Diterpenes From Xylopia Langsdorffiana Inhibit Cell Growth And Induce Differentiation In Human Leukemia Cells

Two new diterpenes were isolated from stems and leaves of Xylopia langsdorffiana, entatisane-7α,16α-diol (xylodiol) and ent-7α-acetoxytrachyloban-18-oic acid (trachylobane), along with the known 8(17),12E,14-labdatrien-18-oic acid (labdane). We investigated their antitumour effects on HL60, U937 and K562 human leukemia cell lines. We found that xylodiol was the most potent diterpene in inhibiting cell proliferation of HL60, U937 and K562 cells, with mean IC 50 values of 90, 80 and 50 μM, respectively. Based on the nitroblue tetrazolium (NBT) reduction assay, all the diterpenes were found to induce terminal differentiation in HL60 and K562 cells, with xylodiol being the most effective. NBT reduction was increased by almost 120% after 12 h exposure of HL60 cells to xylodiol at a concentration lower than the IC 50 (50 μM). Thus, xylodiol inhibited human leukemia cell growth in vitro partly by inducing cell differentiation, and merits further studies to examine its mechanism of action as a potential antitumoural agent. © 2009 Verlag der Zeitschrift für Naturforschung, Tübingen.649-10650656Denizot, F., Lang, R., Rapid colorimetric assay for cell growth and survival, modifications to the tetrazolium dye procedure giving improved sensitivity and reliability (1986) J. Immunol. Methods, 89, pp. 271-277Dimas, K., Demetzos, C., Vãos, V., Ioannidis, P., Trangas, T., Labdane type diterpenes down-regulate the expression of c-Myc protein, but not of Bcl2, in human leukemia T-cells undergoing apoptosis (2001) Leukemia Res, 25, pp. 449-454Faulkner, D.F., Lebby, V., Waterman, P.G., Further diterpenes from stem bark of Xylopia aethiopica (1985) Planta Med, 4, pp. 354-355Graikou, K., Aligiannis, N., Skaltsounis, A.L., Chinou, I., Michel, S., Tillequin, F., Litaudon, M., New diterpenes from Croton insularis (2004) J. Nat. Prod, 67, pp. 685-688Jiang, H., Lin, J., Fisher, P.B., A molecular definition of terminal cell differentiation in human melanoma cells (1994) Mol. Cell Differ, 2, pp. 221-239Kohroki, J., Muto, N., Tanaka, T., Itoh, N., Inada, A., Tanaka, K., Induction of differentiation and apoptosis by dithizone in human myeloid leukemia cell lines (1998) Leukemia Res, 22, pp. 405-412Kondoh, M., Suzuki, I., Sato, M., Nagashima, F., Simizu, S., Harada, M., Fujii, M., Watanabe, Y., Kaurene diterpene induces apoptosis in human leukemia cells partly through a caspase-8-dependent pathway (2004) J. Pharmacol. Exp. Ther, 311, pp. 115-122Leszczyniecka, M., Roberts, T., Dent, P., Grant, S., Fisher, P.B., Differentiation therapy of human cancer: Basic science and clinical applications (2001) Pharmacol. Ther, 90, pp. 105-156Li, W.-X., Cui, C.-B., Cai, B., Yao, X.-S., Labdane-type diterpenes as new cell cycle inhibitors and apoptosis inducers from Vitex trifolia L (2005) J. Asian Nat. Prod. Res, 7, pp. 95-105Maas, P.J.M., Kamer, H.M.V., Junikka, L., Silva, R.M., Rainer, H., Annonnaceae from centraleastern Brazil (2001) Rodriguésia, 80, pp. 65-98Morais, M.P.L., Roque, N.F., Diterpenes from the fruits of Xylopia aromatica (1988) Phytochemistry, 27, pp. 3205-3208Newman, D.J., Cragg, G.M., Snader, K.M., Natural products as sources of new drugs over the period 1981-2002 (2003) J. Nat. Prod, 66, pp. 1022-1037Oliveira, A.P., Furtado, F.F., Silva, M.S., Tavares, J.F., Mafra, R.A., Araújo, D.A.M., Cruz, J.S., Medeiros, I.A., Calcium channel blockade as a target for the cardiovascular effects induced by the 8(17),12E,14-labdatrien-18-oic acid (labdane-302) (2006) Vasc. Pharmacol, 44, pp. 338-344Perry, N.B., Burgess, E.J., Baek, S.-H., Weavers, R.T., The first atisane diterpenoids from a liverwort: Polyols from Lepidolaena clavigera (2001) Org. Lett, 3, pp. 4243-4245Sun, I.C., Kashiwada, Y., Morris-Natschke, S.L., Lee, K.H., Plant-derived terpenoids and analogues as anti-HIV agents (2003) Curr. Top. Med. Chem, 3, pp. 155-169Tavares, J.F., Queiroga, K.F., Silva, M.V.B., Diniz, M.F.F.M., Barbosa-Filho, J.M., Da-Cunha, E.V.L., Simone, C.A., Silva, M.S., Ent-Trachylobane diterpenoids from Xylopia langsdorffiana (2006) J. Nat. Prod, 69, pp. 960-962Tavares, J.F., Silva, M.V.B., Queiroga, K.F., Diniz, M.F.F.M., Barbosa-Filho, J.M., Haun, M., Melo, P.S., Silva, M.S., Xylodiol, a new atisane diterpenoid from Xylopia langsdorffiana St.-Hil. & Tul. (Annonaceae) (2007) Z. Naturforsch, 62 c, pp. 742-74