title: The curcumin analog ca27 down-regulates androgen receptor through an oxidative stress mediated mechanism in human prostate cancer cells.
abstract: BACKGROUND
  The androgen receptor (AR) plays a critical role in prostate cancer development and progression. Therefore, the inhibition of AR function is an established therapeutic intervention. Since the expression of the AR is retained and often increased in progressive disease, AR protein down-regulation is a promising therapeutic approach against prostate cancer. We show here that the curcumin analog 27 (ca27) down-regulates AR expression in several prostate cancer cell lines.
  
  
  METHODS
  ca27 at low micromolar concentrations was tested for its effect on AR expression, AR activation, and induction of oxidative stress in human LNCaP, C4-2, and LAPC-4 prostate cancer cells.
  
  
  RESULTS
  ca27 induced the down-regulation of AR protein expression in LNCaP, C4-2, and LAPC-4 cells within 12 hr. Further, ca27 led to the rapid induction of reactive oxygen species (ROS). To further support this finding, ca27 treatment led to the activation of the cellular redox sensor NF-E2-related factor 2 (Nrf2) and the induction of the Nrf2-regulated genes NAD(P)H quinone oxidoreductase 1 and aldoketoreductase 1C1. We show that ROS production preceded AR protein loss and that ca27-mediated down-regulation of the AR was attenuated by the antioxidant, N-acetyl cysteine.
  
  
  CONCLUSIONS
  ca27 induces ROS and mediates AR protein down-regulation through an oxidative stress mechanism of action. Our results suggest that ca27 represents a novel agent for the elucidation of mechanisms of AR down-regulation, which could lead to effective new anti-androgenic strategies for the treatment of advanced prostate cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Fajardo
authors.forename: Debra A
authors.initials: DA
authors.lastname: MacKenzie
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Deck
authors.forename: David L
authors.initials: DL
authors.lastname: Vander Jagt
authors.forename: Todd A
authors.initials: TA
authors.lastname: Thompson
authors.forename: Marco
authors.initials: M
authors.lastname: Bisoffi
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: C573269:1,5-bis(2-hydroxyphenyl)-1,4-pentadien-3-one; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D003474:Curcumin