ABSTRACT
Some hydroxamate compounds induce cancer cell death by intracellular reactive oxygen species (ROS). This study introduced the hydroxamate core into lovastatin, a fungus metabolite clinically used for the treatment of hypercholesterolemia. The resulting compounds were evaluated for the activity for inducing ROS production. Most compounds exhibited higher activity than original lovastatin. Of these compounds, compound 3c had the most potent activity. Test of cytotoxicity in a panel of human cancer cell lines indicated compound 3c had activities superior to cisplatin in prostate cancer PC-3 cells and breast cancer T47D cells. In contrast, it in amounts up to 40µM had a much lower cytotoxic effect on normal human IMR-90 cells. Further profiling of cell cycle progression, cell apoptosis, and DNA damage activated checkpoint signaling pathway revealed the important role of compound 3c-mediated cytotoxicity in ROS generation.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Lovastatin/analogs & derivatives , Lovastatin/pharmacology , Reactive Oxygen Species/metabolism , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Humans , Neoplasms/drug therapy , Neoplasms/metabolismABSTRACT
Our previous studies demonstrated that eight prenylated flavanones (1-8), isolated from Taiwanese propolis, were capable of a broad spectrum of biological activities. Among them, nymphaeol A (3), nymphaeol B (4) and nymphaeol C (7), abundant in Taiwanese propolis, exhibited cytotoxicity against cancer cell lines. It therefore seemed interesting to improve their activity via a semi-synthetic strategy. In this study, 12 novel prenylated flavanones were synthesised in our laboratory and their activities were assessed for two human prostate cancer cell lines, PC-3 and DU-145, and a human hepatoma cell line, Hep-3B. Of these compounds, 10c, 11 and 12 showed more potent cytotoxicity against the PC-3 cell line than 5-Fu. Using cytometric analysis followed by double staining with annexin V-FITC and propidium iodide, it was observed that these compounds induced apoptosis as well. This suggests that prenylated flavanones 10c, 11 and 12 may have anticancer potential for further development.
