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2018 ; 9
(21
): 15606-15615
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Selective lysis of breast carcinomas by simultaneous stimulation of sodium
channels and blockade of sodium pumps
#MMPMID29643996
Gould HJ 3rd
; Norleans J
; Ward TD
; Reid C
; Paul D
Oncotarget
2018[Mar]; 9
(21
): 15606-15615
PMID29643996
show ga
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.