Abstract
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. We tested the effects of abi on 3βHSD activity, androgen receptor localization, expression of androgen receptor-responsive genes, and CRPC growth in vivo. 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. 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.
Highlights
Metastatic prostate cancer is initially treated with gonadal testosterone deprivation, which typically initially leads to a tumor response [1]
Abi inhibits recombinant 3b-hydroxysteroid dehydrogenase/isomerase (3bHSD) activity in vitro and endogenous 3bHSD activity in LNCaP and LAPC4 cells, including conversion of [3H]-dehydroepiandrosterone (DHEA) to D4-androstenedione, androgen receptor nuclear translocation, expression of androgen receptor–responsive genes, and xenograft growth in orchiectomized mice supplemented with DHEA
We conclude that abi inhibits 3bHSD-mediated conversion of DHEA to active androgens in castration-resistant" prostate cancer (CRPC)
Summary
Metastatic prostate cancer is initially treated with gonadal testosterone deprivation, which typically initially leads to a tumor response [1]. Most tumors eventually progress despite low serum testosterone concentrations, as "castration-resistant" prostate cancer (CRPC), Authors' Affiliations: Divisions of 1Hematology and Oncology and 2Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and 3Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Initial preclinical studies suggest that abi resistance is mediated at least in part by upregulation of steroidogenic enzymes and sustained intratumoral DHT synthesis [14, 15]. Together, these data suggest that concomitantly blocking a second enzyme required for DHT synthesis might yield www.aacrjournals.org
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