title: Suppression of androgen receptor-mediated gene expression by a sequence-specific DNA-binding polyamide.
abstract: Androgen receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. A DNA-binding polyamide that targets the consensus androgen response element binds the prostate-specific antigen (PSA) promoter androgen response element, inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Nickols
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dervan
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D020137:Base Pair Mismatch; D020029:Base Pairing; D001483:Base Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology; D009757:Nylons / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010795:Phthalic Acids / Q000737:chemistry; D011401:Promoter Regions, Genetic; D017430:Prostate-Specific Antigen / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D009757:Nylons; D010795:Phthalic Acids; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; C059768:isophthalate; D004247:DNA; C053541:bicalutamide; D017430:Prostate-Specific Antigen