RETRACTED: Vulnerability of glioblastoma cells to catastrophic vacuolization and death induced by a small molecule.

Abstract

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: Satish Srinivas Kitambi, Enrique M Toledo, Dmitry Usoskin, Shimei Wee, Aditya Harisankar, Richard Svensson, Kristmundur Sigmundsson, Christina Kalderén, Mia Niklasson, Soumi Kundu, Sergi Aranda, Bengt Westermark, Lene Uhrbom, Michael Andäng, Peter Damberg, Sven Nelander, Ernest Arenas, Per Artursson, Julian Walfridsson, Karin Forsberg Nilsson, Lars G J Hammarström, Patrik Ernfors
• Journal: Cell (Cell) Vol. 157 Issue 2 Pg. 313-328 (04 10 2014) ISSN: 1097-4172 [Electronic] United States
• PMID: 24656405 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Hydroxyquinolines
• Piperidines
• Quinolines
• Small Molecule Libraries
• vacquinol-1
• MAP Kinase Kinase 4

Topics

• Animals
• Brain Neoplasms (drug therapy, pathology)
• Cell Death (drug effects)
• Glioblastoma (drug therapy, pathology)
• Heterografts
• Humans
• Hydroxyquinolines (pharmacology)
• MAP Kinase Kinase 4 (metabolism)
• Mice
• Neoplasm Transplantation
• Pinocytosis (drug effects)
• Piperidines (pharmacology)
• Quinolines (pharmacology)
• Small Molecule Libraries (pharmacology)
• Vacuoles (metabolism)
• Zebrafish