Design and synthesis of isothiocyanate‐containing hybrid androgen receptor (AR) antagonist to downregulate AR and induce ferroptosis in GSH–Deficient prostate cancer cells
| Autor: | Gail S. Prins, Siyu Ou, Dan-Ping Hu, Kathleen Sorensen, Wen-Yang Hu, Yingxue Zhang, Liping Xu, Fei Chen, Zhihui Qin, Zhe Yang |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Transcriptional Activation Cell Survival Down-Regulation Biochemistry Article chemistry.chemical_compound Downregulation and upregulation Isothiocyanates Cell Line Tumor Drug Discovery Androgen Receptor Antagonists Ferroptosis Humans Protein Isoforms Buthionine sulfoximine Viability assay Buthionine Sulfoximine Cell Proliferation Pharmacology Binding Sites Organic Chemistry Glutathione Molecular Docking Simulation Androgen receptor Prostatic Neoplasms Castration-Resistant chemistry Receptors Androgen Apoptosis Drug Design Isothiocyanate Cancer research Molecular Medicine Growth inhibition |
| Zdroj: | Chem Biol Drug Des |
| ISSN: | 1747-0285 1747-0277 |
| DOI: | 10.1111/cbdd.13826 |
| Popis: | Sustained androgen receptor (AR) signaling and apoptosis evasion are among the main hurdles of castration-resistant prostate cancer (CRPC) treatment. We designed and synthesized isothiocyanate (ITC)-containing hybrid AR antagonist (ITC-ARi) and rationally combined ITC-ARi with GSH synthesis inhibitor buthionine sulfoximine (BSO) to efficiently downregulate AR/AR splice variant and induce ferroptosis in CRPC cells. The representative ITC-ARi 13 is an AR ligand that contains an N-acetyl cysteine-masked ITC moiety and gradually releases parental unconjugated ITC 12b in aqueous solution. The in vitro anti-PCa activities of 13, such as growth inhibition and AR downregulation, are significantly enhanced when combined with BSO. The drug combination caused notable lipid peroxidation and the cell viability was effectively rescued by iron chelator, antioxidants or the inhibitor of heme oxygenase-1, supporting the induction of ferroptosis. 13 and BSO cooperatively downregulate AR and induce ferroptosis likely through increasing the accessibility of 13/12b to cellular targets, escalating free intracellular ferrous iron and attenuating GSH-centered cellular defense and adaptation. Further studies on the combination of ITC-ARi and GSH synthesis inhibitor could result in a new modality against CRPC. |
| Databáze: | OpenAIRE |
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