Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor – Synergistic action of quercetin and curcumin
| Autor: | Jagdamba P. Maikhuri, Lokesh Kumar, Singh Rajender, Sujit Kumar Mohanty, Gopal Gupta, Vikas Sharma |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Curcumin medicine.drug_class Down-Regulation Apoptosis Epigenetic Repression Biology urologic and male genital diseases Biochemistry Cell Line Androgen deprivation therapy 03 medical and health sciences Prostate cancer 0302 clinical medicine Endocrinology DU145 Cell Line Tumor medicine Humans RNA Messenger Promoter Regions Genetic Molecular Biology Cell Proliferation Prostatic Neoplasms Androgen Antagonists Dihydrotestosterone Drug Synergism DNA Methylation medicine.disease Androgen Molecular biology Androgen receptor 030104 developmental biology Receptors Androgen 030220 oncology & carcinogenesis DNA methylation Androgens Quercetin Androgen Response Element medicine.drug |
| Zdroj: | Molecular and Cellular Endocrinology. 431:12-23 |
| ISSN: | 0303-7207 |
| DOI: | 10.1016/j.mce.2016.04.024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect