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Indolocarbazole compounds have been reported to exert antitumor activity against human and murine tumor cell lines in vitro and/or in v/vo1~13). These compoundsare thought to be divided into two major groups, i.e. protein kinase inhibitors and topoisomerase inhibitors7). The former includes natural compounds such as staurosporine1}, K252a2) and UCN-013~5) as well as chemically synthesized derivatives of the natural compounds2'6'1 1}. The latter includes natural compounds such as rebeccamycin8), AT24339) and several derivatives of the natural compounds which did not exert the apparent inhibitory activities against protein kinases7'10~ 12). Recent studies showed that staurosporine and K-252a exhibited a unique effect on the cell cycle distribution of mammalian cells13~17). At lower concentrations, for example, they induced a Gl (or Gl/S) phase accumulation in the cell cycle in a reversible manner, however, at higher concentrations, they exhibited a block of the cell cycle at G2M phase13~ 17). In addition, staurosporine16) and/or K-252a15) induced a higher DNAploidy in some types of cells. However, at least to our knowledge, there have been few studies comparing the cell cycle effects of indojocarbazole compoundsin relation to their different biological effects. In this study, we compared the effects of non-selective protein kinase inhibitors (staurosporine1'^ and K-252a2'7)), protein kinase C (PKC) selective inhibitors (UCN-013 ~ 5) and CGP 41 2516)), and topoisomerase I inhibitors (the derivatives of K-252a, KT6124, KT6006 and KT652812)) on the cell cycle distribution of ras-transformed rat 3Y1 cells, HR-3Y115'18). This cell line was selected for this study because 1) it was reported that K-252a had induced DNAhigher ploidy in this cell line more effectively than in other cell lines15) and 2) it was suggested that nzs-activated tumor cell lines might be a target for PKCinhibitors such as UCN-015). The chemical structures of all the compounds used in this study are shown in Fig. 1. The inhibitory activities of these indolocarbazole

Diverse effects of indolocarbazole compounds on the cell cycle progression of ras-transformed rat fibroblast cells.