Calcium Electroporation: An Overview of an Innovative Cancer Treatment Approach

Electroporation (EP) involves the application of short (ms to μs), high voltage electric pulses to increase the permeability of biological membranes to external ions or molecules. In the clinical practice, reversible EP is used to increase the uptake of chemotherapeutic drugs in local, nonthermal tumor treatment (electrochemotherapy, ECT), by applying a standard pulsing protocol consisting of 8 rectangular pulses, 1000 V/cm electric field amplitude, 100 μs duration, 1 Hz or 5 kHz pulse repetition rate. In the standard protocol, electric pulses are used in combination with a non- permeant (bleomycin) or a low- permeant (cisplatin) anticancer drug with a very high intrinsic cytotoxicity, and are applied just after, or few minutes after, local or systemic injection of the drug. In the last decades, ECT has been increasingly used for the treatment of cutaneous and subcutaneous metastatic tumor nodules or deep-seated tumors of various histologies at different body sites, and is currently adopted in over 150 clinical centers in Europe. Recently, the use of calcium has been introduced in combination with electric pulses, as a new, EP-based cancer treatment modality (CaEP). In vitro studies have demonstrated that: 1) the introduction of supraphysiological doses of calcium into cells causes necrotic cell death associated with an acute and severe energy depletion.; 2) CaEP kills tumor cells with an efficiency similar to that of ECT with the chemotherapeutic agent bleomycin; 3) cancer cells are more sensitive to CaEP than normal cells; 4) efficacy of CaEP can be increased by optimization of pulsing conditions. The results of in vivo studies and of the first clinical trials further suggest that CaEP: 1) is very efficient at the local level on different tumor types (head and neck cancer, cutaneous metastases from breast cancer and malignant melanoma); 2) is also able to trigger a systemic immune response to target untreated metastases. Due to low intrinsic cytotoxicity of calcium, its easy preparation, handling, and storage procedures, and to the availability of electroporation equipment already used in the clinical practice, CaEP represents an effective, innovative cancer treatment technique, which can be implemented without chemotherapy, and with simplified procedure and reduced costs. An overview of CaEP will be presented in this contribution, spanning from the state of the art of basic research, to the results of recent clinical trials, and to future perspectives.