ArticleMolecular cancer therapeutics2017
Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer.
Article in Molecular cancer therapeutics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed.
- Phase 2 dose-expansion trial of OBI-3424, a DNA-alkylating prodrug, in patients with advanced solid tumors expressing AKR1C3.The oncologist · 2026Trial
- Testicular vs adrenal sources of hydroxy-androgens in prostate cancer.Endocrine-related cancer · 2017Trial
- Characterizing Response to PARP Inhibitor Treatment Combinations in Advanced Prostate Cancer.Biomedicines · 2026Article
- Casticin inhibits AKR1C3 and enhances abiraterone efficacy in castration-resistant prostate cancer.Journal of natural medicines · 2026Article
- The structural basis of aldo-keto reductase 1C3 inhibition by 17α-picolyl and 17(Journal of enzyme inhibition and medicinal chemistry · 2025Article
- PDGFC facilitates enzalutamide resistance in prostate cancer through activation of the Rap1-MAPK pathway.Journal of cancer research and clinical oncology · 2025Article
- Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance.Journal of pharmaceutical analysis · 2025Review
- LX1 Dual Targets AR Variants and AKR1C3 in Advanced Prostate Cancer Therapy.Cancer research · 2024Article
- Nodularin-R Synergistically Enhances Abiraterone Against Castrate- Resistant Prostate Cancer via PPP1CA Inhibition.Journal of cellular and molecular medicine · 2024Article
- Aldo-keto reductase family 1 member C3 mediates radioresistance of esophageal cancer cells through suppressing MAPK and AKT signaling.BMC cancer · 2024Article
- AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications.ACS medicinal chemistry letters · 2024Article
- AKR1C3-negative high-risk metastatic castration-sensitive prostate cancer has long-term response to first-line treatment with abiraterone: Four case reports.Urology case reports · 2024Article
- Synthesis,Future medicinal chemistry · 2024Article
- Targeting sex steroid biosynthesis for breast and prostate cancer therapy.Nature reviews. Cancer · 2023Review
- AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3β,17β-Diol.Cancer research communications · 2023Article
- Exploring the Potential of Sulfur Moieties in Compounds Inhibiting Steroidogenesis.Biomolecules · 2023Article
- Aldo-Keto Reductase 1C3 Inhibitor Prodrug Improves Pharmacokinetic Profile and Demonstrates In Vivo Efficacy in a Prostate Cancer Xenograft Model.Journal of medicinal chemistry · 2023Article
- Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy.Biomedicines · 2023Review
- X-ray structure of human aldo-keto reductase 1C3 in complex with a bile acid fused tetrazole inhibitor: experimental validation, molecular docking and structural analysis.RSC medicinal chemistry · 2023Article
- Novel inhibition of AKR1C3 and androgen receptor axis by PTUPB synergizes enzalutamide treatment in advanced prostate cancer.Oncogene · 2023Article
8 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors.
Funding
Abstract
Abiraterone suppresses intracrine androgen synthesis via inhibition of CYP17A1. However, clinical evidence suggests that androgen synthesis is not fully inhibited by abiraterone and the sustained androgen production may lead to disease relapse. In the present study, we identified AKR1C3, an important enzyme in the steroidogenesis pathway, as a critical mechanism driving resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. We found that overexpression of AKR1C3 confers resistance to abiraterone while downregulation of AKR1C3 resensitizes resistant cells to abiraterone treatment. In abiraterone-resistant prostate cancer cells, AKR1C3 is overexpressed and the levels of intracrine androgens are elevated. In addition, AKR1C3 activation increases intracrine androgen synthesis and enhances androgen receptor (AR) signaling via activating AR transcriptional activity. Treatment of abiraterone-resistant cells with indomethacin, an AKR1C3 inhibitor, overcomes resistance and enhances abiraterone therapy both in vitro and in vivo by reducing the levels of intracrine androgens and diminishing AR transcriptional activity. These results demonstrate that AKR1C3 activation is a critical mechanism of resistance to abiraterone through increasing intracrine androgen synthesis and enhancing androgen signaling. Furthermore, this study provides a preclinical proof-of-principle for clinical trials investigating the combination of targeting AKR1C3 using indomethacin with abiraterone for advanced prostate cancer. Mol Cancer Ther; 16(1); 35-44. ©2016 AACR.
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