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The efficacy of 9-cis retinoic acid in experimental models of cancer

  • Tumor growth pathways and their inhibition
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Summary

9-cis retinoic acid (9-cis RA) is a retinoid receptor pan-agonist that binds with high affinity to both retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Using a variety ofin vivo andin vitro cancer models, we present experimental data that 9-cis RA has activity as a potential chemotherapeutic agent. Treatment of the human promyelocytic leukemia cell line HL-60 with 9-cis RA decreases cell proliferation, increases cell differentiation, and increases apoptosis. Induction of apoptosis correlates with an increase in tissue transglutaminase (type II) activity.In vivo, 9-cis RA induces complete tumor regression of an early passage human lip squamous cell carcinoma xenograft. Finally, 9-cis RA inhibits the anchorage-independent growth of the human breast cancer cell lines MCF-7 and LY2 (an antiestrogen-resistant MCF-7 variant). Transient co-transfection assays indicate that 9-cis RA inhibits estrogen receptor transcription of an ERE-tk-LUC reporter through RAR or RXR receptors. These data suggest that retinoid receptors can antagonize estrogen-dependent transcription and provides one possible mechanism for the inhibition of cell growth by 9-cis RA in breast cancer cell lines. In summary, these findings present evidence that 9-cis RA has a wide range of activities in human cancer models.

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Authors and Affiliations

  1. Department of Pharmacology, Ligand Pharmaceuticals, 9393 Towne Centre Drive, San Diego, CA, USA

    Marco M. Gottardis & David R. Shalinsky

  2. Department of Cell Biology, Ligand Pharmaceuticals, San Diego, CA, USA

    William W. Lamph & Richard A. Heyman

  3. Department of Pharmacology and Vincent T. Lombardi Cancer Center, Georgetown University, Washington DC, USA

    Anton Wellstein

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  1. Marco M. Gottardis
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  2. William W. Lamph
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  4. Anton Wellstein
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  5. Richard A. Heyman
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Gottardis, M.M., Lamph, W.W., Shalinsky, D.R. et al. The efficacy of 9-cis retinoic acid in experimental models of cancer. Breast Cancer Res Tr 38, 85–96 (1996). https://doi.org/10.1007/BF01803787

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