ANTITUMOR-ACTIVITY OF DAPHNANE-TYPE DITERPENE GNIDIMACRIN ISOLATED FROM STELLERA-CHAMAEJASME L

The daphnane-type diterpene gnidimacrin, isolated from the root of the Chinese plant, Stellera chamaejasme L., was found to strongly inhibit cell growth of human leukemias, stomach cancers and non-small cell lu ng cancers in vitro at concentrations of 10(-9) to 10(-10) M. On the o ther hand, even at 10(-6) to 10(-5) M, the small cell lung cancer cell line H69 and the hepatoma cell line HLE were refractory to gnidimacri n. The agent showed significant antitumor activity against murine leuk emias and solid tumors in an in vivo system. In K562, a sensitive huma n leukemia cell line, gnidimacrin induced blebbing of the cell surface , which was completely inhibited by staurosporine at concentrations ab ove 10(-8) M, and arrested the cell cycle transiently to G(2) and fina lly the GI phase at growth-inhibitory concentrations. It inhibited pho rbol- 12,13-dibutyrate(PDBu) binding to K562 cells and directly stimul ated protein kinase C (PKC) activity in the cells in a dose-dependent manner (3-100 nM). Although activation of PKC isolated from refractory H69 cells was observed only with 100 nM gnidimacrin, the degree of ac tivation was lower than that produced by 3 nM in K562 cells. Our resul ts suggest that gnidimacrin acts as a PKC activator for tumor cells an d that this mechanism may be responsible for its antitumor activity. ( C) 1996 Wiley-Liss, Inc.