Comparison of ability of protein kinase c inhibitors to arrest cell growth and to alter cellular protein kinase c localisation

ABSTRACT Inhibitors of protein kinase C (PKC) such as the staurosporine analogues UCN-01 and CGP 41251 possess antineoplastic properties, but the mechanism of their cytostatic action is not

understood. We tested the hypothesis that the ability of these compounds to arrest growth is intrinsically linked with their propensity to inhibit PKC. Compounds with varying degrees of

potency and specificity for PKC were investigated in A549 and MCF-7 carcinoma cells. When the log values of drug concentration which arrested cell growth by 50% (IC50) were plotted against

the logs of the IC50 values for inhibition of cytosolic PKC activity, two groups of compound could be distinguished. The group which comprised the more potent inhibitors of enzyme activity

(calphostin C, staurosporine and its analogues UCN-01, RO 31-8220, CGP 41251) were the stronger growth inhibitors, whereas the weaker enzyme inhibitors (trimethylsphingosine, miltefosine,

NPC-15437, H-7, H-7I) affected proliferation less potently. GF 109203X was exceptional in that it inhibited PKC with an IC50 in the 10(-8) M range, yet was only weakly cytostatic. To

substantiate the role of PKC in the growth inhibition caused by these agents, cells were depleted of PKC by incubation with bryostatin 1 (1 microM). The susceptibility of these

enzyme-depleted cells towards growth arrest induced by staurosporine, RO 31-8220, UCN-01 or H-7 was studied. The drug concentrations which inhibited incorporation of [3H]thymidine into

PKC-depleted A549 cells by 50% were slightly, but not significantly, lower than significantly, lower than those observed in control cells. These results suggest that PKC is unlikely to play

a direct role in the arrest of the growth of A549 and MCF-7 cells mediated by these agents. Staurosporine is not only a strong inhibitor of PKC but also mimics activators of this enzyme in

that it elicits the cellular redistribution of certain PKC isoenzymes. The ability of kinase inhibitors other than staurosporine to exert a similar effect was investigated. Calphostin C,

H-7, H-7I, miltefosine, staurosporine, UCN-01, RO 31-8220, CGP 41251 or GF 109203X were incubated for 30 min with A549 cells in the absence or presence of the PKC activator

12-O-tetradecanoyl phorbol-13-acetate. The subcellular distribution of PKC-alpha-, -epsilon and -zeta was measured by Western blot analysis. None of the agents affected PKC-alpha or

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Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS MARINE ALKALOID MONANCHOXYMYCALIN C: A NEW SPECIFIC ACTIVATOR OF JNK1/2 KINASE WITH ANTICANCER PROPERTIES

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INFORMATION AUTHORS AND AFFILIATIONS * Medical Research Council Toxicology Unit, University of Leicester, UK C Courage Authors * C Courage View author publications You can also search for

this author inPubMed Google Scholar * J Budworth View author publications You can also search for this author inPubMed Google Scholar * A Gescher View author publications You can also search

for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Courage, C., Budworth, J. & Gescher, A. Comparison of

ability of protein kinase C inhibitors to arrest cell growth and to alter cellular protein kinase C localisation. _Br J Cancer_ 71, 697–704 (1995). https://doi.org/10.1038/bjc.1995.137

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