title: Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide.
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.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Hargrove
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Martinez
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Alissa A
authors.initials: AA
authors.lastname: Hare
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Kurmis
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Phillips
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Sudha
authors.initials: S
authors.lastname: Sud
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, United States of America.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D026942:DNA Topoisomerases / Q000737:chemistry / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008297:Male; D051379:Mice; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011758:Pyrroles / Q000737:chemistry; D011944:Receptors, Androgen / Q000378:metabolism; D017423:Sequence Analysis, RNA; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D009757:Nylons; D015514:Oncogene Proteins, Fusion; D011758:Pyrroles; D011944:Receptors, Androgen; C515553:TMPRSS2-ERG fusion protein, human; C029899:imidazole; D004247:DNA; D026942:DNA Topoisomerases