MDM2 Antagonists Counteract Drug-Induced DNA Damage
| Autor: | Brian Higgins, Nabil Saleh, Anna E. Vilgelm, Mark C. Kelley, Brandon A. Vara, Gregory D. Ayers, Sheau-Chiann Chen, Kiran Malikayil, David K. Flaherty, Dayanidhi Raman, Ann Richmond, Douglas B. Johnson, Priscilla Cobb, Jeffrey N. Johnston, C. Andrew Johnson |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
p53 Pyrrolidines medicine.medical_treatment lcsh:Medicine Piperazines chemistry.chemical_compound Mice Antineoplastic Combined Chemotherapy Protocols para-Aminobenzoates Melanoma lcsh:R5-920 biology p21 MDM2 antagonist Imidazoles Proto-Oncogene Proteins c-mdm2 General Medicine Azepines 3. Good health Mitotic inhibitor Mdm2 lcsh:Medicine (General) Research Paper Protein Binding Cyclin-Dependent Kinase Inhibitor p21 DNA Replication DNA damage General Biochemistry Genetics and Molecular Biology Polyploidy 03 medical and health sciences Cell Line Tumor medicine Animals Humans Mitosis Chemotherapy lcsh:R DNA replication Replication stress medicine.disease HCT116 Cells Xenograft Model Antitumor Assays 030104 developmental biology Pyrimidines chemistry biology.protein Cancer research Tumor Suppressor Protein p53 DNA |
| Zdroj: | EBioMedicine EBioMedicine, Vol 24, Iss C, Pp 43-55 (2017) |
| ISSN: | 2352-3964 |
| Popis: | 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. Highlights • Mitotic inhibitors induce polyploidy which leads to replication stress and DNA damage. • MDM2 antagonists reduce mitotic inhibitor-induced DNA damage by blocking DNA re-replication. • Loss of p21 alleviates DNA protection by MDM2 antagonism and increases efficacy of combined MDM2 and mitotic inhibition. Many anti-cancer therapies work by damaging DNA in cancer cells. Here we demonstrate that investigational cancer drugs that target MDM2 (MDM2 antagonists) can protect cancer cells from drug-induced DNA damage. They do so by increasing the levels of protein p21 which prevents cells from replicating DNA. Disabling of p21 increases drug-induced DNA damage and promotes killing of cancer cells. This study improves our understanding of how to combine different anti-cancer drugs to generate most effective treatment regimens and demonstrates the need for development of therapies that inactivate p21. |
| Databáze: | OpenAIRE |
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