Vol. 304, Issue 3, 1103-1110, March 2003

Isostrychnopentamine, an Indolomonoterpenic Alkaloid from Strychnos usambarensis, Induces Cell Cycle Arrest and Apoptosis in Human Colon Cancer Cells

Michel Frédérich, Mohamed Bentires-Alj, Monique Tits, Luc Angenot, Roland Greimers, Jacques Gielen, Vincent Bours and Marie-Paule Merville

Natural and Synthetic Drug Research Center, Laboratory of Pharmacognosy and Structural Chemistry (M.F., M.T., L.A.); Center for Molecular and Cellular Therapy, Laboratory of Medical Chemistry and Medical Oncology (M.B.-A., J.G., V.B., M.-P.M.); and Laboratory of Cell Pathology, Institute of Pathology (R.G.), University of Liège, Liège, Belgium

Isostrychnopentamine (ISP) is an indolomonoterpenic alkaloid that is present in the leaves of Strychnos usambarensis, a well known African shrub or little tree. The roots contain quaternary alkaloids, which are used to make a curare-like arrow poison. However, tertiary alkaloids isolated from the same plant possess cytotoxic activities against mammalian cells and protozoa. The effect of ISP has been investigated on the growth and viability of HCT-116 colon cancer cells during their exponentially growing phase. ISP induced apoptotic cell death as shown by the translocation of phosphatidylserine from the inner layer to the outer layer of the plasma membrane, chromatin condensation, DNA fragmentation, and caspase-3 and -9 activation. ISP provoked also cell cycle arrest in the G₂-M phase. We also showed that the expression of p53 was not modified in ISP-treated cells, but that p21 was induced in a p53-independent manner. Finally, we demonstrated that ISP did not affect the catalytic activity of human topoisomerases I and II. In conclusion, ISP, which promotes cell death by a p53-independent apoptotic pathway, could be an interesting lead for cancer chemotherapy.