Targeted osmotic lysis of metastatic carcinomas by simultaneous blockade of sodium pumps and stimulation of voltage‐gated sodium channels (842.1)

Abstract

Metastatic carcinomas (MCs) overexpress voltage‐gated sodium channels (VGSCs) by up to 1500‐fold. We reasoned that electrical stimulation of VGSCs with concomitant blockade of Na+, K+‐ATPase (sodium pumps) would produce a rapid increase in intracellular sodium, causing an influx of water. This would cause the MC cells to swell and burst. To test this hypothesis in vitro, we cultured MDA‐MB‐231 cells, which overexpress NaV1.5 VGSCs by 1400‐fold. Treatment with the sodium pump blocker ouabain then electrical stimulation of the cells produced lysis in as little as 16 sec. Ouabain or electric current alone did not lyse the cells. Treatment did not lyse MCF‐10a (normal breast) cells. To test the hypothesis in vivo, we established MDA‐MB‐231 allographs in nude mice. When tumor diameter reached approximately 1 cm, we administered 10 mg/kg ouabain s.c. or saline. 30 and 60 min later, tumors received 60 sec of 10V DC delivered through direct contact stimulation. This single‐treatment produced 70% cell lysis in tumors treated with both ouabain and stimulation. Tumors treated with saline alone and saline plus stimulation averaged 10% lysis. Ouabain alone produced 15% cell death. Treatment did not affect noncancerous tissue. In survival studies, single day treatment attenuated tumor growth by 45%. 3‐Day treatment attenuated growth by 60%. Thus, targeted osmotic lysis can be an effective treatment of MCs that overexpress VGSCs.