A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer
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- Alexis A. Kurmis
- 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
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- Fei Yang
- 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
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- Timothy R. Welch
- 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
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- Nicholas G. Nickols
- 2Department of Radiation Oncology, David Geffen School of Medicine at UCLA, VA Greater Los Angeles Healthcare System, Los Angeles, California.
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- Peter B. Dervan
- 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California.
書誌事項
- 公開日
- 2017-04-30
- DOI
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- 10.1158/0008-5472.can-16-2503
- 公開者
- American Association for Cancer Research (AACR)
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>The LREX' prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor, glucocorticoid receptor (GR), which has similar DNA-binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein–DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand-binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX' cells, Py-Im polyamide interfered with both AR- and GR-driven gene expression, whereas enzalutamide interfered with only that of AR. Genomic analyses indicated immediate interference with the AR transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer. Cancer Res; 77(9); 2207–12. ©2017 AACR.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 77 (9), 2207-2212, 2017-04-30
American Association for Cancer Research (AACR)
