Abstract
The structure/activity relationship of the protein kinase inhibitors, staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (ID50 of about 6.0 x 10(-8) M) as well as spontaneous and colchicine-stimulated locomotion at 10(-7) M. K 252a suppresses cell polarity (ID50 of about 4.5 x 10(-6) M) and inhibits spontaneous and colchicine-stimulated locomotion at 10(-5) M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a staurosporine derivative with a much higher specificity for protein kinase C (PKC) than staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotide-dependent protein kinases, and CGP 42700, an inactive staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.
Highlights
Human serum albumin (HSA; Behringwerke, Marburg, Germany); colchicine and glutaraldehyde (Serva, Heidelberg, Germany); phorbol 12-myristate 13-acetate
Staurosporine produced a dose-dependent suppression of cell polarity of both unstimulated tumour cells and of cells exposed to 10-5 M colchicine (Figure 2)
Several mechanisms involved in growth, differentiation and spread of tumour cells are modulated by a phosphoinositideprotein kinase C (PKC) signal transducing pathway
Summary
Human serum albumin (HSA; Behringwerke, Marburg, Germany); colchicine and glutaraldehyde (Serva, Heidelberg, Germany); phorbol 12-myristate 13-acetate (PMA; Sigma; St. Louis, MO, USA); staurosporine and K 252a (Fluka, Buchs, Switzerland); KT 5720 and KT 5822 were a kind gift from Professor H. Tokyo Research Laboratories, Kyowa Hakko Kogyo Co Ltd, Japan. Zimmermann, Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3010 Bern, Switzerland. Received 15 January 1992; and in revised form 27 July 1992
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