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

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.

The anti-tumor effect of citrate, an inhibitor of phosphofructokinase, was tested on particularly chemoresistant MSTO-211H human mesothelioma cells.

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.

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.