Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide

Amanda E. Hargrove, Thomas F. Martinez, Alissa A. Hare, Alexis A. Kurmis, John W. Phillips, Sudha Sud, Kenneth Pienta, Peter B. Dervan

Research output: Contribution to journalArticle

Abstract

Pyrrole-imidazole (Py-Im) polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE)-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress.

Original languageEnglish (US)
Article numbere0143161
JournalPLoS One
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2015

Fingerprint

pyrroles
Pyrroles
imidazoles
Nylons
Heterografts
Tumors
neoplasms
Neoplasms
prostatic neoplasms
DNA Damage
DNA
Prostatic Neoplasms
DNA topoisomerase
Type I DNA Topoisomerase
gene fusion
response elements
Gene Fusion
Response Elements
Transcription
androgens

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Hargrove, A. E., Martinez, T. F., Hare, A. A., Kurmis, A. A., Phillips, J. W., Sud, S., ... Dervan, P. B. (2015). Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide. PLoS One, 10(11), [e0143161]. https://doi.org/10.1371/journal.pone.0143161

Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide. / Hargrove, Amanda E.; Martinez, Thomas F.; Hare, Alissa A.; Kurmis, Alexis A.; Phillips, John W.; Sud, Sudha; Pienta, Kenneth; Dervan, Peter B.

In: PLoS One, Vol. 10, No. 11, e0143161, 01.11.2015.

Research output: Contribution to journalArticle

Hargrove, AE, Martinez, TF, Hare, AA, Kurmis, AA, Phillips, JW, Sud, S, Pienta, K & Dervan, PB 2015, 'Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide', PLoS One, vol. 10, no. 11, e0143161. https://doi.org/10.1371/journal.pone.0143161
Hargrove AE, Martinez TF, Hare AA, Kurmis AA, Phillips JW, Sud S et al. Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide. PLoS One. 2015 Nov 1;10(11). e0143161. https://doi.org/10.1371/journal.pone.0143161
Hargrove, Amanda E. ; Martinez, Thomas F. ; Hare, Alissa A. ; Kurmis, Alexis A. ; Phillips, John W. ; Sud, Sudha ; Pienta, Kenneth ; Dervan, Peter B. / Tumor repression of VCaP xenografts by a pyrrole-imidazole polyamide. In: PLoS One. 2015 ; Vol. 10, No. 11.
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