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.
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.
Min
Hye-Young
HY
Ewha Womans University, Seoul, Republic of Korea.
Chung
Hwa-Jin
HJ
Kim
Eun-Hye
EH
Kim
Sanghee
S
Park
Eun-Jung
EJ
Lee
Sang Kook
SK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019938:Cyclin D1 / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010618:Phenanthrolines / Q000494:pharmacology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051153:Wnt Proteins / Q000502:physiology
D007211:Indoles; D010618:Phenanthrolines; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; C473343:antofine; D019938:Cyclin D1