دورية أكاديمية
أعرض في EDS

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer.

التفاصيل البيبلوغرافية
العنوان: Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer.
المؤلفون: Norris JD; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Ellison SJ; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Baker JG; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Stagg DB; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Wardell SE; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Park S; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Alley HM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Baldi RM; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Yllanes A; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Andreano KJ; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Stice JP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Lawrence SA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA., Eisner JR; Innocrin Pharmaceuticals Inc., Durham, North Carolina, USA., Price DK; Genitourinary Malignancies Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA., Moore WR; Innocrin Pharmaceuticals Inc., Durham, North Carolina, USA., Figg WD; Genitourinary Malignancies Branch, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA., McDonnell DP; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina, USA.
المصدر: The Journal of clinical investigation [J Clin Invest] 2017 Jun 01; Vol. 127 (6), pp. 2326-2338. Date of Electronic Publication: 2017 May 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Androgen Receptor Antagonists/*pharmacology , Antineoplastic Agents, Hormonal/*pharmacology , Prostatic Neoplasms, Castration-Resistant/*drug therapy , Steroid 17-alpha-Hydroxylase/*antagonists & inhibitors, Active Transport, Cell Nucleus ; Animals ; Benzamides ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm ; Drug Synergism ; HEK293 Cells ; Humans ; Inhibitory Concentration 50 ; Male ; Metribolone/pharmacology ; Mice, Inbred NOD ; Mice, SCID ; Nitriles ; Phenylthiohydantoin/analogs & derivatives ; Phenylthiohydantoin/pharmacology ; Protein Binding ; Receptors, Androgen/metabolism ; Steroid 17-alpha-Hydroxylase/metabolism ; Testosterone/pharmacology ; Transcriptional Activation/drug effects ; Xenograft Model Antitumor Assays
مستخلص: The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC). Recently, however, it has been reported that CYP17 inhibitors can interact directly with the androgen receptor (AR). A phase I study recently reported that seviteronel, a CYP17 lyase-selective inhibitor, ædemonstrated a sustained reduction in prostate-specific antigen in a patient with CRPC, and another study showed seviteronel's direct effects on AR function. This suggested that seviteronel may have therapeutically relevant activities in addition to its ability to inhibit androgen production. Here, we have demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor-bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC.
التعليقات: Comment in: Transl Cancer Res. 2017 Oct;6(Suppl 7):S1128-S1131. (PMID: 30613487)
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معلومات مُعتمدة: T32 GM007105 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (Androgen Receptor Antagonists)
0 (Antineoplastic Agents, Hormonal)
0 (Benzamides)
0 (Nitriles)
0 (Receptors, Androgen)
2010-15-3 (Phenylthiohydantoin)
2C323EGI97 (Metribolone)
3XMK78S47O (Testosterone)
93T0T9GKNU (enzalutamide)
EC 1.14.14.19 (CYP17A1 protein, human)
EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase)
تواريخ الأحداث: Date Created: 20170503 Date Completed: 20170926 Latest Revision: 20211204
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC5451248
DOI: 10.1172/JCI87328
PMID: 28463227
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI87328