Journal
CELL
Volume 157, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.02.021
Keywords
-
Categories
Funding
- Swedish Research Council for Medicine and Health
- Swedish Cancer Society
- Swedish strategic funds (DBRM, StratNeuro)
- Swedish Brain Foundation
- Hallsten Foundation
- Torsten Soderberg Professorship
- Wallenberg Foundation (Wallenberg Scholar grant)
- ERC advanced grant [232675]
- Chemical Biology Consortium Sweden (CBCS)
- Swedish Research Council
- European Research Council (ERC) [232675] Funding Source: European Research Council (ERC)
Ask authors/readers for more resources
Glioblastoma multiforme (GBM) is the most aggressive form of brain cancer with marginal life expectancy. Based on the assumption that GBM cells gain functions not necessarily involved in the cancerous process, patient-derived glioblastoma cells (GCs) were screened to identify cellular processes amenable for development of targeted treatments. The quinine-derivative NSC13316 reliably and selectively compromised viability. Synthetic chemical expansion reveals delicate structure-activity relationship and analogs with increased potency, termed Vacquinols. Vacquinols stimulate death by membrane ruffling, cell rounding, massive macropinocytic vacuole accumulation, ATP depletion, and cytoplasmic membrane rupture of GCs. The MAP kinase MKK4, identified by a shRNA screen, represents a critical signaling node. Vacquinol-1 displays excellent in vivo pharmacokinetics and brain exposure, attenuates disease progression, and prolongs survival in a GBM animal model. These results identify a vulnerability to massive vacuolization that can be targeted by small molecules and point to the possible exploitation of this process in the design of anticancer therapies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available