Study on differentiation therapy of prostatic cancer

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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. Of the 3 agents examined papaverine (10ィイD1-5ィエD1 M) is the most effective inducer of morphologic change and raised intracellular cyclic AMP levels in LNCaP cells as well. LNCaP cells appears like neuroendocrine cells, characterized by small cell bodies and long processes after papaverine treatment. Flow cytometric cell cycle analysis showed that LNCaP cells treated with papaverine were arrested in G0/G1. LNCaP cells showed intense expression of neuronal marker AchE by western blot analysis. Papaverine significantly inhibits PSA secretion and expression both at the mRNA and protein levels in LNCaP cells. Additionally, proliferation and invasive potential of LNCaP cells measured by cell counting and the MatrigelィイD1TMィエD1 invasion chamber assay were significantly inhibited by papaverine. The results suggest that papaverine induces terminal differentiation in LNCaP cells, which is correlated with an intracellular cyclic AMP-mediated pathway. In conclusion, these findings suggest that agents which induce cellular differentiation, including papaverine, may be useful in treating patients with advanced prostate cancer.