Disruption of gene expression and induction of apoptosis in prostate cancer cells by a DNA-damaging agent tethered to an androgen receptor ligand

Chem Biol. 2005 Jul;12(7):779-87. doi: 10.1016/j.chembiol.2005.05.009.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgen Receptor Antagonists
  • Androgens
  • Animals
  • Apoptosis / drug effects*
  • DNA Adducts / chemistry
  • DNA Adducts / metabolism
  • DNA Damage / drug effects*
  • Estradiol / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Intercalating Agents / pharmacology*
  • Ligands
  • Male
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Receptors, Androgen / metabolism*
  • Steroids, Chlorinated / pharmacology
  • Tumor Cells, Cultured

Substances

  • Androgen Receptor Antagonists
  • Androgens
  • DNA Adducts
  • Intercalating Agents
  • Ligands
  • Receptors, Androgen
  • Steroids, Chlorinated
  • Estradiol