UCN-01, AN ANTITUMOR DRUG, IS A SELECTIVE INHIBITOR OF THE CONVENTIONAL PKC SUBFAMILY

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, cPKC alpha, beta and gamma, nPKC delta, epsilon and eta, and aPKC zeta. Of the PKC isozymes examined, cPKC alpha was inhibited by UCN-01 most effectively (K-i = 0.44 nM), suggesting cPKC alpha 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 aPKC zeta is 3.8 mu M. Thus, UCN-01 discriminates between PKC subfamilies. In addition, the inhibitory effects of staurosporine, H7, and calphostin C on aPKC zeta mere examined and compared with those for cPKC alpha.