کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8437921 | 1546875 | 2017 | 38 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
MDM2 Antagonists Counteract Drug-Induced DNA Damage
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
پیش نمایش صفحه اول مقاله
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چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: EBioMedicine - Volume 24, October 2017, Pages 43-55
Journal: EBioMedicine - Volume 24, October 2017, Pages 43-55
نویسندگان
Anna E. Vilgelm, Priscilla Cobb, Kiran Malikayil, David Flaherty, C. Andrew Johnson, Dayanidhi Raman, Nabil Saleh, Brian Higgins, Brandon A. Vara, Jeffrey N. Johnston, Douglas B. Johnson, Mark C. Kelley, Sheau-Chiann Chen, Gregory D. Ayers, Ann Richmond,