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1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit proliferation of estrogen receptor-negative breast cancer cells by activation of multiple pathways

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Abstract

1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes containing para-trifluoromethyl (DIM-C-pPhCF3), t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC6H5) groups are methylene-substituted diindolylmetyhanes (C-DIMs) that activate peroxisome proliferator-activated receptor γ (PPARγ) in estrogen receptor α-negative MDA-MB-231 and MDA-MB-453 breast cancer cells. C-DIMs inhibit breast cancer cell proliferation; however, inhibition of G0/G1 to S phase progression and cyclin D1 downregulation was observed in MDA-MB-231 but not MDA-MB-453 cells. Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a transforming growth factor β-like peptide, was also induced by these compounds, and the response was dependent on cell-context dependent activation of kinase pathways. However, inhibition of cell growth, induction of NAG-1 and activation of kinases by C-DIMs were not inhibited by PPARγ antagonists. Despite the induction of NAG-1 and downregulation of the antiapoptotic protein survivin by C-DIMs in both MDA-MB-231 and MDA-MB-453 cells, apoptotic cell death was not observed. Nevertheless, the cytotoxicity of C-DIMs in vitro was complemented by inhibition of tumor growth in athymic nude mice bearing MDA-MB-231 cells as xenografts and treated with DIM-C-pPhC6H5 (40 mg/kg/day). The growth inhibition of tumors derived from highly aggressive MDA-MB-231 cells suggests a potential role for the C-DIM compounds in the clinical treatment of ER-negative breast cancer.

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Acknowledgements

The financial assistance of the National Institutes of Health (CA108178 and ES09106) and the Texas Agricultural Experiment Station is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, 77843, USA

    Kathy Vanderlaag, Shaheen Khan & Stephen Safe

  2. Cancer Research Institute, Scott and White Memorial Hospital, Temple, TX, 76502, USA

    Yunpeng Su & Arthur E. Frankel

  3. Plantacor, 526 University Dr. E., Suite 101A, College Station, TX, 77840, USA

    Henry Grage

  4. Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA

    Roger Smith III

  5. Institute of Biosciences and Technology, Houston, TX, 77030, USA

    Stephen Safe

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  1. Kathy Vanderlaag
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  2. Yunpeng Su
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Vanderlaag, K., Su, Y., Frankel, A.E. et al. 1,1-Bis(3′-indolyl)-1-(p-substituted phenyl)methanes inhibit proliferation of estrogen receptor-negative breast cancer cells by activation of multiple pathways. Breast Cancer Res Treat 109, 273–283 (2008). https://doi.org/10.1007/s10549-007-9648-y

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  • DOI: https://doi.org/10.1007/s10549-007-9648-y

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