UCN-01, an anti-tumor 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 a PKC zeta. Of the PKC isozymes examined, cPKC alpha was inhibited by UCN-01 most effectively (Ki = 0.44 nM), suggesting cPKC alpha is the prime candidate for the physiological target of UCN-01. The Ki values of UCN-01 estimated from Dixon plots for cPKC isozymes are approximately 1 nM, whereas the Ki values for nPKC isozymes are about 20 nM. Moreover, the Ki value for aPKC zeta is 3.8 microM. Thus, UCN-01 discriminates between PKC subfamilies. In addition, the inhibitory effects of staurosporine, H7, and calphostin C on aPKC zeta were examined and compared with those for cPKC alpha.
Mizuno
K
K
Department of Molecular Biology, Yokohama City University School of Medicine, Japan.
Noda
K
K
Ueda
Y
Y
Hanaki
H
H
Saido
T C
TC
Ikuta
T
T
Kuroki
T
T
Tamaoki
T
T
Hirai
S
S
Osada
S
S
D000470:Alkaloids / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001921:Brain / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D019311:Staurosporine / Q000031:analogs & derivatives
D000470:Alkaloids; D000970:Antineoplastic Agents; D007527:Isoenzymes; D011994:Recombinant Proteins; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine