From delocalized lipophilic cations to hypoxia: Blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors

Metin Kurtoglu, Theodore Lampidis

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

An unexpected similarity between cancer and cardiac muscle cells in their sensitivity to anthracy-clines and delocalized lipophilic cations (DLC) prompted a series of studies in which it was shown that the positive charge of these compounds is central to their selective accumulation and toxicity in these two distinct cell types. An initial finding to explain this phenomenon was that cancer and cardiac muscle cells exhibit high negative plasma membrane potentials resulting in increased uptake of these agents. However, the p-glycoprotein efflux pump was shown to be another factor underlying differential accumulation of these compounds, since it recognizes positively charged drugs and thereby actively reduces their intracellular concentrations. The delocalized positive charge and lipophilicity of DLCs leads to their retention and inhibition of ATP synthesis in mitochondria. Years later it was realized that cancer cells in the hypoxic portions of solid tumors were similar to those treated with DLCs in relying mainly on anaerobic metabolism for survival and could thus be targeted with a glycolytic inhibitor, 2-deoxy-D-glucose (2-DG). This hypothesis has lead to a Phase I clinical trial in which 2-DG is used to selectively kill the hypoxic tumor cell population which are resistant to standard chemotherapy or radiation.

Original languageEnglish
Pages (from-to)68-75
Number of pages8
JournalMolecular Nutrition and Food Research
Volume53
Issue number1
DOIs
StatePublished - Jan 1 2009

Fingerprint

Muscle Neoplasms
Cations
hypoxia
cations
Deoxyglucose
Cardiac Myocytes
therapeutics
neoplasms
Anaerobiosis
Neoplasms
Clinical Trials, Phase I
glucose
anaerobiosis
hydrophobicity
membrane potential
Membrane Potentials
drug therapy
transporters
glycoproteins
clinical trials

Keywords

  • Anthracycline
  • Cancer
  • Delocalized lipohilic cation
  • Hypoxia
  • Mitochondria

ASJC Scopus subject areas

  • Food Science
  • Biotechnology

Cite this

@article{36f3af42fbd84428b721c446f6568cde,
title = "From delocalized lipophilic cations to hypoxia: Blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors",
abstract = "An unexpected similarity between cancer and cardiac muscle cells in their sensitivity to anthracy-clines and delocalized lipophilic cations (DLC) prompted a series of studies in which it was shown that the positive charge of these compounds is central to their selective accumulation and toxicity in these two distinct cell types. An initial finding to explain this phenomenon was that cancer and cardiac muscle cells exhibit high negative plasma membrane potentials resulting in increased uptake of these agents. However, the p-glycoprotein efflux pump was shown to be another factor underlying differential accumulation of these compounds, since it recognizes positively charged drugs and thereby actively reduces their intracellular concentrations. The delocalized positive charge and lipophilicity of DLCs leads to their retention and inhibition of ATP synthesis in mitochondria. Years later it was realized that cancer cells in the hypoxic portions of solid tumors were similar to those treated with DLCs in relying mainly on anaerobic metabolism for survival and could thus be targeted with a glycolytic inhibitor, 2-deoxy-D-glucose (2-DG). This hypothesis has lead to a Phase I clinical trial in which 2-DG is used to selectively kill the hypoxic tumor cell population which are resistant to standard chemotherapy or radiation.",
keywords = "Anthracycline, Cancer, Delocalized lipohilic cation, Hypoxia, Mitochondria",
author = "Metin Kurtoglu and Theodore Lampidis",
year = "2009",
month = "1",
day = "1",
doi = "10.1002/mnfr.200700457",
language = "English",
volume = "53",
pages = "68--75",
journal = "Molecular Nutrition and Food Research",
issn = "1613-4125",
publisher = "Wiley-VCH Verlag",
number = "1",

}

TY - JOUR

T1 - From delocalized lipophilic cations to hypoxia

T2 - Blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors

AU - Kurtoglu, Metin

AU - Lampidis, Theodore

PY - 2009/1/1

Y1 - 2009/1/1

N2 - An unexpected similarity between cancer and cardiac muscle cells in their sensitivity to anthracy-clines and delocalized lipophilic cations (DLC) prompted a series of studies in which it was shown that the positive charge of these compounds is central to their selective accumulation and toxicity in these two distinct cell types. An initial finding to explain this phenomenon was that cancer and cardiac muscle cells exhibit high negative plasma membrane potentials resulting in increased uptake of these agents. However, the p-glycoprotein efflux pump was shown to be another factor underlying differential accumulation of these compounds, since it recognizes positively charged drugs and thereby actively reduces their intracellular concentrations. The delocalized positive charge and lipophilicity of DLCs leads to their retention and inhibition of ATP synthesis in mitochondria. Years later it was realized that cancer cells in the hypoxic portions of solid tumors were similar to those treated with DLCs in relying mainly on anaerobic metabolism for survival and could thus be targeted with a glycolytic inhibitor, 2-deoxy-D-glucose (2-DG). This hypothesis has lead to a Phase I clinical trial in which 2-DG is used to selectively kill the hypoxic tumor cell population which are resistant to standard chemotherapy or radiation.

AB - An unexpected similarity between cancer and cardiac muscle cells in their sensitivity to anthracy-clines and delocalized lipophilic cations (DLC) prompted a series of studies in which it was shown that the positive charge of these compounds is central to their selective accumulation and toxicity in these two distinct cell types. An initial finding to explain this phenomenon was that cancer and cardiac muscle cells exhibit high negative plasma membrane potentials resulting in increased uptake of these agents. However, the p-glycoprotein efflux pump was shown to be another factor underlying differential accumulation of these compounds, since it recognizes positively charged drugs and thereby actively reduces their intracellular concentrations. The delocalized positive charge and lipophilicity of DLCs leads to their retention and inhibition of ATP synthesis in mitochondria. Years later it was realized that cancer cells in the hypoxic portions of solid tumors were similar to those treated with DLCs in relying mainly on anaerobic metabolism for survival and could thus be targeted with a glycolytic inhibitor, 2-deoxy-D-glucose (2-DG). This hypothesis has lead to a Phase I clinical trial in which 2-DG is used to selectively kill the hypoxic tumor cell population which are resistant to standard chemotherapy or radiation.

KW - Anthracycline

KW - Cancer

KW - Delocalized lipohilic cation

KW - Hypoxia

KW - Mitochondria

UR - http://www.scopus.com/inward/record.url?scp=58149343972&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149343972&partnerID=8YFLogxK

U2 - 10.1002/mnfr.200700457

DO - 10.1002/mnfr.200700457

M3 - Article

C2 - 19072739

AN - SCOPUS:58149343972

VL - 53

SP - 68

EP - 75

JO - Molecular Nutrition and Food Research

JF - Molecular Nutrition and Food Research

SN - 1613-4125

IS - 1

ER -