Differential effects of UCN-01, staurosporine and CGP 41 251 on cell cycleprogression and CDC2 cyclin B-1 regulation in A431 cells synchronized at Mphase by nocodazole
T. Akiyama et al., Differential effects of UCN-01, staurosporine and CGP 41 251 on cell cycleprogression and CDC2 cyclin B-1 regulation in A431 cells synchronized at Mphase by nocodazole, ANTI-CANC D, 10(1), 1999, pp. 67-78
UCN-01 (7-hydroxystaurosporine) and CGP 41 251 (4'-N-benzoyl staurosporine)
, both of which were discovered as protein kinase C selective inhibitors, h
ave entered in phase 1 clinical trials as anti-cancer drugs. In this study,
we have directly compared the effects of these drugs as well as staurospor
ine (STP) on cell cycle progression of A431 human epidermoid carcinoma cell
s synchronized at M phase by treatment with nocodazole. The nocodazole-sync
hronized cells progressed from M to G(1) phase in the absence of the drug,
which was accompanied by a decrease of cyclin B-1 protein expression, disap
pearance of the complex formation of CDCS with cyclin B-1 and reduction of
the kinase activity. Treatments of the M phase cells with UCN-01, STP and C
GP 41 251 at 80% growth-inhibitory concentrations (IC(80)s) resulted in spe
cific G(1) block, G(2)M block and polyploidy, respectively. Decrease of cyc
lin B-1 protein expression was partially prevented by treatments with STP a
nd cop 41 251 but not with UCN-01 at IC(80)s. Reductions of active complex
and kinase activity of CDC2/cyclin B-1 were also observed in the presence o
f the three drugs. In addition, augmentation of CDCS protein tyrosine phosp
horylation was induced only when the cells were treated with STP. These obs
ervations demonstrated that higher concentrations of UCN-01, STP and CGP 41
251 showed different effects on cell cycle progression as well as CDC2/cyc
lin B-1 regulation in A431 cells synchronized at M phase. The data suggest
that UCN-01 and CGP 41 251 may act at quite different points on the cell cy
cle. [(C) 1999 Lippincott Williams & Wilkins.]