Hypoxia increases tumor cell sensitivity to glycolytic inhibitors

A strategy for solid tumor therapy (Model C)

Huaping Liu, Niramol Savaraj, Waldemar Priebe, Theodore Lampidis

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

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 ρ0 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 O2 (0, 0.1, 0.5, 1, 5, 10, and 21%). At the lower levels of O2 that we tested, 143B cells were hypersensitive to 2-DG and oxamate when compared with cells grown at a normal level of O2. In contrast, 143B cells under hypoxic or aerobic conditions showed equal sensitivity to a standard chemotherapeutic agent, vinblastine. Furthermore, when treated under reduced O2 amounts, ρ0 cells displayed no hypersensitivity to 2-DG and, in fact, were slightly more resistant than under aerobic conditions. At 0-5% O2 levels, untreated 143B cells displayed reduced growth and elevated lactic acid levels, while ρ0 cell growth remained unaffected except at 0% O2 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.

Original languageEnglish
Pages (from-to)1745-1751
Number of pages7
JournalBiochemical Pharmacology
Volume64
Issue number12
DOIs
StatePublished - Dec 15 2002

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Tumors
Cells
Neoplasms
Deoxyglucose
Therapeutics
Oxidative Phosphorylation
Growth
Tumor Hypoxia
Biochemistry
Vinblastine
Cell growth
Mitochondrial DNA
Lactic Acid
Osteosarcoma
Hypersensitivity

Keywords

  • 2-Deoxy-D-glucose
  • Glycolysis
  • Hypoxia
  • Mitochondria
  • Oxamate

ASJC Scopus subject areas

  • Pharmacology

Cite this

Hypoxia increases tumor cell sensitivity to glycolytic inhibitors : A strategy for solid tumor therapy (Model C). / Liu, Huaping; Savaraj, Niramol; Priebe, Waldemar; Lampidis, Theodore.

In: Biochemical Pharmacology, Vol. 64, No. 12, 15.12.2002, p. 1745-1751.

Research output: Contribution to journalArticle

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abstract = "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 ρ0 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 O2 (0, 0.1, 0.5, 1, 5, 10, and 21{\%}). At the lower levels of O2 that we tested, 143B cells were hypersensitive to 2-DG and oxamate when compared with cells grown at a normal level of O2. In contrast, 143B cells under hypoxic or aerobic conditions showed equal sensitivity to a standard chemotherapeutic agent, vinblastine. Furthermore, when treated under reduced O2 amounts, ρ0 cells displayed no hypersensitivity to 2-DG and, in fact, were slightly more resistant than under aerobic conditions. At 0-5{\%} O2 levels, untreated 143B cells displayed reduced growth and elevated lactic acid levels, while ρ0 cell growth remained unaffected except at 0{\%} O2 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.",
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