Effects of analogs of indole-3-carbinol cyclic trimerization product in human breast cancer cells

5,6,11,12,17,18-Hexahydrocyclonona[1,2- b:4,5- b*:7,8- b**]triindole (CTr) is a major digestive product of indole-3-carbinol (I3C) from Brassica vegetables and exhibits strong estrogenic activities. CTr increases proliferation of estrogen-dependent breast tumor cells, binds with strong affinity for...

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Veröffentlicht in:Chemico-biological interactions 2005-04, Vol.152 (2), p.119-129
Hauptverfasser: Xue, Ling, Schaldach, Charlene M., Janosik, Tomasz, Bergman, Jan, Bjeldanes, Leonard F.
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Sprache:eng
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Zusammenfassung:5,6,11,12,17,18-Hexahydrocyclonona[1,2- b:4,5- b*:7,8- b**]triindole (CTr) is a major digestive product of indole-3-carbinol (I3C) from Brassica vegetables and exhibits strong estrogenic activities. CTr increases proliferation of estrogen-dependent breast tumor cells, binds with strong affinity for the estrogen receptor-alpha (ERα), and activates expression of estrogen (E 2)-dependent genes. To begin to examine the structural features that determine the biological activity of CTr, we prepared and studied the effects of two analogs, 9,18-dihydro-12 H-[1,2,5]trithionino[3,4- b:6,7- b*:9,8- b**]triindole (S 3CTr) and 5,6,11,12,17,18-hexahydro-5,11,17-trimethylcyclonona[1,2- b:4,5- b*:7,8- b**]triindole (Me 3CTr). N-Methylation of CTr completely ablated the estrogenic activities of CTr. In the dose range in which CTr was clearly estrogenic, Me 3CTr exhibited no detectable effect on cell growth, ERα binding to E 2, or ERα-responsive gene expression. S 3CTr showed mixed ERα agonist activities. It bound to the ERα and activated receptor binding with DNA, weakly activated expression of transfected E 2-responsive reporter gene constructs, and strongly inhibited the E 2-induced activation of these reporter constructs. S 3CTr activated aryl hydrocarbon receptor (AhR)-mediated pathways, consistent with the moderately strong binding affinity of S 3CTr for the AhR. Comparisons of the conformational characteristics among CTr and its two analogs indicated that the estrogenic effects of CTr are highly sensitive to apparently minor structural modifications, and further supported the hypothesis for a central role of hydrogen bonding around the nitrogen atom in CTr binding to the ligand binding site of ERα.
ISSN:0009-2797
1872-7786
DOI:10.1016/j.cbi.2005.02.007