Chloroacetaldehyde (CAA), a product of hepatic metabolism of the widely used anticancer
drug ifosfamide (IFO), has been reported to decrease
cancer cell proliferation. The basis of this effect is not completely known but has been attributed to a drop of cellular
ATP content. Given the importance of
glucose metabolism and of the 'Warburg effect' in
cancer cells, we examined in the present study the ability of CAA to inhibit
cancer cell proliferation by altering the glycolytic pathway. Cell proliferation,
ATP content,
glucose transport and metabolism as well as the activities of the main
enzymes of glycolysis were determined in human
breast cancer cells MCF-7 in the presence of various CAA concentrations (5-50 microm). Our results show that low CAA concentrations inhibited cell proliferation in a concentration-dependent manner. This inhibition was explained by a decrease in
glucose utilization. Cellular
ATP content was not reduced but even increased with 25 microm CAA. The inhibition of
glucose metabolism was mainly explained by the decrease in
glucose transport and
hexokinase activity. The activity of
glyceraldehyde-3-phosphate dehydrogenase, but not that of
phosphofructokinase, was also inhibited. Glycolysis inhibition by CAA was effective in decreasing the proliferation of MCF-7 cells. Interestingly, this decrease was not due to
ATP depletion; rather, it was linked to a drop of biosynthetic precursors from glycolytic intermediates. This CAA-induced inhibition of cell proliferation suggests that it might play a role in the antitumor activity of IFO.