Searching for antitumor agents from natural sources
Sang Kook Lee
College of Pharmacy, Seoul National University
San 56-1, Sillim-dong, Gwanak-gu, Seoul 151-742, Korea
Natural products have been played major roles in drug discovery programs including development of anticancer agents. In our continuous efforts to identify and characterize antitumor agents from natural products, we found the extract of the root of Cynanchum paniculatum (Asclepiadaceae) exhibited potent anti-proliferative effects in cultured human cancer cells. Bioassay-guided fractionation further led to the isolation of the bioactive constituent and was elucidated as antofine, a phenanthroindolizidine alkaloid. Antofine markedly inhibited the growth of several human cancer cells with the IC50 values in the nanomolar range. With the potential anti-proliferative effects against cancer cells we developed the procedure of total synthesis of antofine and its derivatives for procurement of druggable candidates. The synthetic antofine analogues also showed potential growth inhibition of cancer cells in vitro and antitumor activity in vivo animal models. The mechanism of action in the antitumor activity of antofine was newly elucidated through negative regulation of Met endosomal signaling in Met-mutated Caki-1 renal cancer cells. In addition, daphnane-type diterpenoids were isolated from the flower of Daphne genkwa (Thymelaceae) with a potential anti-proliferative activity against human lung cancer cells. Yuanhuadine (YD), one of the most potent isolates from D. genkwa, showed a potent growth inhibition and a relatively strong selectivity against human lung cancer cells. YD also exhibited a potential antitumor activity in acquired gefitinib-resistant non-small cell lung cancer (NSCLC) cells in vitro and in vivo. One plausible mechanism of action in the overcome of EGFR TKI-resistance by YD was newly identified with the down-regulation of AXL and acceleration of AXL degradation. This presentation will highlight the findings of biologically active natural products associated with the antitumor activity and elucidation of the mechanism of action with the bioactive compounds.
