Targeted Osmotic Lysis of Highly Invasive Breast Carcinomas Using Pulsed Magnetic Field Stimulation of Voltage-Gated Sodium Channels and Pharmacological Blockade of Sodium Pumps.

Dennis Paul,Fabio Del Piero,Kelly Jean Sherman,Samantha Edenfield,Paul Maggi,Harry J Gould,Steven D Scahill

doi:10.3390/cancers12061420

Abstract

Concurrent activation of voltage-gated sodium channels (VGSCs) and blockade of Na+ pumps causes a targeted osmotic lysis (TOL) of carcinomas that over-express the VGSCs. Unfortunately, electrical current bypasses tumors or tumor sections because of the variable resistance of the extracellular microenvironment. This study assesses pulsed magnetic fields (PMFs) as a potential source for activating VGSCs to initiate TOL in vitro and in vivo as PMFs are unaffected by nonconductive tissues. In vitro, PMFs (0–80 mT, 10 msec pulses, 15 pps for 10 min) combined with digoxin-lysed (500 nM) MDA-MB-231 breast cancer cells stimulus-dependently. Untreated, stimulation-only, and digoxin-only control cells did not lyse. MCF-10a normal breast cells were also unaffected. MDA-MB-231 cells did not lyse in a Na+-free buffer. In vivo, 30 min of PMF stimulation of MDA-MB-231 xenografts in J/Nu mice or 4T1 homografts in BALB/c mice, concurrently treated with 7 mg/kg digoxin reduced tumor size by 60–100%. Kidney, spleen, skin and muscle from these animals were unaffected. Stimulation-only and digoxin-only controls were similar to untreated tumors. BALB/C mice with 4T1 homografts survived significantly longer than mice in the three control groups. The data presented is evidence that the PMFs to activate VGSCs in TOL provide sufficient energy to lyse highly malignant cells in vitro and to reduce tumor growth of highly malignant grafts and improve host survival in vivo, thus supporting targeted osmotic lysis of cancer as a possible method for treating late-stage carcinomas without compromising noncancerous tissues.

Highlights

Metastatic carcinomas express high levels of voltage-gated sodium channels (VGSCs), a feature that imparts an increased ability to invade normal tissue and to metastasize [1,2,3]
[17].InInthe thein invitro vitro experiments, experiments, the whilewhile preserving treated normal breast cells thelysis lysisofofthe the cancer cells was dependent upon the intensity of the pulsed magnetic fields (PMFs), with greater than of the digoxin cancer cells was dependent upon the intensity of the PMF, with greater than 95% of the digoxin treated treated cancer within cells lysing within
We have provided evidence that targeted osmotic lysis (TOL) can kill both highly malignant human (MDA-MB-231) and murine (4T1) breast cancer cells in vitro and can reduce growth of xenografts and increase the survival of mice in vivo when compared with controls while sparing normal cells and tissues

Summary

Introduction

Metastatic carcinomas express high levels of voltage-gated sodium channels (VGSCs), a feature that imparts an increased ability to invade normal tissue and to metastasize [1,2,3] This feature of epithelium-derived cancer cells provides the basis for proposed treatments using cytotoxic agents that target VGSCs with the goal to destroy or to block the function of these channels in an attempt to eliminate the cancer [3,4,5,6,7,8]. 12, 1420 carcinomas express high levels of voltage-gated sodium channels (VGSCs), a feature that imparts an increased ability to invade normal tissue and to metastasize [1,2,3] This feature of epithelium-derived cancer cells provides the basis for proposed treatments using cytotoxic agents that target.

Results

Discussion

Conclusion