THE EFFECT OF CALPHOSTIN-C, A POTENT PHOTODEPENDENT PROTEIN-KINASE-C INHIBITOR ON THE PROLIFERATION OF GLIOMA-CELLS IN-VITRO

Recent studies have suggested that the proliferation of malignant glio mas may result from activation of protein kinase C (PKC)-mediated path ways; conversely, inhibition of PKC may provide a strategy for blockin g tumor growth. In the current studies, we examined the effect of a no vel PKC inhibitor, calphostin C, which is a selective, highly potent, photo-activatable inhibitor of the PKC regulatory domain, on the proli feration and viability of three established and three low-passage mali gnant glioma cell lines, four low-passage low-grade glioma cell lines, and in adult human and neonatal rat non-neoplastic astrocyte cell lin es in vitro. Under light-treated conditions, calphostin C consistently inhibited cell proliferation in each of the tumor cell lines and in t he neonatal rat astrocyte cell line with a 50% effective concentration of 30 to 50 ng/ml (40 to 60 nm), which was comparable to the previous ly reported median inhibitory concentration (IC50) for PKC inhibition by calphostin C. Complete elimination of proliferation was achieved at concentrations of 50 to 100 ng/ml (60 to 125 nM). Cell viability decr eased sharply with calphostin C concentrations of 100 to 300 ng/ml (12 5 to 380 nM). In contrast, under light-shielded conditions, calphostin C had a comparatively modest effect on cell proliferation and viabili ty, with a median effective concentration of approximately 300 ng/ml. No significant inhibition of proliferation was noted in the non-neopla stic adult astrocyte cell line under either light-treated or light-shi elded conditions. These findings provide further evidence that PKC may play an essential role in mediating the proliferation of both benign and malignant glioma cells in vitro and may also contribute to the pro liferation of non-neoplastic immature astrocytes. Light-sensitive inhi bition of proliferation and viability by agents such as calphostin C m ay provide a novel strategy for applying photodynamic therapy to the t reatment of neoplastic glial cells.