Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells

Raffaella Spina, Dillon M. Voss, Laura Asnaghi, Andrew Sloan, Eli E. Bar

Research output: Contribution to journalArticle

Abstract

Glioblastoma multiforme (GBM) are the most common primary malignant brain tumor in adults, with a median survival of about one year. This poor prognosis is attributed primarily to therapeutic resistance and tumor recurrence after surgical removal, with the root cause suggested to be found in glioblastoma stem cells (GSCs). Using glial fibrillary acidic protein (GFAP) as a reporter of astrocytic differentiation, we isolated multiple clones from three independent GSC lines which express GFAP in a remarkably stable fashion. We next show that elevated expression of GFAP is associated with reduced clonogenicity in vitro and tumorigenicity in vivo. Utilizing this in vitro cell-based differentiation reporter system we screened chemical libraries and identified the non-depolarizing neuromuscular blocker (NNMB), Atracurium Besylate, as a small molecule which effectively induces astroglial but not neuronal differentiation of GSCs. Functionally, Atracurium Besylate treatment significantly inhibited the clonogenic capacity of several independent patient-derived GSC neurosphere lines, a phenomenon which was largely irreversible. A second NNMB, Vecuronium, also induced GSC astrocytic differentiation while Dimethylphenylpiperazinium (DMPP), a nicotinic acetylcholine receptor (nAChR) agonist, significantly blocked Atracurium Besylate pro-differentiation activity. To investigate the clinical importance of nAChRs in gliomas, we examined clinical outcomes and found that glioma patients with tumors overexpressing CHRNA1 or CHRNA9 (encoding for the AChR-α1 or AChR-α9) exhibit significant shorter overall survival. Finally, we found that ex-vivo pre-treatment of GSCs, expressing CHRNA1 and CHRNA9, with Atracurium Besylate significantly increased the survival of mice xenotransplanted with these cells, therefore suggesting that tumor initiating subpopulations have been reduced.

Original languageEnglish (US)
Pages (from-to)459-472
Number of pages14
JournalOncotarget
Volume7
Issue number1
DOIs
StatePublished - Jan 5 2016

Fingerprint

Atracurium
Neuromuscular Blocking Agents
Glioblastoma
Stem Cells
Glial Fibrillary Acidic Protein
Glioma
Cell Differentiation
Dimethylphenylpiperazinium Iodide
Small Molecule Libraries
Vecuronium Bromide
Cell Line
Cholinergic Agonists
Neoplasms
Survival
Nicotinic Receptors
Brain Neoplasms
Therapeutics
Clone Cells
Recurrence

Keywords

  • astrocytic differentiation
  • Atracurium Besylate
  • glioma
  • neurotransmitter signaling
  • stem cells

ASJC Scopus subject areas

  • Oncology

Cite this

Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells. / Spina, Raffaella; Voss, Dillon M.; Asnaghi, Laura; Sloan, Andrew; Bar, Eli E.

In: Oncotarget, Vol. 7, No. 1, 05.01.2016, p. 459-472.

Research output: Contribution to journalArticle

Spina, Raffaella ; Voss, Dillon M. ; Asnaghi, Laura ; Sloan, Andrew ; Bar, Eli E. / Atracurium Besylate and other neuromuscular blocking agents promote astroglial differentiation and deplete glioblastoma stem cells. In: Oncotarget. 2016 ; Vol. 7, No. 1. pp. 459-472.
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