Disruption of gene expression and induction of apoptosis in prostate cancer cells by a DNA-damaging agent tethered to an androgen receptor ligand.
The goal of our work was the design of DNA-damaging agents that disrupt both DNA repair and signaling pathways in prostate tumor cells. A DNA alkylator (N,N-bis-2-chloroethyl aniline) was linked to a steroid ligand (17beta-hyroxy-estra-Delta(4(5),9(10))-3-one) to produce a complex molecule (11beta-dichloro) that forms DNA adducts that bind the androgen receptor (AR). We speculated that DNA adducts in an AR-DNA adduct complex would be camouflaged from DNA repair proteins that would otherwise remove the adducts in prostate cancer cells. Furthermore, transcription dependent on the AR would be antagonized by AR redistribution to sites distant from AR-driven promoters. The anticancer potential of 11beta-dichloro was demonstrated against prostate cancer cells in vitro and in vivo. 11beta-dichloro induces a unique pattern of gene disruption, induces apoptosis in apoptosis-resistant cells, and shows promising anticancer activity in animals.
Marquis
John C
JC
Department of Chemistry and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Hillier
Shawn M
SM
Dinaut
A Nicole
AN
Rodrigues
Denise
D
Mitra
Kaushik
K
Essigmann
John M
JM
Croy
Robert G
RG
D059002:Androgen Receptor Antagonists; D000728:Androgens; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007364:Intercalating Agents / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D013258:Steroids, Chlorinated / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D059002:Androgen Receptor Antagonists; D000728:Androgens; D018736:DNA Adducts; D007364:Intercalating Agents; D008024:Ligands; D011944:Receptors, Androgen; D013258:Steroids, Chlorinated; D004958:Estradiol