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RETRACTED ARTICLE

See: Retraction Notice

Cell. 2014 Apr 10;157(2):313-328. doi: 10.1016/j.cell.2014.02.021. Epub 2014 Mar 20.

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

Author information

1
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
2
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
3
Department of Medicine, HERM, Karolinska Institutet, 141 86 Stockholm, Sweden.
4
Department of Pharmacy, UDOPP, Chemical Biology Consortium Sweden, Uppsala University, 751 05 Uppsala, Sweden.
5
Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine & Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
6
Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
7
Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden.
8
Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: patrik.ernfors@ki.se.

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.

PMID:
24656405
DOI:
10.1016/j.cell.2014.02.021
[Indexed for MEDLINE]
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