Omeprazole Inhibits Proliferation and Modulates Autophagy in Pancreatic Cancer Cells

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 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

On the Statistics of Lightning Strikes into Towers and Antenna Masts Measured by LINET

The European lightning detection network LINET, which has been operated and expanded since May 2006, can very accurately detect lightning activity over most parts of Europe. To test the location accuracy we investigated lightning strikes into elevated structures like radio or TV towers, masts or high-rise buildings. Locations of more than one hundred structures were determined and occurrence of lightning strikes at or close to these positions were analyzed for a period of three years. During summer thunderstorms lightning strikes were distributed more uniformly, but during the winter month single "hot spots" around the selected objects were detectable. The position of registered strokes relating to the location of the objects were analyzed for the time period from October to March. At some sites a systematic location offset was found, probably caused by inhomogeneous propagation conditions, requiring certain network corrections. The mean distance before and after correction have been calculated for each structure

Microwave measurements of two-dimensional electron systems on thin helium-films

Im Rahmen dieser Arbeit wurden zweidimensionale Elektronensysteme (2DES) mit hoher Elektronendichte auf dünnen Heliumfilmen erzeugt und deren Beweglichkeit mit Hilfe einer indirekten Transportmessung in einem Mikrowellen-Hohlraumresonator bestimmt.Als Alternative zur bisher verwendete Messmethode durch einen LockIn-gesteuerten Regelkreis wurde eine neue Messmethode unter Verwendung eines Netzwerkanalysators mit direkter Detektion der Resonanzlinienparameter entwickelt. Damit lassen sich zu jedem Zeitpunkt alle Parameter der Resonanzlinie bestimmen was Artefakte im Vergleich zur alleinigen Bestimmung des Resonanzmaximums ausschließt.Um das Phasendiagramm des 2DES bei hohen Elektronendichten zu untersuchen, wurde die Elektronendichte im 2DES schrittweise und reproduzierbar erhöht. Hierbei wurden auf Silizium-Substraten mit oxidierter Oberfläche eine Dichte von mehr als 10^15 Elektronen pro Quadratmeter erreicht. Für den im Bereich sehr hoher Elektronendichten vorhergesagte Übergang vom Wigner-Elektronenkristall zum entarteten Fermi-Gas Dichten konnten Anzeichen ausgemacht werden.Es wurde nachgewiesen, dass die Genauigkeit und das erreichte Signal-Rausch-Verhältnis für die neue Messmethoden im Rahmen der erreichbaren Messbedingungen mit der bisherigen vergleichbar ist und im Prinzip nur durch das von der Umgebung im Messsystem verursachten Rauschen abhängt.Im zweiten Teil der Arbeit wurde das von Valeri Shikin entwickelte Zweikomponentenmodell für Elektronen auf dünnen Heliumfilmen auf experimentelle Ergebnisse der Messung der Zyklotronresonanz an 2DES angewendet. Dieses Modell macht eine indirekte Bestimmung der Oberflächenparameter des Substrats im Experiment möglich.Die Magnetfeldabhängigkeit der Resonatorsignale von vorhandene Messdaten von G. Mistura und auch die eigens aufgenommener Messdaten konnten mit diesem Modell sehr gut beschrieben werden. Die aus dem Modell erhaltenen Daten können in beschreibende Parameter eines Modellsubstrats umgerechnet werden, die wiederum als wichtige Grundlage bei der entscheidenden Optimierung der Qualität der Substratoberfläche dienen kann

Cyclotron resonance for 2D electrons on helium films above rough substrates

An investigation of the microwave absorption for two-dimennonal electron systems (2DES) on helium films and in the presence of a cyclotron resonance (CR) inagietic field are presented. Measured data are expIained by a recently proposed two-fraction model of the 2DES, which makes the general structure of the microwave absorption understandable. The fraction of localized and free electrons can be precisely determrned and rts dependence on the thickness of the helium film above the roughness of the underlying sollid substrate is understood

Electrons on liquid helium in a resonator

An investigation of the microwave absorption for 2-dimensional electron layers in a resonator cavity are presented. The difference in the eigenmodels of the resonator in case of an empty cavity and in presence of a 2-dimensional electron layer on a helium film within the cavity and are calculated. When introducing electrons into the cavity a pronounced frequency dependence is found. The expected shift in the resonance frequency is compared to previous and new data of resonance response measurements

Chemical reaction between hydrogen atoms and electrons on the surface of superfluid 4He

Two-dimensional mixture of atomic hydrogen and electrons on the surface of superfluid 4He was realized below 0.5 K. Vibrating capacitor electrometer was employed to show that after the electron capture reaction, H + e- -> H-, the product, H-, might penetrate into the bulk liquid

Dip problem of the electron mobility on a thin helium film

Electrons floating above liquid helium form an ideal two-dimensional system with an extremely high mobility. However, the mobility can change substantially when decreasing the thickness of the helium film from bulk to a thin film of a few hundred Å. Furthermore it is observed that for certain film thicknesses there is a pronounced dip in the mobility. We present theoretical investigations and measurements concerning this problem. Taking into account the roughness of the substrate, which supports the helium film, we find theoretically a discontinuity in the chemical potential of the electrons which results in a diplike behavior in the electron current and hence in the electron mobility. This scenario is supported by direct measurements of the electron current on substrates with different roughness and at different electron densities

Detection of growth-stimulatory effects of 5-FU and GEM in lower doses.

<p>Significant elevations of cell counts compared to the control groups could be observed upon 5-FU in ASPC-1 (at 0.5 µg/ml 5-FU), Panc-1 (at 0.5 and 1 µg/ml 5-FU) and PancTu-1 (at 0.125 and 0.25 µg/ml) cells. In contrast, no hormesis could be observed upon GEM.</p><p>Abbreviations: c-concentration, fu-unaffected fraction (cell count related to control).</p