Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53
| Autor: | Michelle Dean, Ruiqiong Ye, Jeffrey D. Hamill, Eiji Kubota, Huong Muzik, Chris T. Williamson, LiRen Tu, Susan P. Lees-Miller, Alexander C. Klimowicz, Bruce C. McKay, Anthony M. Magliocco, D. Gwyn Bebb, David Gilley |
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| Rok vydání: | 2012 |
| Předmět: |
p53
Cell cycle checkpoint Cell Survival Poly ADP ribose polymerase Antineoplastic Agents Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Lymphoma Mantle-Cell Poly(ADP-ribose) Polymerase Inhibitors Protein Serine-Threonine Kinases Biology olaparib Poly (ADP-Ribose) Polymerase Inhibitor Piperazines PARP Olaparib DNA-PK Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor medicine Animals Humans Cytotoxic T cell Enzyme Inhibitors Research Articles 030304 developmental biology 0303 health sciences Tumor Suppressor Proteins medicine.disease Molecular biology 3. Good health DNA-Binding Proteins Disease Models Animal chemistry Cell culture ATM 030220 oncology & carcinogenesis Mutation PARP inhibitor Cancer research Phthalazines Molecular Medicine Female Mantle cell lymphoma Tumor Suppressor Protein p53 |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | Poly-ADP ribose polymerase (PARP) inhibitors have shown promise in the treatment of human malignancies characterized by deficiencies in the DNA damage repair proteins BRCA1 and BRCA2 and preclinical studies have demonstrated the potential effectiveness of PARP inhibitors in targeting ataxia-telangiectasia mutated (ATM)-deficient tumours. Here, we show that mantle cell lymphoma (MCL) cells deficient in both ATM and p53 are more sensitive to the PARP inhibitor olaparib than cells lacking ATM function alone. In ATM-deficient MCL cells, olaparib induced DNA-PK-dependent phosphorylation and stabilization of p53 as well as expression of p53-responsive cell cycle checkpoint regulators, and inhibition of DNA-PK reduced the toxicity of olaparib in ATM-deficient MCL cells. Thus, both DNA-PK and p53 regulate the response of ATM-deficient MCL cells to olaparib. In addition, small molecule inhibition of both ATM and PARP was cytotoxic in normal human fibroblasts with disruption of p53, implying that the combination of ATM and PARP inhibitors may have utility in targeting p53-deficient malignancies. |
| Databáze: | OpenAIRE |
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