Hypersensitization of Tumor Cells to Glycolytic Inhibitors
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- 作者：H. Liu ; Y. P. Hu ; N. Savaraj ; W. Priebe ; and T. J. Lampidis
- 刊名：Biochemistry
- 出版年：2001
- 出版时间：May 8, 2001
- 年：2001
- 卷：40
- 期：18
- 页码：5542 - 5547
- 全文大小：135K
- 年卷期：v.40,no.18(May 8, 2001)
- ISSN：1520-4995
文摘
The slow growth of cells in the inner core of solid tumors presents a form of multidrug resistanceto 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 opportunityto exploit their dependence on glycolysis for therapeutic gain. We have developed two in vitro models toinvestigate this possibility. Model A represents osteosarcoma wild-type (wt) cells treated with agentswhich inhibit mitochondrial oxidative phosphorylation (Oxphos) by interacting with complexes I, III, andV of the electron transport chain in different ways, i.e., rhodamine 123 (Rho 123), rotenone, antimycinA, and oligomycin. All of these agents were found to hypersensitize wt cells to the glycolytic inhibitor2-deoxyglucose. Cells treated with Rho 123 also become hypersensitive to oxamate, an analogue ofpyruvate, which blocks the step of glycolysis that converts pyruvate to lactic acid. Model B is 
0 cellswhich have lost their mitochondrial DNA and therefore cannot undergo Oxphos. These cells are 10 and4.9 times more sensitive to 2-deoxyglucose and oxamate, respectively, than wt cells. Lactic acid levels,which are a measure of anaerobic metabolism, were found to be >3 times higher in 0 than in wt cells.Moreover, when wt cells were treated with Rho 123, lactic acid amounts increased as a function ofincreasing Rho 123 doses. Under similar Rho 123 treatment, 0 cells did not increase their lactic acidlevels. These data confirm that cell models A and B are similarly sensitive to glycolytic inhibitors due totheir dependence on anaerobic metabolism. Overall, our in vitro results suggest that glycolytic inhibitorscould be used to specifically target the slow-growing cells of a tumor and thereby increase the efficacyof current chemotherapeutic and irradiation protocols designed to kill rapidly dividing cells. Moreover,glycolytic inhibitors could be particularly useful in combination with anti-angiogenic agents, which, apriori, should make tumors more anaerobic.
0 cellswhich have lost their mitochondrial DNA and therefore cannot undergo Oxphos. These cells are 10 and4.9 times more sensitive to 2-deoxyglucose and oxamate, respectively, than wt cells. Lactic acid levels,which are a measure of anaerobic metabolism, were found to be >3 times higher in 0 than in wt cells.Moreover, when wt cells were treated with Rho 123, lactic acid amounts increased as a function ofincreasing Rho 123 doses. Under similar Rho 123 treatment, 0 cells did not increase their lactic acidlevels. These data confirm that cell models A and B are similarly sensitive to glycolytic inhibitors due totheir dependence on anaerobic metabolism. Overall, our in vitro results suggest that glycolytic inhibitorscould be used to specifically target the slow-growing cells of a tumor and thereby increase the efficacyof current chemotherapeutic and irradiation protocols designed to kill rapidly dividing cells. Moreover,glycolytic inhibitors could be particularly useful in combination with anti-angiogenic agents, which, apriori, should make tumors more anaerobic.