Repurposing diclofenac for combination therapy: targeting the Warburg effect to enhance breast cancer treatment.

BACKGROUND/AIM: Diclofenac (Diclo), a widely used nonsteroidal antiinflammatory drug, has emerged as a potential candidate for drug repurposing in oncology, with reported anticancer effects extending beyond cyclooxygenase (COX) inhibition, including modulation of tumor metabolism. This study investigated the antiproliferative and glycolysis-associated effects of Diclo in MCF-7 breast cancer cells, alone and in combination with docetaxel (Doc) or 5-fluorouracil (5-FU).

MATERIALS AND

METHODS

Cell viability was assessed using the sulforhodamine B (SRB) assay. To evaluate metabolic alterations, glucose uptake and lactate release were quantified following treatment. In addition, Triosephosphate Isomerase (TPI) protein levels and Lactate Dehydrogenase (LDH) activity were measured to explore potential modulation of glycolytic pathways.

RESULTS

Diclo reduced MCF-7 viability in a dose-dependent manner (IC50: 78.37 μg/mL). Combining Diclo with Doc or 5-FU enhanced cytotoxicity compared with single agents. Although Diclo alone did not significantly change glucose uptake, Diclo+Doc and Diclo+5-FU significantly decreased glucose uptake, and lactate release was reduced, particularly in Diclo-containing treatments. Diclo decreased TPI levels, and Diclo-based combinations further reduced TPI. LDH activity decreased with Diclo, while certain combinations produced divergent LDH responses, suggesting treatment-dependent effects on lactate metabolism and/or cellular stress.

CONCLUSION

Diclo potentiated the cytotoxic effects of Doc and 5-FU and was associated with reduced glycolytic readouts and decreased TPI in MCF-7 cells, supporting a potential role for Diclo as a metabolic modulator in breast cancer combination therapy.