Abstract
Calcium electroporation may offer a simple general tool for anticancer therapy. Transient permeabilization of cancer cell membranes created by applying short, high-voltage pulses in tumors enables high calcium influxes that trigger cell death. In this study, we compared the relative sensitivity of different human tumor models and normal tissues to calcium electroporation. Plasma membrane Ca2+-ATPase (PMCA) protein expression was confirmed in vitro in all cancer cell lines and normal primary dermal fibroblasts studied. In all tumor types tested in vivo, calcium electroporation effectively induced necrosis, with a range of sensitivities observed (36%-88%) 2 days after treatment. Necrosis was induced using calcium concentrations of 100-500 mmol/L and injection volumes 20%-80% of tumor volume. Notably, only limited effects were seen in normal tissue. Calcium content increased >7-fold in tumor and skin tissue after calcium electroporation but decreased in skin tissue 4 hours after treatment to levels comparable with untreated controls, whereas calcium content endured at high levels in tumor tissue. Mechanistic experiments in vitro indicated that calcium influx was similar in fibroblasts and cancer cells. However, we observed decreased PMCA expression in cancer cells compared with fibroblasts, offering a potential explanation for the different calcium content in tumor cells versus normal tissues. Overall, our results suggest that calcium electroporation can elicit a rapid and selective necrosis of solid tumors, with limited deleterious effects on surrounding normal tissues. Cancer Res; 77(16); 4389-401. ©2017 AACR.
Highlights
Calcium electroporation is a promising novel anticancer treatment in which electroporation induces high calcium influx into treated cells [1]
Our results suggest that calcium electroporation can elicit a rapid and selective necrosis of solid tumors, with limited deleterious effects on surrounding normal tissues
Tumor necrosis in different tumor types To test the effect of calcium electroporation on different tumor types in vivo, we treated three different tumor types; colon, breast, and bladder cancer, with calcium electroporation and estimated fraction of necrosis after treatment
Summary
Calcium electroporation is a promising novel anticancer treatment in which electroporation induces high calcium influx into treated cells [1]. A more than 1,000-fold inward directed calcium gradient may lead to considerable influx of calcium that can reach cytotoxic levels if cells cannot extrude calcium efficiently. This novel treatment has previously been shown to induce cell death in vitro and tumor necrosis in vivo, associated with acute ATP depletion and thereby loss of energy for, among others, calcium pumps [1, 7].
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