Members of the K252 family of
kinase inhibitors have been demonstrated to inhibit a number of
neurotrophin-mediated cellular responses, and to preferentially inhibit the activity of
neurotrophin receptors. In this study, we examined the effects of
K252a and K252b on the growth of human prostate
carcinoma cells, whose growth is, in part, mediated by a prostatic
nerve growth factor(
NGF)-like
protein(s).
K252a inhibited [3H]
thymidine incorporation by three
androgen-independent prostate tumor cell lines (TSU-pr1, DU-145, and PC-3), under basal growth conditions, and in response to growth stimulation by human prostatic stromal (hPS) cell
proteins and serum. K252b, which does not readily penetrate cell membranes, had no significant effect on [3H]
thymidine incorporation by the prostate tumor cell lines. The decrease in [3H]
thymidine incorporation by the cell lines in response to
K252a did not appear to be the result of
K252a cytotoxicity at concentrations as high as 100 nM, as measured by the
Trypan blue assay for cell viability. Treatment of cells for 25 hours with 100 nM
K252a resulted in accumulation of TSU-pr1, DU-145, and PC-3 cells in G0/G1, concurrent with a substantial decrease in cells synthesizing
DNA. Treatment of
androgen-responsive LNCaP prostatic
carcinoma cells for 25 hours with 100 nM
K252a also resulted in a significant decrease in
DNA synthesis. Human recombinant
NGF-mediated phosphorylation of a 140-kDa Trk
NGF receptor in the TSU-pr1 cell line was inhibited by treatment with 100 nM
K252a. Hence,
K252a inhibition of Trk phosphorylation most probably contributed, in part, to the inhibition of prostate
tumor cell growth in vitro. These results suggest that the mechanism of
K252a action may be useful in the design of potential
therapies for
prostate cancer treatment.