Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule

Menée sur un modèle murin de glioblastome multiforme, cette étude évalue les mécanismes d'activité antitumorale d'une molécule appelée Vacquinol-1

Résumé en anglais

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.

"Glioblastoma cells are vulnerable to vacuolization, ATP depletion, and death
"Vacquinols are potent inducers of vacuolization and cell death
"The MAP kinase MKK4 is required for Vacquinol-induced vacuolization
"Vacquinol-1 has good pharmacokinetics, halts disease, and prolongs mice survival

Vacquinol-1, a small molecule that induces massive vacuolization of glioblastoma cells, halts disease and prolongs survival in a mouse model of glioblastoma multiforme.