Oncotarget

Research Papers:

Selective lysis of breast carcinomas by simultaneous stimulation of sodium channels and blockade of sodium pumps

Harry J. Gould III _, Jack Norleans, T. David Ward, Chasiti Reid and Dennis Paul

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Oncotarget. 2018; 9:15606-15615. https://doi.org/10.18632/oncotarget.24581

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Abstract

Harry J. Gould III1,3,5,6,7, Jack Norleans2, T. David Ward4, Chasiti Reid2 and Dennis Paul1,2,3,5,6,7

1Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, USA

2Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, USA

3Department of Anesthesiology, Louisiana State University Health Sciences Center, New Orleans, LA, USA

4Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, LA, USA

5Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA

6Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA

7Center of Excellence for Oral and Craniofacial Biology, Louisiana State University Health Sciences Center, New Orleans, LA, USA

Correspondence to:

Harry J. Gould III, email: hgould@lsuhsc.edu

Dennis Paul, email: dpaul@lsuhsc.edu

Keywords: targeted osmotic lysis; epithelial carcinoma; cancer; sodium channels; sodium pumps

Received: October 29, 2017     Accepted: February 21, 2018     Epub: February 26, 2018     Published: March 20, 2018

ABSTRACT

Sodium influx through voltage-gated sodium channels (VGSCs) coupled with balanced removal of sodium ions via Na+, K+-ATPase is a major determinant of cellular homeostasis and intracellular ionic concentration. Interestingly, many metastatic carcinomas express high levels of these channels. We hypothesized that if excess VGSCs are activated and Na+, K+-ATPase is simultaneously blocked, the intracellular Na+ concentration should increase, resulting in water movement into the cell, causing swelling and lytic cell death. MDA-MB-231 breast cancer cells over-express VGSCs by 7-fold. To test our hypothesis, we treated these cells in vitro with the Na+, K+-ATPase blocker, ouabain, and then stimulated with a sublethal electric current. For in vivo histologic and survival studies, MDA-MB-231 xenografts were established in Nu/J mice. Mice injected with saline or ouabain were electrically stimulated with trains of 10 msec 10V DC pulses. Within seconds to minutes, the cells swelled and lysed. MCF-10a cells, which express normal VGSCs levels, were unaffected by this treatment. Cells from the weakly-malignant cell line, MCF-7, which express 3-fold greater VGSCs than MCF-10a cells, displayed an intermediate time-to-lysis. The rate of lysis correlated directly with the degree of sodium channel expression and malignancy. We also demonstrated efficacy in cell lines from prostate, colon and lung carcinomas. Treated MDA-MB-231 xenografts showed 60–80% cell death. In survival studies, TOL-treated mice showed significantly slower tumor growth vs. controls. These results are evidence that this ”targeted osmotic lysis” represents a novel method for selectively killing cancer cells and warrants further investigation as a potential treatment for advanced and end-stage breast cancer.


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