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Inhibition of Rodent Protein Kinase C by the Anticarcinoma Agent Dequalinium¹

Institute of Cancer Research, Columbia University, New York, New York 10032 [S. A. R., M. U., R. S. K., I. B. W.], and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [S. S., L. B. C.]

Dequalinium has previously been shown to be an anticarcinoma agent (M. J. Weiss et al., Proc. Natl. Acad. Sci. USA, 84: 5444–5448, 1987). The present study demonstrates that it can inhibit protein kinase C-ß₁ isolated from an overproducing cell line with a 50% inhibitory concentration of 8–15 µM. Further examination of the inhibition by using structural analogues of dequalinium reveals that the length of the methylene bridge between the two quinaldinium moieties, the presence of the ring substituents, and the bipartite character of the compound each contributes to the inhibitory potency. Related studies show that the analogues display the same rank order of inhibitory potency when tested with the trypsingenerated catalytic fragment of the enzyme, indicating that dequalinium inhibits kinase activity through an interaction with the catalytic subunit. Further studies argue that the ability of a given analogue to inhibit phosphotransferase activity correlates with its ability to complete with [³H]phorbol-12,13-dibutyrate binding on the intact enzyme (50% inhibitory concentration of 2–5 µM). This suggests that the inhibitor is either binding directly to the regulatory subunit as well, or that due to its interaction with the catalytic subunit, dequalinium produces an indirect effect on sites defined by phorbol ester binding. Kinetic analysis revealed that inhibition is noncompetitive with respect to ATP or phosphatidylserine. Studies conducted with types I, II, and III rat brain isozymes, resolved by hydroxylapatite chromatography, demonstrate that dequalinium inhibits each of them with similar potency (50% inhibitory concentration of 11 µM) and imply that the site of contact on the enzyme is a highly conserved region. Morphology studies with dequalinium in intact cells demonstrate that the inhibitor can protect control cells against phorbol ester-induced morphology changes but cannot protect protein kinase C-overproducing cells, suggesting that an elevation in protein kinase C levels alone is sufficient to overturn the protection conferred by dequalinium. On the basis of these results, we propose that protein kinase C could be a critical in vivo target of dequalinium.

¹ This work was supported by the following grants: NIH CA 02656 (S. A. R., I. B. W.); National Research Service Award CA 08346 (R. S. K.); CA 19589-11 and CA 22427-10 (S. S., L. B. C.); M. U. was a recipient of a DAAD fellowship (Federal Republic of Germany) in the Gene Technology Program.

² To whom requests for reprints should be addressed, at Room 1020, Institute of Cancer Research, Columbia University, 701 W. 168th St., New York, NY 10032.

Received 5/19/89. Revised 9/27/89. Accepted 10/17/89.

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