Targeting tumor metabolism: biguanides as anti-neoplastic agents

Abstract

e14592 Background: During the process of malignant transformation, the tumor cell adopts a new form of metabolism, characterized by aerobic glycolysis and altered TCA cycle flux, that enable it to meet the energetic and biosynthetic demands of proliferation. This shift to anabolic metabolism results from oncogene-driven activation of signaling pathways, and therefore represents a potential therapeutic target that lies downstream of these genetic events. Methods: We have characterized the proliferative and metabolic effects of phenformin, a member of the biguanide family of compounds used in the treatment of diabetes, on the bcr-abl expressing K562 erythroleukemia cell line, and compared the resulting phenotype to those of imatinib and rapamycin, two targeted agents used in the treatment of malignant disease. Results: Phenformin induced the most profound growth inhibition of K562 cells, in a manner distinct from the targeted agents. Phenformin treatment eliminated the mitochondrial contribution to anabolic metabolism, through inhibition of Complex I of the Electron Transport Chain, as demonstrated by reduced oxygen consumption and intracellular ATP levels. Glutamine metabolism was also inhibited, consistent with TCA cycle inhibition as a secondary effect. The phenformin-induced mitochondrial dysfunction made K562 cells dependent upon glycolysis for survival. In contrast, the growth arrest resulting from imatinib treatment was associated with a complete reversion from the anabolic phenotype, as demonstrated by dramatically decreased glucose and glutamine consumption. Rapamycin, a poor inhibitor of K562 proliferation, decreased glycolysis but left mitochondrial function intact. Conclusions: Our results confirm the importance of metabolism to the proliferation of malignant cells, thereby validating anabolic metabolism's potential for therapeutic intervention. The direct inhibition of tumor cell metabolism by phenformin warrants further clinical study as a promising new approach to cancer therapy. No significant financial relationships to disclose.