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Mol Cancer Res. 2018 May;16(5):777-790. doi: 10.1158/1541-7786.MCR-17-0413. Epub 2018 Feb 5.

Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma.

Author information

1
Department of Neurology, University of California, San Francisco, San Francisco, California.
2
Brain Tumor Research Center (BTRC) at the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
3
Sandler Neurosciences Center, University of California, San Francisco, San Francisco, California.
4
Department of Surgery, University of California, San Francisco, San Francisco, California.
5
Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.
6
Institute of Biophysics, CNR and FBK, Trento, Italy.
7
CIBIO, University of Trento, Trento, Italy.
8
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
9
Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.
10
Department of Pathology, University of California, San Francisco, San Francisco, California.
11
Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania.
12
Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California.
13
Department of Neurology, University of California, San Francisco, San Francisco, California. Anders.Persson@ucsf.edu.
#
Contributed equally

Abstract

Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopied in vitro by the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models. In vitro, the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's ability to sensitize GBM cells to the alkylating agent temozolomide, standard of care in GBM patients, was evaluated. Importantly, combination of AF induction and temozolomide treatment blocked regrowth in GBM xenografts. Thus, AF-mediated inhibition of cell volume regulation represents a novel strategy to increase drug uptake and improve outcome in GBM. Mol Cancer Res; 16(5); 777-90. ©2018 AACR.

PMID:
29431617
PMCID:
PMC5932284
[Available on 2019-05-01]
DOI:
10.1158/1541-7786.MCR-17-0413

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