An indomethacin analogue, N-(4-chlorobenzoyl)-melatonin, is a selective inhibitor of aldo-keto reductase 1C3 (type 2 3α-HSD, type 5 17β-HSD, and prostaglandin F synthase), a potential target for the treatment of hormone dependent and hormone independent malignancies
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Aldo-keto reductase (AKR) 1C3 (type 2 3alpha-HSD, type 5 17beta-HSD, and prostaglandin F synthase) regulates ligand access to steroid hormone and prostaglandin receptors and may stimulate proliferation of prostate and breast cancer cells. NSAIDs are known inhibitors of AKR1C enzymes. An NSAID analogue that inhibits AKR1C3 but is inactive against the cyclooxygenases and the other AKR1C family members would provide an important tool to examine the role of AKR1C3 in proliferative signaling. We tested NSAIDs and NSAID analogues for inhibition of the reduction of 9,10-phenanthrenequinone (PQ) catalyzed by AKR1C3 and the closely related isoforms AKR1C1 and AKR1C2. Two of the compounds initially screened, indomethacin and its methyl ester, were specific for AKR1C3 versus the other AKR1C isoforms. Based on these results and the crystal structure of AKR1C3, we predicted that N-(4-chlorobenzoyl)-melatonin (CBM), an indomethacin analogue that does not inhibit the cyclooxygenases, would selectively inhibit AKR1C3. CBM inhibited the reduction of PQ by AKR1C3, but did not significantly inhibit AKR1C1 or AKR1C2. Indomethacin and CBM also inhibited the AKR1C3-catalyzed reduction of Delta(4)-androstene-3,17-dione but did not significantly inhibit the reduction of steroid hormones catalyzed by AKR1C1 or AKR1C2. The pattern of inhibition of AKR1C3 by indomethacin and CBM was uncompetitive versus PQ, but competitive versus Delta(4)-androstene-3,17-dione, indicating that two different inhibitory complexes form during the ordered bi bi reactions. The identification of CBM as a specific inhibitor of AKR1C3 will aid the investigation of its roles in steroid hormone and prostaglandin signaling and the resultant effects on cancer development.
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AKR1C3, also called 17β-HSD type 5, is the AKR1C enzyme with the highest catalytic efficiency for reducing Δ4-androstene-3,17-dione to testosterone.
“AKR1C3, also known as 17β-HSD type 5, acts as 17-ketosteroid reductase and has the highest catalytic efficiency of the AKR1C enzymes for the reduction of Δ4-androstene-3,17-dione to form testosterone”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [31]
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- Authors
- Byrns, M. C., Steckelbroeck, S., & Penning, T. M.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Penning, Trevor M.
- ORCID
- Penning, Trevor M.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 75
- Issue
- 2
- Pages
- 484-493
- ISSN
- 0006-2952 (ISSN-L)
- PMC
- PMC2245880
- OpenAlex
- W2011974240
- Cited by
- 145
- References
- 53
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 9 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 8 · 2015: 4 · 2014: 6 · 2013: 7 · 2012: 15
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alberta Biodiversity Monitoring Institute
- National Institutes of Health
- National Cancer Institute (R01 CA 90744, R01CA090744)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007314)
- National Institute of Environmental Health Sciences (P30ES013508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- aldo-keto reductase 1C3, AKR1C1, AKR1C2, selective enzyme inhibitors, uncompetitive inhibition, steroid hormone metabolism, prostaglandin F synthase, prostate cancer, breast cancer, enzyme crystal structure
- MeSH terms
- Aldo-Keto Reductase Family 1 Member C3, Anti-Inflammatory Agents, Non-Steroidal, Antineoplastic Agents, Catalysis, Enzyme Inhibitors, Humans, Hydroxyprostaglandin Dehydrogenases, Indoles, Indomethacin, Melatonin, Neoplasms, Hormone-Dependent, Oxidation-Reduction, Phenanthrenes, Dihydrotestosterone, 3-Hydroxysteroid Dehydrogenases
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