CYTOSTATIC MECHANISM AND ANTITUMOR POTENTIAL OF NOVEL 1H-CYCLOPENTA[B]BENZOFURAN LIGNANS ISOLATED FROM AGLAIA-ELLIPTICA

A total of five 1H-cyclopenta[b]benzofuran lignans (1-5) isolated from the stems of Aglaia elliptica Bl. (Meliaceae) inhibited the growth of human cancer cells in culture. Of particular note, the IC50 values ob served with 1 (methyl rocaglate), 2 (4'-demethoxy-3',4'-methylenedioxy -methyl rocaglate) and 5 -O-formyl-4'-demethoxy-3',4'-methylenedioxy-m ethyl rocaglate) were in the 1-30 ng/ml range. Prompted by the high po tency of these responses, additional studies were performed with 2, a structurally representative isolate that was available in sufficient q uantity as a result of the isolation process. Utilizing cultured Lu1 ( human lung carcinoma) cells as a model, compound 2 induced accumulatio n in the G(1)/G(0) phase of the cell cycle after 24 or 32 h of incubat ion; normal cell-cycle dynamics were observed at subsequent time perio ds. Cell proliferation was inhibited in a dose-dependent manner, but d uring the course of wash-out experiments, colony formation was not red uced. In addition, as judged by [H-3]leucine incorporation, the test c ompound strongly inhibited protein biosynthesis (IC50 = 25 ng/ml). In analogous studies, nucleic acid biosynthesis was not reduced, even whe n cells were treated with concentrations as high as 1 mu g/ml. These d ata suggest inhibition of protein synthesis is a key mode of action, a nd the compound functions by a cytostatic mechanism. Utilizing a human breast cancer cell line (BC1) sensitive to compound 2 in culture (IC5 0 = 0.9 ng/ml), an initial assessment of antitumor potential was perfo rmed. In accord with the in vitro results, the growth of BCl in athymi c mice was delayed by treatment with compound 2 (10 mg/kg body weight, three times per week, i.p.). Body weight was unaffected and no signs of overt toxicity were observed. However, growth paralleled that of th e control group at later time points. Thus, novel 1H-cyclopenta[b]benz ofuran lignans are patent cytostatic inhibitors of protein biosynthesi s and are capable of delaying tumor growth in an in vivo model. Their full clinical or basic utility requires further investigation. (C) 199 8 Elsevier Science Ireland Ltd. All rights reserved.