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

Int J Cancer. 1998 Sep 25;78(1):86-94. doi: 10.1002/(sici)1097-0215(19980925)78:1<86::aid-ijc14>3.0.co;2-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Retinoids / pharmacology*
  • Transforming Growth Factor beta / drug effects
  • Transforming Growth Factor beta / metabolism
  • Tumor Cells, Cultured / drug effects
  • Tumor Suppressor Protein p53 / drug effects*
  • Tumor Suppressor Protein p53 / metabolism


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