kalthoff, H.
    Leithaeuser, F.
    Trauzold, A.
    Knippschild, U.
    [J]. GUT, 2008, 57 (06) : 799 - 806
  • [10] Hormesis and medicine
    Calabrese, Edward J.
    [J]. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2008, 66 (05) : 594 - 617