Flavaglines: a group of efficient growth inhibitors block cell cycle progression and induce apoptosis in colorectal cancer cells.
Flavaglines are flavonol-cinnamate-derived cyclopenta[b]benzofurans, so far reported only for the genus Aglaia of the plant family Meliaceae. They represent a group of highly bioactive metabolites already known for their strong antileukemic activities. To assess their suitability as chemotherapeutic drugs in colorectal cancer, their cytostatic effects and the underlying mechanisms of action were analyzed in colorectal tumor cell lines. Aglaiastatin was the most active flavagline, inhibiting growth and inducing apoptosis at nanomolar concentrations in SW480 and HT29/HI1 carcinoma cells, while the premalignant adenoma cell lines VACO235 and LT97 as well as the normal intestinal epithelial cell line IEC18 were 1,000 times less sensitive (IC50>10 microM). In SW480 cells, aglaiastatin caused cell cycle block in early mitosis, demonstrated by a shift of cell cycle distribution 24 and 48 hr after addition of aglaiastatin and by an increased content of cyclin B after 6 hr together with a decreased level of cyclin A as early as 2 hr after exposure. In addition, induction of apoptosis could be shown by the characteristic morphology of apoptotic nuclei, loss of MMP and downmodulation of bcl(xl). Strong activation of p38 was observed after 2 hr of exposure, indicating that apoptosis may be induced via a p38-mediated stress pathway.
Hausott
Barbara
B
Institute of Cancer Research, University of Vienna, Vienna, Austria.
Greger
Harald
H
Marian
Brigitte
B
D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004847:Epithelial Cells / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D029582:Meliaceae / Q000737:chemistry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D051020:bcl-X Protein; D048051:p38 Mitogen-Activated Protein Kinases
C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D001572:Benzofurans; D006131:Growth Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases