Document Detail

Hypersensitization of tumor cells to glycolytic inhibitors.
MedLine Citation:
PMID:  11331019     Owner:  NLM     Status:  MEDLINE    
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 are a measure of anaerobic metabolism, were found to be > 3 times higher in rho(0) than in wt cells. Moreover, when wt cells were treated with Rho 123, lactic acid amounts increased as a function of increasing Rho 123 doses. Under similar Rho 123 treatment, rho(0) cells did not increase their lactic acid levels. These data confirm that cell models A and B are similarly sensitive to glycolytic inhibitors due to their dependence on anaerobic metabolism. Overall, our in vitro results suggest that glycolytic inhibitors could be used to specifically target the slow-growing cells of a tumor and thereby increase the efficacy of 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, a priori, should make tumors more anaerobic.
H Liu; Y P Hu; N Savaraj; W Priebe; T J Lampidis
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Biochemistry     Volume:  40     ISSN:  0006-2960     ISO Abbreviation:  Biochemistry     Publication Date:  2001 May 
Date Detail:
Created Date:  2001-05-01     Completed Date:  2001-07-26     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0370623     Medline TA:  Biochemistry     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5542-7     Citation Subset:  IM    
Department of Cell Biology and Anatomy, University of Miami School of Medicine, and Sylvestor Comprehensive Cancer Center, Miami, Florida 33136, USA.
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MeSH Terms
Antimycin A / pharmacology
Culture Media / metabolism
Deoxyglucose / metabolism,  pharmacology
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm*
Enzyme Inhibitors / pharmacology
Glucose / metabolism,  pharmacology
Glycolysis / drug effects
Growth Inhibitors / metabolism,  pharmacology
Lactic Acid / metabolism
Oligomycins / pharmacology
Osteosarcoma / metabolism,  pathology
Oxamic Acid / metabolism,  pharmacology
Oxidative Phosphorylation / drug effects
Rhodamine 123 / pharmacology
Rotenone / pharmacology
Tumor Cells, Cultured / drug effects*,  metabolism*
Uncoupling Agents / pharmacology
Grant Support
Reg. No./Substance:
0/Culture Media; 0/Enzyme Inhibitors; 0/Growth Inhibitors; 0/Oligomycins; 0/Uncoupling Agents; 154-17-6/Deoxyglucose; 471-47-6/Oxamic Acid; 50-21-5/Lactic Acid; 50-99-7/Glucose; 62669-70-9/Rhodamine 123; 642-15-9/Antimycin A; 83-79-4/Rotenone

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