Cm. Seynaeve et al., CELL-CYCLE ARREST AND GROWTH-INHIBITION BY THE PROTEIN-KINASE ANTAGONIST UCN-01 IN HUMAN BREAST-CARCINOMA CELLS, Cancer research, 53(9), 1993, pp. 2081-2086
UCN-01 is a derivative of staurosporine, initially developed as a pote
ntially selective inhibitor of the Ca2+- and phospholipid-dependent pr
otein kinase C, but with the capacity to inhibit a number of tyrosine
and serine/threonine kinases. UCN-01 inhibits the growth of 5 breast c
arcinoma cell lines with a 50% inhibitory concentration range of 30-10
0 nM during 6 days of continuous exposure. In MCF-7, MDA-MB453, and SK
-BR-3 cells, UCN-01 is 5-fold more potent in growth inhibition than it
s diastereomer UCN-02, but the 2 compounds are equipotent in the inhib
ition of MDA-MB468 and H85787 cell growth. A differential sensitivity
to a 24-h period of exposure to UCN-01 followed by drug removal and gr
owth for 5 subsequent days was observed. The rank order for persistent
inhibition of cells by UCN-01 was MCF-7, MDA-MB453 >> SK-BR-3 > H8578
7 > MDA-MB468. MCF-7 and MDA-MB453 cells did not resume proliferation
within the 5 days after brief exposure to UCN-01. In contrast, MDA-MB4
68 and H85787 cells showed no net growth inhibition after a 24-h pulse
of UCN-01, followed by 5 more days of growth in drug-free medium. In
MDA-MB468 cells, 150 nm UCN-01 retards but does not prevent cell cycle
progression through S phase, but the cells are clearly blocked from e
xit of G1 and entry into S. Progression through S phase is completely
inhibited by 600 nm UCN-01. The development of a G1 to S block by UCN-
01 in MDA-MB468 cells occurs in conjunction with inhibition of [P-32]o
rthophosphate labeling and decreased phosphotyrosine mass of discrete
cellular phosphoproteins.