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

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• 作者：Satish Srinivas Kitambi¹ ; Enrique M. Toledo¹ ; Dmitry Usoskin¹ ; Shimei Wee¹ ; ⁴ ; Aditya Harisankar⁵ ; Richard Svensson³ ; Kristmundur Sigmundsson² ; Christina Kalderé ; n² ; Mia Niklasson⁶ ; Soumi Kundu⁶ ; Sergi Aranda¹ ; Bengt Westermark⁶ ; Lene Uhrbom⁶ ; Michael Andä ; ng¹ ; ⁴ ; Peter Damberg⁷ ; Sven Nelander⁶ ; Ernest Arenas¹ ; Per Artursson³ ; Julian Walfridsson⁵ ; Karin Forsberg Nilsson⁶ ; Lars G.J. Hammarströ ; m² ; Patrik Ernfors¹ ; ^{patrik.ernfors@ki.se" class="auth_mail}
• 刊名：Cell
• 出版年：10 April, 2014
• 年：2014
• 卷：157
• 期：2
• 页码：313-328
• 全文大小：7478 K

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Summary

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聽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.