Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin

Mol Cell Endocrinol. 2016 Aug 15;431:12-23. doi: 10.1016/j.mce.2016.04.024. Epub 2016 Apr 28.


Epigenetic repression of Androgen Receptor (AR) gene by hypermethylation of its promoter causes resistance in prostate cancer (CaP) to androgen deprivation therapy with anti-androgens. Some dietary phytocompounds like quercetin (Q) and curcumin (C) with reported DNMT-inhibitory activity were tested for their ability to re-express the AR in AR-negative CaP cell lines PC3 and DU145. Combined treatment with Q+C was much more effective than either Q or C in inhibiting DNMT, causing global hypomethylation, restoring AR mRNA and protein levels and causing apoptosis via mitochondrial depolarization of PC3 and DU145. The functional AR protein expressed in Q+C treated cells sensitized them to dihydrotestosterone (DHT)-induced proliferation, bicalutamide-induced apoptosis, bound to androgen response element to increase luciferase activity in gene reporter assay and was susceptible to downregulation by AR siRNA. Bisulfite sequencing revealed high methylation of AR promoter CpG sites in AR-negative DU145 and PC3 cell lines that was significantly demethylated by Q+C treatment, which restored AR expression. Notable synergistic effects of Q+C combination in re-sensitizing androgen refractory CaP cells to AR-mediated apoptosis, their known safety in clinical use, and epidemiological evidences relating their dietary consumption with lower cancer incidences indicate their potential for use in chemoprevention of androgen resistance in prostate cancer.

Keywords: Androgen receptor; Curcumin; DNA methylation; Prostate cancer; Quercetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Androgens / metabolism
  • Apoptosis / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Curcumin / pharmacology*
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Dihydrotestosterone / pharmacology
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Drug Synergism
  • Epigenetic Repression / drug effects*
  • Epigenetic Repression / genetics
  • Humans
  • Male
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Quercetin / pharmacology*
  • RNA, Messenger / metabolism
  • Receptors, Androgen / metabolism*


  • AR protein, human
  • Androgen Antagonists
  • Androgens
  • RNA, Messenger
  • Receptors, Androgen
  • Dihydrotestosterone
  • Quercetin
  • Curcumin