We are interested in the possibility of new prostate cancer therapy that would control tumor malignancy via the induction of terminal cell differentiation. Here, we investigated the combined effect of various cAMP reagents on LNCaP human prostate carcinoma cells. Papaverine and prostaglandin E2 (PGE2), combined synergistically induced morphological changes. Electron microscope study suggested that cells treated with both reagents become like neuroendocrine cells. We then investigated the effect of both reagents on proliferation and malignancy of LNCaP cells. The malignancy of cells was analyzed by soft agar colony-forming assay and an in vitro invasion assay. Proliferation and malignancy of LNCaP cells treated with both reagents were significantly decreased in comparison to the proliferation and malignancy of untreated cells. Furthermore, the expression of oncogenes such as c-myc and Bcl-2 was suppressed in differentiated LNCaP cells. These results suggest that papaverine combined with PGE2 can synergistically induce neuronal differentiation as well as decrease the malignancy of human prostatic cancer LNCaP cells.