Specific conditions of tumor microenvironment enhance cytotoxicity of disulfiram, tetrathiomolybdate and wedelolactone to breast cancer and neuroblastoma cells

Microenvironment of solid tumors exhibit several features that are not found in corresponding normal tissues. Ability of the malformed tumor vasculature to deliver nutrients and remove waste products is badly compromised resulting in hypoxia and acidosis. These specific features of the tumor microenvironment can reduce the effectiveness of numerous chemotherapeutics. Hypoxia, acidosis and supply of nutritients can be manipulated in vitro and in vivo to provide more favorable conditions for effective chemotherapy. Our study was designed to analyze the effect of hypoxia, acidosis and limited glucose supply to cytotoxicity of disulfiram, tetrathiomolybdate and wedelolactone to breast cancer and neuroblastoma cells. We found that cytotoxicity of these drugs can be strongly enhanced by manipulating tissue culture conditions that simulate the character of tumor microenvironment. We believe that information about cytotoxicity of newly developed/tested chemotherapeutics in conditions of specific tumor microenvironment can be helpful for improvement of treatment strategies and provide further benefit for cancer patients.

This work was funded by the NT 13441–4/2012 grant of the Internal Grant Agency of Ministry of Health of the Czech Republic, and by the European Regional Development Fund and the State Budget of the Czech Republic (RE CAMO, CZ.1.05/2.1.00/03.0101) via the human resources project „IntegRE CAMO: Intelectual Anchor“ (CZ.1.07/2.3.00/20.0097).