Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione

Abstract

Despite continuous advancement in skin cancer therapy, the disease is still fatal in many patients, demonstrating the need to improve existing therapies, such as electrochemotherapy (ECT). ECT can be applied in the palliative or curative setting and is based on the application of pulsed electric fields (PEF), which by themselves exerts none to low cancer toxicity but become potently toxic when combined with low-dosed chemotherapeutics such as bleomycin and cisplatin. Albeit their favorable side-effect profiles, not all patients respond to standard ECT, and some responders experience tumor recurrence. To identify potential adjuvant or alternative agents to standard electrochemotherapy, we explored the possibility of combining PEF with a physiological compound, glutathione (GSH), to amplify anticancer toxicity. GSH is an endogenous antioxidant and is available as a dietary supplement. Surprisingly, neither GSH nor PEF mono treatment but GSH + PEF combination treatment exerted strong cytotoxic effects and declined metabolic activity in four skin cancer cell lines in vitro. The potential applicability to other tumor cells was verified by corroborating results in two leukemia cell lines. Strikingly, GSH+PEF treatment did not immediately increase intracellular GSH levels, while levels 24 h following treatment were enhanced. Similar tendencies were made for intracellular reactive oxygen species (ROS) levels, while extracellular ROS increased following combination treatment. ROS levels and the degree of cytotoxicity could be partially reversed by pre-incubating cells with the NADPH-oxidase (NOX) inhibitor diphenyleneiodonium (DPI) and the H2O2-degrading enzyme catalase. Collectively, our findings suggest a promising new “endogenous” drug to be combined with PEF for future anticancer research approaches.

Glutathione: Lights and Shadows in Cancer Patients

“…Of the 411 resulting articles screened by full text and abstract, 398 were excluded; 13 articles were assessed for eligibility and 3 were eventually included in the analysis. The three selected articles [ 122 , 127 , 128 ] are analyzed hereafter.…”

“…In the first article by Wolff C.M. et al, “Synergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione” [ 128 ], the authors display their analysis of the potential synergistic in vitro activity between pulsed electric field (PEF) and glutathione against skin cancer cells. Although being a preclinical study that might not imply a strict correspondence with in vivo results, their strategy of comparing different treatments (e.g., GSH alone vs. PEF alone vs. GSH combined with PEF) and of different types of skin cancer cells (A375 and MNT-1 for malignant melanoma cells and A431 and SSC-25 for squamous skin cell carcinoma) increases their work reliability.…”