UCN-01 (7-hydroxystaurosporine) and other indolocarbazole compounds: a new generation of anti-cancer agents for the new century?
UCN-01 (7-hydroxystaurosporine) is a protein kinase inhibitor which is under development as an anti-cancer agent in the USA and Japan. Although UCN-01 was originally isolated from the culture broth of Streptomyces sp. as a protein kinase C-selective inhibitor, its ultimate target as an anti-cancer agent remains elusive. As a single agent, UCN-01 exhibits two key biochemical effects, namely accumulation of cells in the G1 phase of the cell cycle and induction of apoptosis. Both these effects may be important for its anti-cancer activity. As a modulator, UCN-01 enhances the cytotoxicity of other anti-cancer drugs such as DNA-damaging agents and anti-metabolite drugs through putative abrogation of G2 and/or S phase accumulation induced by these anti-cancer agents. Currently, in addition to UCN-01, four other indolocarbazole anti-cancer drugs-two protein kinase inhibitors, CGP 41251, CEP-751, and two DNA-damaging agents, NB-506 and a Rebeccamycin analog-are undergoing clinical investigations in the USA, Europe or Japan. In this review, we would like to address the differences and similarities of these indolocarbazole compounds as anti-cancer agents with regard to their mechanism(s) of action, the effects on cell cycle progression, induction of apoptosis and modulation of drug sensitivity.
Akinaga
S
S
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd, Sunto-gun, Shizuoka, Japan. shiro.akinaga@kyowa.co.jp
Sugiyama
K
K
Akiyama
T
T
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D019311:Staurosporine / Q000031:analogs & derivatives
D000470:Alkaloids; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C054852:7-hydroxystaurosporine; D019311:Staurosporine