RARalpha antagonist Ro 41-5253 inhibits proliferation and induces apoptosis in breast-cancer cell lines.
Ro 41-5253 is a RARalpha-selective antagonist that binds RARalpha but does not induce transcriptional activation and does not influence RAR/RXR heterodimerization and DNA binding. This retinoid inhibits proliferation and induces apoptosis in MCF-7 and ZR-75.1 estrogen-receptor-positive breast-carcinoma cells in a dose-dependent way. The anti-proliferative effect is more evident in ZR-75.1 cells than in MCF-7 cells and is probably mediated by anti-AP1 activity, a mechanism known to be implied in the action of several retinoids. In the induction of apoptosis also ZR-75.1 cells are more sensitive to treatment with Ro 41-5253 than MCF-7 cells. In ZR-75.1 cells an apoptotic/hypodiploid DNA peak is already evident after 2 days of incubation, whereas in MCF-7 cells it appears only after 4 days. The highest percentage of apoptotic cells, for both cell lines, is reached after 6 days of treatment. The apoptosis pathway is p53-independent and bcl-2 downregulation seems to be correlated with an increase in TGF-beta1 protein. The MDA-MB-231 estrogen-receptor-negative cell line is poorly responsive to Ro 41-5253 treatment, both in terms of proliferation inhibition and apoptosis induction. Ro 41-5253 has proliferation-inhibiting and apoptosis-inducing properties that are not mediated by transcriptional activation from retinoic-acid response elements. This retinoid antagonist seems to be a compound that exerts an anti-tumor activity but does not induce the toxic side effects of retinoids and might, therefore, be considered as a candidate for cancer therapy.
Toma
S
S
National Institute for Cancer Research, Department of Clinical and Experimental Oncology, University of Genoa, Italy. Toma@sirio.cba.unige.it
Isnardi
L
L
Raffo
P
P
Riccardi
L
L
Dastoli
G
G
Apfel
C
C
LeMotte
P
P
Bollag
W
W
D017209:Apoptosis / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D053938:DNA Fragmentation; D005260:Female; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000378:metabolism
D001565:Benzoates; D002839:Chromans; D019253:Proto-Oncogene Proteins c-bcl-2; D012176:Retinoids; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; C084904:Ro 41-5253