The effect of papaverine on morphologic differentiation, proliferation and invasive potential of human prostatic cancer LNCaP cells.
BACKGROUND
Intracellular cyclic adenosine monophosphate (AMP) level changes are thought to play an important role in inhibiting cell proliferation and inducing differentiation in several types of cells. It has been reported that cyclic AMP analogs induce terminal differentiation in human prostate cancer cells. Consequently, phosphodiesterase inhibitors may be useful in delineating the role of cyclic AMP in the differentiation of these cells. Therefore, the effect of phosphodiesterase inhibitors on morphologic differentiation, proliferation and invasive potential of human prostate cancer cells was investigated.


METHODS
Three human prostate cancer cell lines PC-3, DU145 and LNCaP were treated with one of the phosphodiesterase inhibitors, papaverine, 3-isobutyl-1-methylxanthine (IBMX) or theophylline, for 6 days. Morphologic changes of these cells induced by phosphodiesterase inhibitors were observed by microscopy. Intracellular cyclic AMP levels in LNCaP cells were measured by radioimmunoassay using a cyclic AMP assay kit. The effect of papaverine on the proliferation and invasive potential of LNCaP cells were measured by cell counting and the Matrigel invasion chamber assay.


RESULTS
Of the three agents, examined papaverine (10(-5) mol/L) is the most effective inducer of morphologic change and also raised intracellular cyclic AMP levels in LNCaP cells. However, unlike LNCaP cells, PC-3 and DU145 cells treated with phosphodiesterase inhibitors, including papaverine, showed little change in morphology. Additionally, proliferation and invasive potential of LNCaP cells were significantly inhibited by papaverine.


CONCLUSIONS
The results suggest that papaverine induces terminal differentiation in LNCaP cells, which is correlated with an intracellular cyclic AMP-mediated pathway.
Goto
T
T
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Japan. gotout-e@ebara-hp.ota.tokyo.jp
Matsushima
H
H
Kasuya
Y
Y
Hosaka
Y
Y
Kitamura
T
T
Kawabe
K
K
Hida
A
A
Ohta
Y
Y
Simizu
T
T
Takeda
K
K
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D015194:Diffusion Chambers, Culture; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010208:Papaverine / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011863:Radioimmunoassay; D013806:Theophylline / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D010726:Phosphodiesterase Inhibitors; D013806:Theophylline; D010208:Papaverine; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine