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4 PKC Inhibition Promotes Apoptosis Granulocyte macrophage colony-stimulating factor or interleukin-3 suppressed apoptosis in hemopoietic ceils. H-7, staurosporine, and sphingosine reverted this suppression of apoptosis. , 1992). , 1990). , 1994). Expression of v-abl prevented apoptosis in a haemopoietic cell line. Calphostin C restored apoptosis. , 1995). , 1996a). GFI09203X reverted the suppression of apoptosis mediated by IL-2 or IL-2 plus dexarnethasone in murine T-cells. The use of TPA allowed a bypass of the IL-2/IL-2R interaction in the sup- 28 J.
1991). The PKC activators TPA and DAG increased the activity as well as the levels of PGP in several cell lines derived from leukemias and solid tumors. The increase was observed at the mRNA and protein level and was suppressed by staurosporine (Chaudhary and Roninson, 1992). , 1999). Cells exposed to 100 nM of TPA for one hour were approximately 3-fold more resistant to adriamycin than cells exposed to adriamycine alone. The PKC inhibitor H-7 completely blocked the TPA-induced effect, but did not reverse the MDR phenotype.
PKCct, ~, y, r and 0, but not 8, ~, ~ and ~. were found to coimmunoprecipitate with PGP. These studies indicated that 48 J. Hofmann PGP closely interacts with PKC and serves as a substrate. , 1996). , 1992). , 1994). Several phorbol esters sensitized MCF-7/ADR cells to PGP substrate drugs. However, there was no correlation with activation of PKC and the sensitization was not antagonized by staurosporine. Mezerein, K-252a and H-89 sensitized MCF-7/ADR cells, increased intraceUular accumulation of [3H]vinblastine and antagonized photolabeling of PGP by [3H]azidopine.