Protein kinase C inhibitors augment tumor-necrosis-factor-induced apoptosis in normal human diploid cells.

Abstract

In this report we show augmentation of tumor necrosis factor (TNF)-induced apoptosis by protein kinase C (PKC) inhibitors in human embryonic lung fibroblast (HEL) cells. Staurosporine (STS) reportedly potentiates TNF-mediated cytotoxicity in cancer cell lines via inhibition of PKC. We investigated whether STS or another potent PKC inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), augmented TNF-induced apoptosis in normal human diploid cells and examined the effects of the PKC inhibitors on the expression of endogenous TNF (enTNF) and manganous superoxide dismutase (MnSOD) as possible cell resistance factors opposing TNF-induced apoptosis. Both PKC inhibitors augmented TNF-mediated DNA fragmentation in HEL cells, which are normally TNF resistant and constitutively express high amounts of enTNF and MnSOD activity. Neither the number nor the affinity of TNF receptors were altered by STS and H7. The expression of enTNF and MnSOD was suppressed by the presence of STS or H7 along with TNF. The results indicate that PKC inhibitors augment TNF-induced apoptosis not only in tumor cells but also in normal cells by inhibitory effects on cellular resistance factors such as enTNF and MnSOD.