Inhibition of cell growth and potentiation of tumor necrosis factor-α (TNF-α)-induced apoptosis by a phenanthroindolizidine alkaloid antofine in human colon cancer cells

Abstract

Based on the potential of natural products as a source for the development of cancer chemotherapeutic agents, this study was performed to investigate the anti-proliferative and antitumor effects of antofine, a phenanthroindolizidine alkaloid derived from Cynanchum paniculatum. Antofine showed potent anti-proliferative effects in several human cancer cells with IC 50 values in the nanomolar range. Treatment with antofine for 24h did not result in the induction of apoptotic cell death but moderately induced cell cycle arrest at G0/G1 phase and inhibited the expression of cyclin D1, cyclin E, and CDK4. In addition, antofine inhibited the transcriptional activity of β-catenin/Tcf in human colon HCT 116 cells, and the expression level of β-catenin and cyclin D1 was also down-regulated by antofine in human colon SW480 cells. Moreover, antofine potentiated tumor necrosis factor-α (TNF-α)-induced apoptosis, which was demonstrated by the increase of Annexin V-positive cell population and of the cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-8. Antofine also effectively suppressed tumor growth in the HCT 116 implanted xenograft nude mouse model. Taken together, these findings suggest that antofine might be a potential candidate for the development of cancer chemotherapeutic agents derived from natural products. © 2010 Elsevier Inc.