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Small molecule makes brain cancer cells collapse and die
by Ashley Yeager
9:02am, March 21, 2014

A new study suggests that certain small molecules may help kill the damaged cells that cause glioblastomas, highly malignant brain tumors.

Damaged cells that cause the most aggressive type of brain cancer collapse and die when exposed to the molecule Vacquinol-1.
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more:
https://www.sciencenews.org/blog/science-ticker/small-molecule-makes-brain-cancer-cells-collapse-and-die


The abstract of the article in "cell":

http://www.cell.com/abstract/S0092-8674%2814%2900220-7

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

Cell, 20 March 2014
Copyright © 2014 Elsevier Inc. All rights reserved.
10.1016/j.cell.2014.02.021

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 Ernforssend
email See Affiliations

    Highlights
    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

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 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.
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