Halenaquinone, a novel phosphatidylinositol 3-kinase inhibitor from a marine sponge, induces apoptosis in PC12 cells

In nerve growth factor-treated PC12 cells, 12b-methyl-(S)-1H-benzo[6,7]phenanthro[10,1-bc]furan-3,6,8,11(2H,12-bH)-tetrone (halenaquinone) caused cytotoxicity in a concentration-dependent manner (EC50 value; 10 muM). Gel electrophoretic DNA analysis of PC12 cells treated with halenaquinone (10 muM) and 11-(acetyloxy)-1,6b,7,8,9a,10,11,11b-octahydro-1-(methoxymethyl)-9a,11b-dimethyl-1 1S-(1 alpha ,6 b alpha ,9 a beta ,11 alpha ,11b beta)]-3 H-furo[4,3,2-de]indeno[4,5-h]-2-benzopyran-3,6,9-trione (wortmannin) (3 muM) showed a typical apoptotic DNA ladder. In the flow cytometric analysis, halenaquinone: caused apoptosis in a concentration- and time-dependent manner (EC50 value; 10 muM), whereas 2,3-dihydro-12b-methyl-(S)-1H-benzo[6,7]phenanthro[10,1-bc]furan-6,8,11(12 bH)-trione (xestoquinone) with the methylene group at the C-3 position failed to cause apoptosis, suggesting that the carbonyl group at the C-3 position in halenaquinone is important for exerting apoptotic effects in PC12 cells. Phosphatidylinositol 3-kinase was inhibited by halenaquinone (IC50 value: 3 muM) as well as wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase. Halenaquinone inhibited phosphatidylinositol 3-kinase activity at lower concentrations than those at which it induced apoptosis in PC12 cells. These results suggest that halenaquinone causes the death of PC12 cells through an apoptotic process and that the mechanism of halenaquinone-induced apoptosis may he partially explained by the inhibition of phosphatidylinositol 3-kinase activity. (C) 2001 Elsevier Science B.V. All rights reserved.