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 gliomas may result from activation of protein kinase C (PKC)-mediated pathways; conversely, inhibition of PKC may provide a strategy for blocking tumor growth. In the current studies, we examined the effect of a novel PKC inhibitor, calphostin C, which is a selective, highly potent, photo-activatable inhibitor of the PKC regulatory domain, on the proliferation and viability of three established and three low-passage malignant glioma cell lines, four low-passage low-grade glioma cell lines, and in adult human and neonatal rat non-neoplastic astrocyte cell lines in vitro. Under light-treated conditions, calphostin C consistently inhibited cell proliferation in each of the tumor cell lines and in the 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 previously 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 decreased sharply with calphostin C concentrations of 100 to 300 ng/ml (125 to 380 nM). In contrast, under light-shielded conditions, calphostin C had a comparatively modest effect on cell proliferation and viability, with a median effective concentration of approximately 300 ng/ml. No significant inhibition of proliferation was noted in the non-neoplastic adult astrocyte cell line under either light-treated or light-shielded 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 proliferation of non-neoplastic immature astrocytes. Light-sensitive inhibition of proliferation and viability by agents such as calphostin C may provide a novel strategy for applying photodynamic therapy to the treatment of neoplastic glial cells.
Pollack
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Department of Neurosurgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Kawecki
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D000818:Animals; D000903:Antibiotics, Antineoplastic; D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D009281:Naphthalenes; D011493:Protein Kinase C; C058819:calphostin C