Synergistic cytotoxicity exhibited by combination treatment of selective retinoid ligands with taxol (Paclitaxel).
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.
Vivat-Hannah
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Department of Oncology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA. valerie.vivat@bms.com
You
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D
Rizzo
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Daris
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JP
Lapointe
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Zusi
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Marinier
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Lorenzi
M V
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Gottardis
M M
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D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D006131:Growth Inhibitors / Q000008:administration & dosage; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists*; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids / Q000008:administration & dosage / Q000494:pharmacology*; D013379:Substrate Specificity; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D006131:Growth Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012176:Retinoids; D018808:Transcription Factor AP-1; D014404:Tubulin; C082925:retinoic acid receptor beta; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel