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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Preuss, Ellen Reimann, Romy Fulda, Simone Hugle, Manuela Schlecht, Marcel |
| Description | Author Affiliation: Preuss E ( From the Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, Komturstrasse 3a, 60528 Frankfurt, Germany.) |
| Abstract | The PI3K/mammalian Target of Rapamycin (mTOR) pathway is often aberrantly activated in rhabdomyosarcoma (RMS) and represents a promising therapeutic target. Recent evaluation of AZD8055, an ATP-competitive mTOR inhibitor, by the Preclinical Pediatric Testing Program showed in vivo antitumor activity against childhood solid tumors, including RMS. Therefore, in the present study, we searched for AZD8055-based combination therapies. Here, we identify a new synergistic lethality of AZD8055 together with ABT-737, a BH3 mimetic that antagonizes Bcl-2, Bcl-xL, and Bcl-w but not Mcl-1. AZD8055 and ABT-737 cooperate to induce apoptosis in alveolar and embryonal RMS cells in a highly synergistic fashion (combination index < 0.2). Synergistic induction of apoptosis by AZD8055 and ABT-737 is confirmed on the molecular level, as AZD8055 and ABT-737 cooperate to trigger loss of mitochondrial membrane potential, activation of caspases, and caspase-dependent apoptosis that is blocked by the pan-caspase inhibitor Z-VAD-fmk. Similar to AZD8055, the PI3K/mTOR inhibitor NVP-BEZ235, the PI3K inhibitor NVP-BKM120 and Akt inhibitor synergize with ABT-737 to trigger apoptosis, whereas no cooperativity is found for the mTOR complex 1 inhibitor RAD001. Interestingly, molecular studies reveal a correlation between the ability of different PI3K/mTOR inhibitors to potentiate ABT-737-induced apoptosis and to suppress Mcl-1 protein levels. Importantly, knockdown of Mcl-1 increases ABT-737-induced apoptosis similar to AZD8055/ABT-737 cotreatment. This indicates that AZD8055-mediated suppression of Mcl-1 protein plays an important role in the synergistic drug interaction. By identifying a novel synergistic interaction of AZD8055 and ABT-737, our findings have important implications for the development of molecular targeted therapies for RMS. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 49 |
| Volume Number | 288 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2013-12-06 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Biphenyl Compounds Administration & Dosage Morpholines Myeloid Cell Leukemia Sequence 1 Protein Metabolism Nitrophenols Rhabdomyosarcoma Drug Therapy Sulfonamides TOR Serine-Threonine Kinases Antagonists & Inhibitors Antineoplastic Agents Apoptosis Drug Effects Caspases Cell Line, Tumor Down-Regulation Drug Synergism Gene Knockdown Techniques Multiprotein Complexes Genetics Phosphatidylinositol 3-Kinases Piperazines Protein Kinase Inhibitors Pathology Signal Transduction Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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