The radiation- and chemo-sensitizing capacity of diclofenac can be predicted by a decreased lactate metabolism and stress response

Abstract

Abstract Background An enhanced aerobic glycolysis (Warburg effect) associated with an increase in lactic acid in the tumor microenvironment contributes to tumor aggressiveness and resistance to radiation and chemotherapy. We investigated the radiation- and chemo-sensitizing effects of the nonsteroidal anti-inflammatory drug (NSAID) diclofenac in different cancer cell types. Methods The effects of a non-lethal concentration of diclofenac was investigated on the MYC expression, lactate dehydrogenase (LDH) activity and heat shock protein response in human colorectal (LS174T, LoVo), lung (A549), breast (MDA-MB-231) and adeno pancreatic (COLO357) carcinoma cells. Radiation- and chemo-sensitization of diclofenac was determined in clonogenic cell survival assays and in a xenograft tumor mouse model. Results We demonstrated that a non-lethal concentration of diclofenac affects the LDH activity, decreases MYC expression, reduces cytosolic Heat shock factor 1 (HSF1), Hsp70 and Hsp27 levels and membrane Hsp70 positivity in colorectal LS174T and LoVo cancer cells but not in lung A549 carcinoma cells, MDA-MB-231 breast cancer cells and COLO357 pancreatic adenocarcinoma cells. The impaired lactate metabolism and stress response in diclofenac-sensitive colorectal cancer cell lines was associated with a significant increase in the sensitivity towards radiation and 5fluorouracil (5-FU), in vitro, and in a xenograft colon carcinoma mouse model diclofenac induces radio-sensitization, in vivo. Conclusion Our results suggest that a decrease in the LDH activity and/or stress response upon diclofenac treatment predicts its radiation/chemo-sensitizing capacity.