PROTEIN-KINASE-C INHIBITORS SUPPRESS CELL-GROWTH IN ESTABLISHED AND LOW-PASSAGE GLIOMA CELL-LINES - A COMPARISON BETWEEN STAUROSPORINE AND TAMOXIFEN

WE HAVE PREVIOUSLY demonstrated that the proliferation of established human glioma cell lines correlated with protein kinase C (PKC) activit y and that a relatively selective PKC inhibitor, staurosporine, inhibi ts glioma cell proliferation. The purpose of this study was to determi ne whether low-passage glioma cell lines were also sensitive to stauro sporine and to compare the antimitotic effects of staurosporine with t amoxifen, an antiestrogen with a known PKC inhibitory effect presently being investigated in the treatment of recurrent glioma. We measured the effects of treatment with staurosporine or tamoxifen on the prolif eration rate of five established glioma cell lines (A172, U251, U87, U 373, U563) and four low-passage glioma cell lines. The proliferation o f all cell lines was inhibited by staurosporine, at an IC50 value (con centration at which activity is 50% inhibited) of approximately 2 nmol /L. All established lines, but only one low-passage line, were suscept ible to tamoxifen, with an IC50 value of 10 mumol/L. Three of the four low-passage lines were poorly inhibited by tamoxifen. The IC50 values for the inhibition of cellular proliferation by staurosporine and tam oxifen closely corresponds to the IC50 data for the inhibition of part iculate PKC activity in gliomas. We conclude that staurosporine is mor e effective in the inhibition of glioma proliferation than tamoxifen a nd that staurosporine is potentially useful in the adjuvant treatment of gliomas. The correspondence in IC50 results for proliferation and P KC activity further strengthens the hypothesis that an aberrant PKC sy stem in gliomas drives their hyperproliferative state.