title: Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin.
abstract: 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.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Lokesh
authors.initials: L
authors.lastname: Kumar
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Mohanty
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Jagdamba P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Singh
authors.initials: S
authors.lastname: Rajender
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: g_gupta@cdri.res.in.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003474:Curcumin / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D013196:Dihydrotestosterone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D063185:Epigenetic Repression / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000728:Androgens; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D011794:Quercetin; D003474:Curcumin
keywords: Androgen receptor; Curcumin; DNA methylation; Prostate cancer; Quercetin