title: Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9(R) Lead to promotion versus suppression of prostate cancer metastasis.
abstract: Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9® and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 μm Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9® led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-β1/Smad3/MMP9 pathway, but ASC-J9® and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9® to battle PCa metastasis at the castration-resistant stage.
authors.affiliation: George Whipple Laboratory for Cancer Research, Department of Pathology, Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Tzu-Hua
authors.initials: TH
authors.lastname: Lin
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Niu
authors.forename: Defeng
authors.initials: D
authors.lastname: Xu
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Shauh-Der
authors.initials: SD
authors.lastname: Yeh
authors.forename: Naohiro
authors.initials: N
authors.lastname: Fujimoto
authors.forename: Shuyuan
authors.initials: S
authors.lastname: Yeh
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000728:Androgens; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051900:Smad3 Protein / Q000378:metabolism; D014105:Tosyl Compounds / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D001549:Benzamides; D003474:Curcumin; D020780:Matrix Metalloproteinase 9; D009363:Neoplasm Proteins; D009570:Nitriles; D010669:Phenylthiohydantoin; D017430:Prostate-Specific Antigen; D051900:Smad3 Protein; D014105:Tosyl Compounds; D053773:Transforming Growth Factor beta1; C471106:ASC-J9 compound; C497790:SMAD3 protein, human; C540278:enzalutamide; C053541:bicalutamide; C579270:MMP9 protein, human
keywords: Androgen; Anti-androgen; Matrix Metalloproteinase (MMP); Prostate Cancer; Transforming Growth Factor β (TGFbeta); Tumor Metastases