Anti-proliferative effect of the kinase inhibitor K252a on human prostatic
carcinoma cell lines.
Delsite R, Djakiew D.
Department of Cell Biology, Georgetown University, Washington, DC., USA.
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.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Cheap Reseller Hosting 
