Understanding and exploiting the mechanistic basis for selectivity of polyketide inhibitors of F0F1-ATPase

Recently, a family of polyketide inhibitors of F0F1-ATPase, including apopt olidin, ossamycin, and oligomycin. were shown to be among the top 0.1% most cell line selective cytotoxic agents of 37,000 molecules tested against th e 60 human cancer cell lines of the National Cancer Institute. Many cancer cells maintain a high level of anaerobic carbon metabolism even in the pres ence of oxygen, a phenomenon that is historically known as the Warburg effe ct. A mechanism-based strategy to sensitize such cells to this class of pot ent smart molecule cytotoxic agents is presented. These natural products in hibit oxidative phosphorylation by targeting the mitochondrial F0F1: ATP sy nthase. Evaluation of gene expression profiles in a panel of leukemias reve aled a strong correlation between the expression level of the gene encoding subunit 6 of the mitochondrial F0F1 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 s trong drug-gene correlations were also observed for the genes encoding two key enzymes involved in central carbon metabolism. pyruvate kinase, and asp artate aminotransferase. We propose a simple model in which the mitochondri al apoptotic pathway is activated in response to a shift in balance between aerobic and anaerobic ATP biosynthesis. Inhibitors of both lactate formati on and carbon flux through the Embden-Meyerhof pathway significantly sensit ized apoptolidin-resistant tumors to this drug. Nine different cell lines d erived from human leukemias and melanomas, and colon, renal. central nervou s system, and ovarian tumors are also sensitized to killing by apoptolidin.