Recently, a family of
polyketide inhibitors of F(0)F(1)-ATPase, including
apoptolidin,
ossamycin, and
oligomycin, were shown to be among the top 0.1% most cell line selective
cytotoxic agents of 37, 000 molecules tested against the 60 human
cancer cell lines of the National Cancer Institute. Many
cancer cells maintain a high level of anaerobic
carbon metabolism even in the presence of
oxygen, a phenomenon that is historically known as the Warburg effect. A mechanism-based strategy to sensitize such cells to this class of potent small molecule
cytotoxic agents is presented. These natural products inhibit oxidative phosphorylation by targeting the mitochondrial F(0)F(1)
ATP synthase. Evaluation of gene expression profiles in a panel of
leukemias revealed a strong correlation between the expression level of the gene encoding subunit 6 of the mitochondrial F(0)F(1)
ATP synthase (known to be the binding site of members of this class of
macrolides) and their sensitivity to these natural products. Within the same set of
leukemia cell lines, comparably strong
drug-gene correlations were also observed for the genes encoding two key
enzymes involved in central
carbon metabolism,
pyruvate kinase, and
aspartate aminotransferase. We propose a simple model in which the mitochondrial apoptotic pathway is activated in response to a shift in balance between aerobic and anaerobic
ATP biosynthesis. Inhibitors of both
lactate formation and carbon flux through the Embden-Meyerhof pathway significantly sensitized
apoptolidin-resistant
tumors to this
drug. Nine different cell lines derived from human
leukemias and
melanomas, and colon, renal, central nervous system, and ovarian
tumors are also sensitized to killing by
apoptolidin.