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

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.

Emergency Use of Targeted Osmotic Lysis for the Treatment of a Patient with Aggressive Late-Stage Squamous Cell Carcinoma of the Cervix

“…The TOL process takes advantage of a mechanism that is essential for survival because of its role in the maintenance of membrane potentials and cellular homeostasis. Unlike many treatment methods [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ], TOL enhances VGSC activity, thereby greatly increasing the influx of sodium while simultaneously preventing the extrusion of these ions by blocking the sodium pumping mechanism [ 1 , 2 ]. The osmotic influx of water floods the cells beyond their capacity to comply, resulting in lysis of the cells [ 23 ].…”

“…Based upon an evaluation of the available information on TOL [ 1 , 2 ] and given the patient’s extreme distress and that the risk of serious toxicity associated with TOL was lower than exposing the patient to investigational chemotherapeutic agents, an emergency treatment with TOL, a developing technology that uses the overproduction of VGSCs combined with the pharmacological blockade of Na + /K + -ATPase to induce selective lysis of aggressive carcinomas and metastases [ 1 , 2 ], was requested. The patient was admitted to hospice care with an extremely diminished ability to perform the basic activities of daily living, failure to thrive and intractable pain on a high-dose regimen of morphine, methadone, lorazepam, alprazolam and hydromorphone from a patient-controlled analgesia pump that yielded little relief.…”

“…The simultaneous activation of voltage-gated sodium channels (VGSCs) and pharmacological blockade of sodium/potassium-ATPase (Na + /K + -ATPase; sodium pumps) with a cardiac glycoside in highly malignant cancer cells causes increased intracellular sodium and sufficient increased oncotic pressure to produce lysis of cells that overexpress VGSCs [ 1 , 2 ]. This “targeted osmotic lysis” (TOL) selectively lyses the most malignant cancer cells while leaving the cells that express VGSCs normally unaffected.…”

Effect of Cell Cycle on Cell Surface Expression of Voltage-Gated Sodium Channels and Na+,K+-ATPase

“…The modulation of voltage-gated sodium channels (VGSCs) and/or Na + ,K + -ATPase (sodium pumps) plays a key role in the expression and treatment of several disease states including neuropathic pain Gould [1], cancer [2][3][4], hypertension [5], and epilepsy [6] For example, mutations in the SCN-9A gene that encodes the Na V 1.7 VGSC are responsible for erythromelalgia, [7] paroxysmal extreme pain disorder, and congenital insensitivity to pain [8][9][10]. Over-expression of VGSCs and Na + ,K + -ATPase in aggressive carcinomas enhances their ability to invade normal tissues and metastasize, but also makes them suitable targets for cancer therapy [11][12][13].…”

“…Aggressive carcinomas over-express VGSCs compared to their non-cancerous or stromal counterparts [4,21], but even in highly malignant cancers, there is relative heterogeneity in VGSC expression in cells within a given solid tumor that fall into 2 groups. The cells with the highest level of expression comprise 30-45% of the total.…”