Effect of citrate on malignant pleural mesothelioma cells: a synergistic effect with cisplatin
Zhang, X.; Varin, E.; Allouche, S.ép.; Lu, Y.; Poulain, L.; Icard, P.
Anticancer Research 29(4): 1249-1254
2009
ISSN/ISBN: 0250-7005 PMID: 19414371 Document Number: 633774
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.