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Ifosfamide metabolite chloroacetaldehyde inhibits cell proliferation and glucose metabolism without decreasing cellular ATP content in human breast cancer cells MCF‐7
Author(s) -
Knouzy Burhan,
Dubourg Laurence,
Baverel Gabriel,
Michoudet Christian
Publication year - 2010
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1485
Subject(s) - glycolysis , hexokinase , cell growth , metabolism , phosphofructokinase , cancer cell , mcf 7 , biochemistry , carbohydrate metabolism , anaerobic glycolysis , chemistry , biology , cancer , human breast , genetics
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 μ m ). 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 μ m 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. Copyright © 2009 John Wiley & Sons, Ltd.