Isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambarensis, induces cell cycle arrest and apoptosis in human colon cancer cells.
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 G(2)-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.
Frédérich
Michel
M
Natural and Synthetic Drug Research Center, Laboratory of Pharmacognosy and Structural Chemistry, University of Liège, Liège, Belgium. m.frederich@ulg.ac.be
Bentires-Alj
Mohamed
M
Tits
Monique
M
Angenot
Luc
L
Greimers
Roland
R
Gielen
Jacques
J
Bours
Vincent
V
Merville
Marie-Paule
MP
D000470:Alkaloids / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002243:Carbolines / Q000494:pharmacology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000032:analysis; D002453:Cell Cycle / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology; D003574:Cytochrome c Group / Q000032:analysis; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D006801:Humans; D031451:Strychnos / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000470:Alkaloids; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D002243:Carbolines; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003574:Cytochrome c Group; D016159:Tumor Suppressor Protein p53; C473210:isostrychnopentamine; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II