title: 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.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Satish Srinivas
authors.initials: SS
authors.lastname: Kitambi
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Enrique M
authors.initials: EM
authors.lastname: Toledo
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Usoskin
authors.affiliation: 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.
authors.forename: Shimei
authors.initials: S
authors.lastname: Wee
authors.affiliation: Department of Medicine, HERM, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Aditya
authors.initials: A
authors.lastname: Harisankar
authors.affiliation: Department of Pharmacy, UDOPP, Chemical Biology Consortium Sweden, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Svensson
authors.affiliation: 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.
authors.forename: Kristmundur
authors.initials: K
authors.lastname: Sigmundsson
authors.affiliation: 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.
authors.forename: Christina
authors.initials: C
authors.lastname: Kalderén
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Mia
authors.initials: M
authors.lastname: Niklasson
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Soumi
authors.initials: S
authors.lastname: Kundu
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Sergi
authors.initials: S
authors.lastname: Aranda
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Andäng
authors.affiliation: Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Damberg
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
authors.affiliation: Department of Pharmacy, UDOPP, Chemical Biology Consortium Sweden, Uppsala University, 751 05 Uppsala, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
authors.affiliation: Department of Medicine, HERM, Karolinska Institutet, 141 86 Stockholm, Sweden.
authors.forename: Julian
authors.initials: J
authors.lastname: Walfridsson
authors.affiliation: Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg Nilsson
authors.affiliation: 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.
authors.forename: Lars G J
authors.initials: LGJ
authors.lastname: Hammarström
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: patrik.ernfors@ki.se.
authors.forename: Patrik
authors.initials: P
authors.lastname: Ernfors
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D010873:Pinocytosis / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014617:Vacuoles / Q000378:metabolism; D015027:Zebrafish
chemical_list: D006912:Hydroxyquinolines; D010880:Piperidines; D011804:Quinolines; D054852:Small Molecule Libraries; C000588923:vacquinol-1; D048670:MAP Kinase Kinase 4