Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy (Model C)

Previously, we reported that two distinct in vitro tumor cell models of hypoxia (Models A and B) are hypersensitive to glycolytic inhibitors such as 2-deoxy-D-glucose (2-DG) and oxamate [Liu et al., Biochemistry 2001;40:5542-7]. Model A consists of osteosarcoma cells (143B) treated with agents that interfere with mitochondrial oxidative phosphorylation (OxPhos), and Model B represents rho(0) cells, a variant derived from 143B cells, which, due to their deficiency in mitochondrial DNA, cannot perform OxPhos. Extending these studies, we report here on Model C, which is composed of 143B cells grown under various levels of external O-2 (0, 0.1, 0.5, 1, 5, 10, and 21%). At the lower levels Of 02 that we tested, 143B cells were hypersensitive to 2-DG and oxamate when compared with cells grown at a normal level Of O-2. In contrast, 143B cells under hypoxic or aerobic conditions showed equal sensitivity to a standard chemotherapeutic agent, vinblastine. Furthermore, when treated under reduced O-2 amounts, rho(0) cells displayed no hypersensitivity to 2-DG and, in fact, were slightly more resistant than under aerobic conditions. At 0-5% O-2 levels, untreated 143B cells displayed reduced growth and elevated lactic acid levels, while rho(0) cell growth remained unaffected except at 0% O-2 Where growth was inhibited by 19%. The results with Model C are in agreement with our previous data using Models A and B, and extend these studies by illustrating that within a wide range of hypoxia the growth of tumor cells is retarded and that these slow-growing cells become hypersensitized to glycolytic inhibitors. Taken together with Models A and B, the data with Model C support our hypothesis that the hypoxic environment of slow-growing cells found in the inner core of solid tumors renders them amenable to selective targeting with glycolytic inhibitors. (C) 2002 Elsevier Science Inc. All rights reserved.