Abstract
This study evaluated the potential cytotoxicity of the natural diterpenoids kauren‐19‐oic acid (KA), 14‐hydroxy‐kaurane (1) and xylopic acid (2), and semi‐synthetic derivatives of KA (3–5) towards human cancer cell lines (K562, HL60, MDA‐MB435 and SF295) and lymphocytes. Mouse erythrocytes were used to verify a possible hemolytic activity Cytotoxicity mechanisms were investigated in HL60 cells. KA showed a moderate antiproliferative effect in MTT assay towards all cancer cells (IC~50~, 9.1–14.3 µg ml^−1^). However, KA appeared not selective to cancer cells, since it also inhibited the lymphocytes proliferation (IC~50~, 12.6 µg ml^−1^). Unlike KA, compounds 1–5 displayed no cytotoxicity and were also free from antiproliferative and hemolytic effects, suggesting that the exocyclic double bond (C16) unit may be the active pharmacophore of KA cytotoxicity. KA‐treated HL60 cells displayed decreased proliferation (5‐bromo‐2';‐deoxyuridine incorporation assay) and topoisomerase I activity (DNA relaxation assay). These assays revealed that KA primarily intercalates with DNA and not with topoisomerase I. Fluorescence microscopy using AO/EB (acridine orange/ethidium bromide) staining indicated that KA can induce both apoptosis and necrosis in HL‐60 cell cultures, which corroborate the findings with MTT. From these findings, we conclude that KA, although demonstrating cytotoxic potential, may have a limited or poor therapeutic potential due to lack of selectivity to tumor cells. Further studies on the structure modification of KA and the mechanism of the new derivatives are currently in progress. Copyright © 2009 John Wiley & Sons, Ltd.