Natural products have served as an important source for developing novel therapeutic agents. On the anticancer therapy, plant-derived principles, such as paclitaxel, vinblastine, and camptothecin, play important roles as potent therapeutic agents and good lead compounds for the development of more effective drugs. Thus, it may be valuable to discover novel active principles from natural products and elucidate their mechanisms of action. In our previous study, by bioassay-guided fractionation, we isolated a phenantoindolizidine alkaloid antofine from Cynanchum paniculatum (Asclepiadaceae) as one of potent growth-inhibitory principles against human cancer cells. Prompted to the potent growth-inhibitory activity of antofine, we further synthesized and evaluated the growth-inhibitory and antitumor effects of antofine using in vitro and in vivo experimental systems. Antofine exhibited potent anti-proliferative effects against several human cancer cells with the IC50 values of ∼10 nM. In HCT 116 human colon cancer cells, antofine showed the most potent growth-inhibitory effect among tested human cancer cells (IC50 = 6.0 nM). Cell cycle analysis showed that antofine neither induced apoptotic cell death nor markedly arrested any specific phases of the cell cycle. Western blot analysis demonstrated that antofine moderately inhibited the expression of cyclin A, cyclin B1, and c-myc, and interestingly, down-regulated basal expression of p53 and p21 in a time- and dose-dependent manner. These data suggested that the anti-proliferative effect of antofine might be partially mediated by modulation of these biomarkers. In addition, in in vivo tumor xenograft model bearing HCT 116 cells, antofine (8 mg/kg) markedly suppressed tumor growth compared to vehicle-treated control groups, indicating that antofine may be considered to possess antitumor potential. Taken together, these findings suggest that antofine might be a novel candidate for developing cancer chemotherapeutic agents derived from natural products.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]