title: Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells.
abstract: Androgen receptor (AR) is the major therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Here we found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Our results indicated that 0.5 μM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, our data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selectively inhibits AR without repressing the activities of other nuclear receptors, including ERα, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation. Furthermore, we showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Defeng
authors.initials: D
authors.lastname: Xu
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Lin
authors.forename: Shaoshun
authors.initials: S
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Da
authors.forename: Xing-Qiao
authors.initials: XQ
authors.lastname: Wen
authors.forename: Jiang
authors.initials: J
authors.lastname: Ding
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D019281:Dimerization; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009919:Orchiectomy; D010616:Phenanthrenes / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D027561:Salvia miltiorrhiza / Q000737:chemistry; D015533:Transcriptional Activation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; C037886:cryptotanshinone