Hypersensitization of tumor cells to glycolytic inhibitors

Biochemistry
H LiuTheodore J Lampidis

Abstract

The slow growth of cells in the inner core of solid tumors presents a form of multidrug resistance to most of the standard chemotherapeutic agents, which target the outer more rapidly dividing cells. However, the anaerobic environment of the more centrally located tumor cells also provides an opportunity to exploit their dependence on glycolysis for therapeutic gain. We have developed two in vitro models to investigate this possibility. Model A represents osteosarcoma wild-type (wt) cells treated with agents which inhibit mitochondrial oxidative phosphorylation (Oxphos) by interacting with complexes I, III, and V of the electron transport chain in different ways, i.e., rhodamine 123 (Rho 123), rotenone, antimycin A, and oligomycin. All of these agents were found to hypersensitize wt cells to the glycolytic inhibitor 2-deoxyglucose. Cells treated with Rho 123 also become hypersensitive to oxamate, an analogue of pyruvate, which blocks the step of glycolysis that converts pyruvate to lactic acid. Model B is rho(0) cells which have lost their mitochondrial DNA and therefore cannot undergo Oxphos. These cells are 10 and 4.9 times more sensitive to 2-deoxyglucose and oxamate, respectively, than wt cells. Lactic acid levels, which ar...Continue Reading

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