UCN-01, an anti-tumor drug, is a selective inhibitor of the conventional PKC subfamily

Abstract

A selective PKC inhibitor, UCN-01, was shown to exhibit anti-tumor activity in vitro and in vivo. We investigated UCN-01 with respect to isozyme-specific PKC inhibition using purified recombinant or rabbit brain PKC isozymes, cPKCα, β and γ, nPKCδ, ϵ and ν, and aPKCζ. Of the PKC isozymes examined, cPKCα was inhibited by UCN-01 most effectively ( K i = 0.44 nM), suggesting cPKCα is the prime candidate for the physiological target of UCN-01. The K i values of UCN-01 estimated from Dixon plots for cPKC isozymes are approximately 1 nM, whereas the K i values for nPKC isozymes are about 20 nM. Moreover, the K i value for aPKCζ is 3.8 μM. Thus, UCN-01 discriminates between PKC subfamilies. In addition, the inhibitory effects of staurosporine, H7, and calphostin C on aPKCζ were examined and compared with those for cPKCα.