Hypersensitization of tumor cells to glycolytic inhibitors

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, wh ich target the outer more rapidly dividing cells. However, the anaerobic en vironment of the more centrally located tumor cells also provides an opport unity to exploit their dependence on glycolysis for therapeutic gain. We ha ve developed two in vitro models to investigate this possibility. Model A r epresents osteosarcoma wild-type (wt) cells treated with agents which inhib it mitochondrial oxidative phosphorylation (Oxphos) by interacting with com plexes 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 t hese agents were found to hypersensitize wt cells to the glycolytic inhibit or 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 a re 10 and 4.9 times more sensitive to 2-deoxyglucose and oxamate, respectiv ely, than wt cells. Lactic acid levels, which are a measure of anaerobic me tabolism, were found to be >3 times higher in rho (0) than in wt cells. Mor eover, when wt cells were treated with Rho 123, lactic acid amounts increas ed as a function of increasing Rho 123 doses. Under similar Rho 123 treatme nt, rho (0) cells did not increase their lactic acid levels. These data con firm that cell models A and B are similarly sensitive to glycolytic inhibit ors due to their dependence on anaerobic metabolism. Overall, our in vitro results suggest that glycolytic inhibitors could be used to specifically ta rget the slow-growing cells of a tumor and thereby increase the efficacy of current chemotherapeutic and irradiation protocols designed to kill rapidl y dividing cells. Moreover, glycolytic inhibitors could be particularly use ful in combination with anti-angiogenic agents, which, a priori, should mak e tumors more anaerobic.