Synergistic cytotoxicity exhibited by combination treatment of selective retinoid ligands with taxol (Paclitaxel).

نویسندگان

  • V Vivat-Hannah
  • D You
  • C Rizzo
  • J P Daris
  • P Lapointe
  • F C Zusi
  • A Marinier
  • M V Lorenzi
  • M M Gottardis
چکیده

The focus of this study was to develop retinoic acid receptor (RAR) RAR alpha/beta selective agonists with anticancer efficacy and reduced toxicity associated with RAR gamma activity. In these studies, we report the identification and characterization of high-affinity RAR alpha/beta selective agonists with limited RAR gamma activity. These compounds inhibited human tumor cell line proliferation with similar efficacy to that observed for a pan-RAR agonist. However, for most tumor cell lines, the efficacy of these compounds was restricted to the micromolar range. To determine whether the RAR alpha/beta selective agonists could be additive or synergistic with existing agents, we investigated the effects of combining RAR alpha/beta selective agonists with various cytotoxic agents. Our results showed that the alpha/beta selective retinoids dramatically lowered the effective dose of Taxol needed to induce cytotoxicity of a wide range of tumor cell lines. This synergy was specific to tubulin-modifying agents and could not be observed with a variety of other cytotoxic agents of diverse function. Examination of pathways common to Taxol and retinoid signaling revealed that this synergy was related in part to effects on Bcl-2 expression/phosphorylation as well as the activity of the c-Jun NH(2)-terminal kinase and activator protein-1. In contrast, the tubulin polymerization induced by Taxol was not further affected by cotreatment with a variety of retinoid receptor ligands. These observations indicate that potent RAR alpha/beta selective agonists may be of therapeutic benefit in combination with Taxol therapy.

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عنوان ژورنال:
  • Cancer research

دوره 61 24  شماره 

صفحات  -

تاریخ انتشار 2001