Acidic pH of Tumor Microenvironment Enhances Cytotoxicity of the Disulfiram/Cu<sup>2+</sup> Complex to Breast and Colon Cancer Cells

Abstract

<b><i>Background:</i></b> Resistance of cancer cells to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The drug resistance of tumor cells can be significantly modified by specific features of tumor microenvironment, such as oxygen depletion (hypoxia), glucose/energy deprivation and acidosis. <b><i>Methods:</i></b> The effects of acidic tumor-like microenvironment on cytotoxicity of antabuse (disulfiram, DSF)/Cu<sup>2+</sup> complexes to MCF-7 breast carcinoma and HT-29 colon carcinoma cells were studied. <b><i>Results:</i></b> We show that acidic pH significantly potentiates toxicity of DSF/Cu<sup>2+</sup> complex to breast and colon cancer cells. This phenomenon is associated with changes in cell metabolism, altered Akt kinase and NFκB activity and increased reactive oxygen species production. <b><i>Conclusion:</i></b> Specific pH of tumor microenvironment enhances cytotoxicity of DSF/Cu<sup>2+</sup> to breast and colon cancer cells.