Ovarian carcinoma cells with low levels of β-F1-ATPase are sensitive to combined platinum and 2-deoxy-d-glucose treatment

We have here examined chemopotentiating effects of glycolysis inhibitor 2-deoxy-d-glucose (DG) in two epithelial ovarian carcinoma (EOC) cell lines and 17 freshly isolated ascitic EOC cell samples, and we identify low expression of the β-F1-ATPase involved in mitochondrial ATP production as a candidate marker for sensitivity to this strategy. Although in the majority of samples, DG per se did not induce apoptosis, cotreatment with DG potentiated apoptosis and total antiproliferative effects of cisplatin and, to a lesser degree, carboplatin. In the cell lines, combination treatment with DG and cisplatin or carboplatin at noninhibitory concentrations prevented posttreatment regrowth in drug-free medium over a total of 5 days. DG per se allowed complete recuperation in drug-free medium. The more platinum-resistant a cell line was, the more sensitive it was to potentiation by DG and showed higher glucose uptake, DG-sensitive lactate production, and lower β-F1-ATPase levels. In the ascitic samples, DG reduced the median IC50 for cisplatin by 68% and, in the most sensitive samples, up to 90%, and DG-mediated potentiation correlated with low expression of β-F1-ATPase. By contrast, cisplatin sensitivity did not correlate with β-F1-ATPase levels. The findings validate targeting cancer cell glucose metabolism for potentiating platinum chemotherapy in EOC and indicate that reduced β-F1-ATPase/oxidative phosphorylation distinguishes cells that are amenable to this strategy. [Mol Cancer Ther 2009;8(7):1916–23]