Effect of citrate on malignant pleural mesothelioma cells: a synergistic effect with cisplatin.

Abstract

BACKGROUND: Because cancer cells are partly or mainly dependent on glycolysis to generate ATP (Warburg effect), any inhibition of glycolysis may slow down their proliferation or kill them. MATERIALS AND METHODS: The anti-tumor effect of citrate, an inhibitor of phosphofructokinase, was tested on particularly chemoresistant MSTO-211H human mesothelioma cells. RESULTS: A 3-day continuous exposure to citrate led to apoptotic cell death via a mitochondrial pathway, associated with a reduction of anti-apoptotic protein Bcl-x(L) and Mcl-1 expression. However, when citrate was removed, the remaining cells resumed their proliferation. The treatment of cells with a non-cytotoxic dose of cisplatin at the end of the citrate exposure led to a strong cytotoxicity, almost all cells being killed. CONCLUSION: Depletion of ATP, diminution of the expression of the anti-apoptotic proteins and inhibition of hexokinase secondary to inhibition of phosphofructokinase by citrate may explain the cytotoxic activity of this molecule and its synergistic effect with cisplatin.