title: Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer.
abstract: OBJECTIVE
  Previous studies show that inhibition of ABCB1 expression overcomes acquired docetaxel resistance in C4-2B-TaxR cells. In this study, we examined whether antiandrogens, such as bicalutamide and enzalutamide, could inhibit ABCB1 activity and overcome resistance to docetaxel.
  
  
  METHODS
  ABCB1 efflux activity was determined using a rhodamine efflux assay. ABCB1 ATPase activity was determined by Pgp-Glo assay systems. The effects of the antiandrogens bicalutamide and enzalutamide on docetaxel sensitivity were determined by cell growth assays and tumor growth in vivo.
  
  
  RESULTS
  We found that bicalutamide and enzalutamide inhibit ABCB1 ATP-binding cassette transporter activity through blocking ABCB1 efflux activity. Bicalutamide inhibited ABCB1 efflux activity by 40%, whereas enzalutamide inhibited ABCB1 efflux activity by approximately 60%. Both bicalutamide and enzalutamide inhibit ABCB1 ATPase activity. In addition, bicalutamide and enzalutamide inhibit ABCB1 efflux activity and desensitize docetaxel-resistant and androgen receptor (AR)-negative DU145 cells. Combination of bicalutamide with docetaxel had a significant antitumor effect in both AR-positive and AR-negative docetaxel-resistant xenograft models, suggesting that bicalutamide desensitizes docetaxel-resistant cells to docetaxel treatment independent of AR status.
  
  
  CONCLUSIONS
  We identified a novel mechanism of action for antiandrogens such as bicalutamide and enzalutamide as inhibitors of ABCB1 efflux and ATPase activity. Bicalutamide and enzalutamide desensitize docetaxel-resistant prostate cancer cells to docetaxel treatment independent of AR status. These studies may lead to the development of combinational therapies with bicalutamide/enzalutamide and docetaxel as effective regimens to treat advanced prostate cancer independent of AR status, and possibly other types of cancer.
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California. Graduate Program in Pharmacology and Toxicology, University of California at Davis, Sacramento, California.
authors.forename: Yezi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California.
authors.forename: Chengfei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California.
authors.forename: Cameron
authors.initials: C
authors.lastname: Armstrong
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Lou
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California.
authors.forename: Amandeep
authors.initials: A
authors.lastname: Sandher
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California. Graduate Program in Pharmacology and Toxicology, University of California at Davis, Sacramento, California. Comprehensive Cancer Center, University of California at Davis, Sacramento, California. acgao@ucdavis.edu.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry; D000726:Androgen Antagonists / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles / Q000627:therapeutic use; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy; D011944:Receptors, Androgen / Q000378:metabolism; D012235:Rhodamines / Q000737:chemistry; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; C410798:AR protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000726:Androgen Antagonists; D000813:Anilides; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D012235:Rhodamines; D043823:Taxoids; D014105:Tosyl Compounds; D000077143:Docetaxel; D010669:Phenylthiohydantoin; D000255:Adenosine Triphosphate; C540278:enzalutamide; C053541:bicalutamide; D000251:Adenosine Triphosphatases