Direct Therapeutic Applications of Calcium Electroporation to Effectively Induce Tumor Necrosis

Abstract

Electroporation of cells with short, high-voltage pulses causes a transient permeabilization of cell membranes that permits passage of otherwise nonpermeating ions and molecules. In this study, we illustrate how electroporation with isotonic calcium can achieve highly effective cancer cell kill in vivo. Calcium electroporation elicited dramatic antitumor responses in which 89% of treated tumors were eliminated. Histologic analyses indicated complete tumor necrosis. Mechanistically, calcium electroporation caused acute ATP depletion likely due to a combination of increased cellular use of ATP, decreased production of ATP due to effects on the mitochondria, as well as loss of ATP through the permeabilized cell membrane. Taken together, our findings offer a preclinical proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anticancer treatment. Electroporation equipment is already used clinically to enhance the delivery of chemotherapy to superficial tumors, with trials on internal tumors in progress, enabling the introduction of calcium electroporation to clinical use. Moreover, the safety profile, availability, and low cost of calcium facilitate access to this technology for many cancer patients in developed and developing countries. Cancer Res; 72(6); 1336-41. Ó2012 AACR.

The effect of concurrent radiation and calcium in two cancer cell lines

“…Calcium is an important substance that acts as a second messenger in the cell and is involved in numerous cellular processes, such as proliferation, muscle contraction, transcription, and metabolism [7]- [10]. Due to the big impact of calcium regarding the maintenance of cellular homeostasis, the calcium concentration is extremely regulated.…”

“…Due to the big impact of calcium regarding the maintenance of cellular homeostasis, the calcium concentration is extremely regulated. The extracellular calcium concentration is approximately 1 mmol/L and the intracellular calcium concentration is approximately 0.1 µmol/L [10]. Mechanisms that regulate the calcium concentration are therefore extremely important for maintaining the cellular homeostasis.…”

“…Ca %& -ATPase is the membrane pump that contribute to maintaining a low intracellular calcium concentration, and thereby regulates the cellular homeostasis by consuming adenosine triphosphate (ATP) [11]. An increased intracellular calcium concentration will result in an increased activity of Ca %& -ATPases and affect the mitochondria by eliminating the mitochondrial formation of new ATP, thus resulting in ATP depletion and cell death [10], [12], [13]. By combining electroporation, where the cell membrane is permeabilized by exposing the cells to short high-voltage pulses, and calcium injections the intracellular concentration of free calcium is increased and the cell viability is decreased [10], [11], [14].…”

“…An increased intracellular calcium concentration will result in an increased activity of Ca %& -ATPases and affect the mitochondria by eliminating the mitochondrial formation of new ATP, thus resulting in ATP depletion and cell death [10], [12], [13]. By combining electroporation, where the cell membrane is permeabilized by exposing the cells to short high-voltage pulses, and calcium injections the intracellular concentration of free calcium is increased and the cell viability is decreased [10], [11], [14]. An increase in the intracellular concentration of free calcium may induce cell death through necrosis and apoptosis [15] and after treatment with calcium electroporation cells die through necrosis [10].…”

“…By combining electroporation, where the cell membrane is permeabilized by exposing the cells to short high-voltage pulses, and calcium injections the intracellular concentration of free calcium is increased and the cell viability is decreased [10], [11], [14]. An increase in the intracellular concentration of free calcium may induce cell death through necrosis and apoptosis [15] and after treatment with calcium electroporation cells die through necrosis [10].…”