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Updated: Apr 11, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer
Zhenfei Li1, Andrew C Bishop1, Mohammad Alyamani1
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Abstract:
Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Δ(4)-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation-conversion to a more active agent-for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.
Insights
Abiraterone is converted to a more potent form, Δ(4)-abiraterone (D4A), in prostate cancer. D4A inhibits multiple enzymes essential for 5α-dihydrotestosterone (DHT) synthesis and antagonizes the androgen receptor, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Endocrinology
- Pharmacology
Background:
- Prostate cancer resistance to castration is linked to tumor cells synthesizing 5α-dihydrotestosterone (DHT).
- DHT promotes androgen receptor signaling, driving castration-resistant prostate cancer (CRPC).
- Key enzymes in DHT synthesis include 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A), and 17β-hydroxysteroid dehydrogenase (17βHSD).
Purpose of the Study:
- To investigate if abiraterone is converted to a more active metabolite, Δ(4)-abiraterone (D4A).
- To determine if D4A inhibits multiple steroidogenic enzymes and antagonizes the androgen receptor.
- To compare the anti-tumor activity of D4A with abiraterone.
Main Methods:
- Abiraterone conversion to D4A was studied in mice and prostate cancer patients.
- In vitro assays assessed the inhibitory effects of D4A on CYP17A1, 3βHSD, and SRD5A.
- Androgen receptor antagonism by D4A was compared to enzalutamide.
- Anti-tumor activity was evaluated using xenograft tumor models.
Main Results:
- Abiraterone is converted to D4A in vivo in mice and human prostate cancer.
- D4A inhibits CYP17A1, 3βHSD, and SRD5A, enzymes crucial for DHT synthesis.
- D4A exhibits potent androgen receptor antagonism, comparable to enzalutamide.
- D4A demonstrates superior anti-tumor efficacy compared to abiraterone in xenograft models.
Conclusions:
- Abiraterone's clinical activity may be partly explained by its conversion to the more potent D4A.
- D4A inhibits multiple critical enzymes in the DHT synthesis pathway.
- D4A acts as a potent androgen receptor antagonist.
- Direct administration of D4A could offer enhanced clinical efficacy for prostate cancer treatment.
