Epigallocatechin-3-gallate Increases RXRγ-mediated Pro-apoptotic and Anti-invasive Effects in Gastrointestinal Cancer Cell Lines.
Molecules with synergistic effects often enhance the benefits of cancer therapy. We observed that the major catechin of green tea, (-)-Epigallocatechin-3-gallate (EGCG), induced retinoid X receptor-γ (RXRγ) expression in the SK-Ch-A1 cholangiocarcinoma cell line and in two colon carcinoma cell lines (LoVo and the derivative multi-drug resistant LoVoMDR). On this basis, we analyzed the effects of EGCG in combination with an RXRγ ligand, 6-OH-11-O-hydroxyphenantrene (IIF), or with a ligand of retinoic acid receptor, all-trans-retinoic acid (RA). IIF alone and in combination with EGCG activated the retinoic X response elements and induced the germ cell nuclear factor. In parallel, EGCG induced 67 kDa laminin receptor expression alone and in combination with IIF. We observed a synergistic growth inhibition with EGCG and IIF in combination at lower doses. These effects were accompanied by apoptosis activation through the mitochondrial pathway. Moreover, in LoVo cell line we observed an induction of Forkhead box O3 expression, another molecule involved in apoptosis activation. Finally, metalloproteinase activity and extracellular matrix metalloproteinase inducer (EMMPRIN) expression were inhibited and tumor cell invasion was strongly reduced in the SK-Ch-A1 cell line after treatment with EGCG and IIF. In conclusion, the use of specific RXR ligands in combination with catechins could open a new perspective in gastrointestinal tumor chemoprevention.
Department of Biological, Geological, and Environmental Science (BiGea), Via Selmi 3, University of Bologna, 40126 Bologna, Italy. alessio.papi2@unibo.it.
Alessio
A
Papi
Marzia
M
Govoni
Carmen
C
Ciavarella
Enzo
E
Spisni
Marina
M
Orlandi
Fulvia
F
Farabegoli
D017209:Apoptosis / Q000187:drug effects*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D045726:Metalloproteases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D047491:Retinoid X Receptor gamma / Q000378:metabolism*; D013662:Tea / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
C575663:6-OH-11-O-hydroxyphenanthrene; D000071316:Forkhead Box Protein O3; D008024:Ligands; D010616:Phenanthrenes; D047491:Retinoid X Receptor gamma; D013662:Tea; D014212:Tretinoin; D002392:Catechin; C045651:epigallocatechin gallate; D045726:Metalloproteases