دورية أكاديمية
MDM2 Antagonists Counteract Drug-Induced DNA Damage.
العنوان: | MDM2 Antagonists Counteract Drug-Induced DNA Damage. |
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المؤلفون: | Vilgelm AE; Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States. Electronic address: anna.e.vilgelm@vanderbilt.edu., Cobb P; Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States., Malikayil K; Meharry Medical College, Nashville, TN, United States., Flaherty D; Vanderbilt University Flow Cytometry Shared Resource, Nashville, TN, United States., Andrew Johnson C; Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States., Raman D; University of Toledo, Toledo, OH, United States., Saleh N; Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States., Higgins B; Pharma Research and Early Development, Roche Innovation Center, New York, NY, United States., Vara BA; Department of Chemistry, Vanderbilt Institute of Chemical Biology, Nashville, TN, United States., Johnston JN; Department of Chemistry, Vanderbilt Institute of Chemical Biology, Nashville, TN, United States., Johnson DB; Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States., Kelley MC; Division of Surgical Oncology, Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, United States., Chen SC; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States., Ayers GD; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, United States., Richmond A; Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, United States; Vanderbilt University School of Medicine, Department of Cancer Biology, Nashville, TN, United States. |
المصدر: | EBioMedicine [EBioMedicine] 2017 Oct; Vol. 24, pp. 43-55. Date of Electronic Publication: 2017 Sep 19. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Elsevier B.V Country of Publication: Netherlands NLM ID: 101647039 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2352-3964 (Electronic) Linking ISSN: 23523964 NLM ISO Abbreviation: EBioMedicine Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Amsterdam] : Elsevier B.V., [2014]- |
مواضيع طبية MeSH: | Azepines/*administration & dosage , DNA Damage/*drug effects , Imidazoles/*administration & dosage , Melanoma/*drug therapy , Piperazines/*administration & dosage , Proto-Oncogene Proteins c-mdm2/*antagonists & inhibitors , Pyrimidines/*administration & dosage , Pyrrolidines/*administration & dosage , para-Aminobenzoates/*administration & dosage, Animals ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Azepines/pharmacology ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; DNA Replication/drug effects ; HCT116 Cells ; Humans ; Imidazoles/pharmacology ; Melanoma/genetics ; Mice ; Piperazines/pharmacology ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-mdm2/metabolism ; Pyrimidines/pharmacology ; Pyrrolidines/pharmacology ; Tumor Suppressor Protein p53/metabolism ; Xenograft Model Antitumor Assays ; para-Aminobenzoates/pharmacology |
مستخلص: | Antagonists of MDM2-p53 interaction are emerging anti-cancer drugs utilized in clinical trials for malignancies that rarely mutate p53, including melanoma. We discovered that MDM2-p53 antagonists protect DNA from drug-induced damage in melanoma cells and patient-derived xenografts. Among the tested DNA damaging drugs were various inhibitors of Aurora and Polo-like mitotic kinases, as well as traditional chemotherapy. Mitotic kinase inhibition causes mitotic slippage, DNA re-replication, and polyploidy. Here we show that re-replication of the polyploid genome generates replicative stress which leads to DNA damage. MDM2-p53 antagonists relieve replicative stress via the p53-dependent activation of p21 which inhibits DNA replication. Loss of p21 promoted drug-induced DNA damage in melanoma cells and enhanced anti-tumor activity of therapy combining MDM2 antagonist with mitotic kinase inhibitor in mice. In summary, MDM2 antagonists may reduce DNA damaging effects of anti-cancer drugs if they are administered together, while targeting p21 can improve the efficacy of such combinations. (Copyright © 2017. Published by Elsevier B.V.) |
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معلومات مُعتمدة: | U54 CA163069 United States CA NCI NIH HHS; I01 BX002301 United States BX BLRD VA; IK6 BX005225 United States BX BLRD VA; K12 CA090625 United States CA NCI NIH HHS; I01 BX000196 United States BX BLRD VA; P30 CA068485 United States CA NCI NIH HHS; K23 CA204726 United States CA NCI NIH HHS; R01 CA116021 United States CA NCI NIH HHS; R01 GM084333 United States GM NIGMS NIH HHS |
فهرسة مساهمة: | Keywords: DNA damage; MDM2 antagonist; Melanoma; Mitotic inhibitor; Polyploidy; Replication stress; p21; p53 |
المشرفين على المادة: | 0 (Azepines) 0 (CDKN1A protein, human) 0 (Cyclin-Dependent Kinase Inhibitor p21) 0 (Imidazoles) 0 (MLN 8237) 0 (Piperazines) 0 (Pyrimidines) 0 (Pyrrolidines) 0 (RG7388) 0 (TP53 protein, human) 0 (Tumor Suppressor Protein p53) 0 (para-Aminobenzoates) 53IA0V845C (nutlin 3) EC 2.3.2.27 (MDM2 protein, human) EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2) |
تواريخ الأحداث: | Date Created: 20171015 Date Completed: 20180618 Latest Revision: 20210227 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC5652019 |
DOI: | 10.1016/j.ebiom.2017.09.016 |
PMID: | 29030058 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2352-3964 |
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DOI: | 10.1016/j.ebiom.2017.09.016 |