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

機(jī)譯：使用電壓門控鈉通道的脈沖磁場刺激和鈉泵的藥理學(xué)阻斷作用對高浸潤性乳腺癌進(jìn)行靶向滲透溶解

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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.
機(jī)譯：電壓門控鈉通道（VGSC）的同時激活和鈉泵的阻塞會導(dǎo)致過表達(dá)VGSC的癌癥的定向滲透裂解（TOL）。不幸的是，由于細(xì)胞外微環(huán)境的可變電阻，電流繞過了腫瘤或腫瘤切片。這項研究評估了脈沖磁場（PMF）作為激活VGSC在體外和體內(nèi)啟動TOL的潛在來源，因為PMF不受非導(dǎo)電組織的影響。在體外，PMF（0–80 mT，10毫秒脈沖，15 pps，持續(xù)10分鐘）與地高辛溶解的（500 nM）MDA-MB-231乳腺癌細(xì)胞聯(lián)合刺激依賴。未經(jīng)處理，僅刺激和僅地高辛的對照細(xì)胞未裂解。正常的乳腺癌細(xì)胞MCF-10a也未受影響。 MDA-MB-231細(xì)胞未在不含Na的緩沖液中裂解。在體內(nèi)，PMF刺激J / Nu小鼠中的MDA-MB-231異種移植物或BALB / c小鼠中的4T1同種移植物，同時用7 mg / kg地高辛治療可刺激腫瘤縮小60-100％。這些動物的腎臟，脾臟，皮膚和肌肉不受影響。僅刺激和僅地高辛的對照與未經(jīng)治療的腫瘤相似。具有4T1同種移植物的BALB / C小鼠的存活時間明顯長于三個對照組的小鼠。所提供的數(shù)據(jù)證明激活TOL中的VGSC的PMF提供足夠的能量在體外裂解高度惡性細(xì)胞，并減少高度惡性移植物的腫瘤生長并改善體內(nèi)宿主存活率，從而支持癌癥的定向滲透裂解用于治療晚期癌癥而不損害非癌性組織。

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