Structure-activity relationships of resveratrol and derivatives in breast cancer cells.
Resveratrol (RSV) is classified as a phytoestrogen due to its ability to interact with estrogen receptors (ERs). We assessed structure-activity relationships of RSV and the analogs 4,4'-dihydroxystilbene (4,4'-DHS), 3,5-dihydroxystilbene (3,5-DHS), 3,4'-dihydroxystilbene (3,4'-DHS), 4-hydroxystilbene (4-HS) using as model systems the ERalpha-positive and negative MCF7 and SkBr3 breast cancer cells, respectively. In binding assays and transfection experiments RSV and the analogs showed the following order of agonism for ERalpha: 3,4'-DHS > 4,4'-DHS > 4-HS > RSV, while 3,5-DHS did not elicit any ligand properties. Computational docking analysis and real-time PCR revealed for each analog a distinct ERalpha binding orientation and estrogen target gene expression profile. Interestingly, the aforementioned order of ligand activity was confirmed in proliferation assays which also showed the lack of growth stimulation by 3,5-DHS. Our data suggest that subtle changes in the structure of the RSV derivatives examined may be responsible for the different ERalpha-mediated biological responses observed in estrogen-sensitive cancer cells.
Lappano
Rosamaria
R
Dipartimento Farmaco-Biologico, Università della Calabria, Rende, CS, Italy.
Rosano
Camillo
C
Madeo
Antonio
A
Albanito
Lidia
L
Plastina
Pierluigi
P
Gabriele
Bartolo
B
Forti
Luca
L
Stivala
Lucia Anna
LA
Iacopetta
Domenico
D
Dolce
Vincenza
V
Andò
Sebastiano
S
Pezzi
Vincenzo
V
Maggiolini
Marcello
M
D001665:Binding Sites; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D013267:Stilbenes; D000077185:Resveratrol