Inhibition of different intracellular signal cascades in human pancreatic cancer cells.
OBJECTIVE
Pancreatic cancer is still a malignant disease with a poor prognosis. Except for surgery, no curative treatment has been found, albeit large research efforts. Agents, such as growth factors and hormones, have been shown to stimulate cell proliferation, whereas their receptor antagonists have been less efficient to inhibit cell proliferation. The aim of this study was to examine the effect of inhibitors of the intracellular signal cascades on pancreatic cancer cell number.


METHODS
A cell line was developed from a patient with pancreatic cancer and subcloned to three generations. The four cell lines were grown in serum-free medium. The effects of PD98059, LY294002, rapamycin and its analogue CCI-779 were tested in dose-response experiments. The chemotherapeutic agent gemcitabine, with or without combination of the other potential inhibitor drugs in different concentrations, was also examined. The cell number was evaluated with the XTT method.


RESULTS
PD98059 reduced the cell number in all the cell lines tested. At a concentration of 10(-4) M the cell number was reduced by 50-90%. LY294002 reduced the cell number by 40-50% at the same concentration. Two of four cell lines had their cell number reduced by CCI-779 by 60%, whereas the other two cell lines were reduced by 30%. Rapamycin or gemcitabine alone had no or only moderate effect on single cell lines. Different combinations of CCI-779 and gemcitabine led to reduction of the cell number by about 50% in concentrations up to 10(-7) M.


CONCLUSIONS
Inhibitors of the intracellular signal cascades can reduce the cell number of human pancreatic cancer cell lines. Inhibitors of the mitogen-activated protein kinase downstream signalling cascades seem to be more efficient than the other inhibitors. PD98059 and CCI-779, in combination with gemcitabine, could be worth studying in clinical conditions.
Axelson
Jan
J
Department of Surgery, Malmö University Hospital, Malmö, Sweden.
Lindell
Malin
M
Hörlin
Kristina
K
Ohlsson
Bodil
B
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C401859:temsirolimus; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus