title: Abiraterone inhibits 3β-hydroxysteroid dehydrogenase: a rationale for increasing drug exposure in castration-resistant prostate cancer.
abstract: OBJECTIVE
  Treatment with abiraterone (abi) acetate prolongs survival in castration-resistant prostate cancer (CRPC). Resistance to abi invariably occurs, probably due in part to upregulation of steroidogenic enzymes and/or other mechanisms that sustain dihydrotestosterone (DHT) synthesis, which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes. On the basis of the 3β-hydroxyl, Δ(5)-structure, we hypothesized that abi also inhibits 3β-hydroxysteroid dehydrogenase/isomerase (3βHSD), which is absolutely required for DHT synthesis in CRPC, regardless of origins or routes of synthesis.
  
  
  METHODS
  We tested the effects of abi on 3βHSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo.
  
  
  RESULTS
  Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells, including conversion of [(3)H]-dehydroepiandrosterone (DHEA) to Δ(4)-androstenedione, androgen receptor nuclear translocation, expression of androgen receptor-responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA. Abi also blocks conversion of Δ(5)-androstenediol to testosterone by 3βHSD. Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro; blocks conversion from DHEA to androstenedione and DHT with an IC(50) value of less than 1 μmol/L in CRPC cell lines; inhibits androgen receptor nuclear translocation; expression of TMPRSS2, prostate-specific antigen, and FKBP5; and decreases CRPC xenograft growth in DHEA-supplemented mice.
  
  
  CONCLUSIONS
  We conclude that abi inhibits 3βHSD-mediated conversion of DHEA to active androgens in CRPC. This second mode of action might be exploited to reverse resistance to CYP17A1 inhibition at the standard abi dose by dose-escalation or simply by administration with food to increase drug exposure.
authors: Division of Hematology and Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Rui
authors: R
authors: Li
authors: Kristen
authors: K
authors: Evaul
authors: Kamalesh K
authors: KK
authors: Sharma
authors: Kai-Hsiung
authors: KH
authors: Chang
authors: Jennifer
authors: J
authors: Yoshimoto
authors: Jiayan
authors: J
authors: Liu
authors: Richard J
authors: RJ
authors: Auchus
authors: Nima
authors: N
authors: Sharifi
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069501:Abiraterone Acetate; D021581:Active Transport, Cell Nucleus; D000730:Androstadienes / Q000494:pharmacology* / Q000627:therapeutic use; D000735:Androstenedione / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003687:Dehydroepiandrosterone / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D007527:Isoenzymes; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D015096:3-Hydroxysteroid Dehydrogenases; D000069501:Abiraterone Acetate