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10.18632/oncotarget.24581

http://scihub22266oqcxt.onion/10.18632/oncotarget.24581
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suck abstract from ncbi


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pmid29643996
      Oncotarget 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.
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