A cell type-selective apoptosis-inducing small molecule for the treament of brain cancer
- A cell type-selective apoptosis-inducing small molecule for the treament of brain cancer
- 이재욱; Natasha C. Lucki; Genaro R. Villa; Naja Vergani; Michael J. Bollong; Brittney A. Beyer; 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
- Issue Date
- Proceedings of the National Academy of Sciences of the United States of America
- VOL 119, NO 11-6
- 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 redoxdependent 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.
- Appears in Collections:
- KIST Publication > Article
- Files in This Item:
There are no files associated with this item.
- RIS (EndNote)
- XLS (Excel)
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.