التفاصيل البيبلوغرافية
| العنوان: |
A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer. |
| المؤلفون: |
Lucki, Natasha C.1, Villa, Genaro R.2,3, Vergani, Naja1,4, Bollong, Michael J.4, Beyer, Brittney A.1,4, Jae Wook Lee4,5, Anglin, Justin L.1, Spangenberg, Stephan H.4, Chin, Emily N.4, Sharma, Amandeep4, Johnson, Kevin6, Sander, Philipp N.4, Gordon, Perry6, Skirboll, Stephen L.7, Wurdak, Heiko8, Schultz, Peter G.1,4 schultz@scripps.edu, Mischel, Paul S.3 pmischel@ucsd.edu, Lairson, Luke L.4 llairson@scripps.edu |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America. 3/26/2019, Vol. 116 Issue 13, p6435-6440. 6p. |
| مصطلحات موضوعية: |
*TREATMENT of brain cancer, *APOPTOSIS, *SMALL molecules, *GLIOBLASTOMA multiforme, *CANCER stem cells |
| مستخلص: |
Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease. [ABSTRACT FROM AUTHOR] |
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