Abstract
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.
Footnotes
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This research was supported by grants from the “Centre Anti-Cancéreux” (Liège, Belgium) and the “Fond de la Recherche Scientifique Médicale” (Belgium). M.F. is Senior Research Assistant and M.-P.M. is Research Associate from the Belgian National Fund for Scientific Research. M.B.-A. is supported by a Télévie fellowship (National Fund for Scientific Research, Belgium).
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DOI: 10.1124/jpet.102.044867
- Abbreviations:
- ISP
- isostrychnopentamine
- WST-1
- 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium
- DAPI
- 4′-6-diamidino-2-phenylindole
- PI
- propidium iodide
- PBS
- phosphate-buffered saline
- FACS
- fluorescence-activated cell sorting
- PAGE
- polyacrylamide gel electrophoresis
- PARP
- poly(ADP-ribose) polymerase
- FLUOS
- fluorescein
- Received October 1, 2002.
- Accepted November 20, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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