Year: 2019
Type: article
Abstract: 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.
Authors: Natasha C. Lucki, Genaro R. Villa, Naja Vergani, Michael J. Bollong, Brittney A. Beyer, Jae Wook Lee, Justin L. Anglin, Stephan H. Spangenberg, Emily N. Chin, Amandeep Sharma, Kevin Johnson, Philipp N. Sander, Perry Gordon, Stephen L. Skirboll, Heiko Wurdak, Peter G. Schultz, Paul S. Mischel, Luke L. Lairson
Institutions: California Institute for Biomedical Research, University of California, Los Angeles, University of California San Diego, Scripps Research Institute, Korea Institute of Science and Technology, Genomics Institute of the Novartis Research Foundation, VA Palo Alto Health Care System, Stanford University, University of Leeds, St James's University Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W2921877864