RARalpha antagonist Ro 41-5253 inhibits proliferation and induces apoptosis in breast-cancer cell lines.

Abstract

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.

• Authors: S Toma, L Isnardi, P Raffo, L Riccardi, G Dastoli, C Apfel, P LeMotte, W Bollag
• Journal: International journal of cancer (Int J Cancer) Vol. 78 Issue 1 Pg. 86-94 (Sep 25 1998) ISSN: 0020-7136 [Print] United States
• PMID: 9724098 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoates
• Chromans
• Proto-Oncogene Proteins c-bcl-2
• Retinoids
• Transforming Growth Factor beta
• Tumor Suppressor Protein p53
• Ro 41-5253

Topics

• Apoptosis (genetics)
• Benzoates (pharmacology)
• Breast Neoplasms (pathology)
• Cell Division (drug effects)
• Chromans (pharmacology)
• DNA Fragmentation
• Female
• Humans
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• Retinoids (pharmacology)
• Transforming Growth Factor beta (drug effects, metabolism)
• Tumor Cells, Cultured (drug effects)
• Tumor Suppressor Protein p53 (drug effects, metabolism)