Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy

Rob A. Cairns, Ioanna Papandreou, Patrick D. Sutphin, Nicholas C. Denko

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

Solid tumors frequently contain large regions with low oxygen concentrations (hypoxia). The hypoxic microenvironment induces adaptive changes to tumor cell metabolism, and this alteration can further distort the local microenvironment. The net result of these tumor-specific changes is a microenvironment that inhibits many standard cytotoxic anticancer therapies and predicts for a poor clinical outcome. Pharmacologic targeting of the unique metabolism of solid tumors could alter the tumor microenvironment to provide more favorable conditions for anti-tumor therapy. Here, we describe a strategy in which the mitochondrial metabolism of tumor cells is increased by pharmacologic inhibition of hypoxia-inducible factor 1 (HIF1) or its target gene pyruvate dehydrogenase kinase 1 (PDK1). This acute increase in oxygen consumption leads to a corresponding decrease in tumor oxygenation. Whereas decreased oxygenation could reduce the effectiveness of some traditional therapies, we show that it dramatically increases the effectiveness of a hypoxia-specific cytotoxin. This treatment strategy should provide a high degree of tumor specificity for increasing the effectiveness of hypoxic cytotoxins, as it depends on the activation of HIF1 and the presence of hypoxia, conditions that are present only in the tumor, and not the normal tissue.

Original languageEnglish (US)
Pages (from-to)9445-9450
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number22
DOIs
StatePublished - May 29 2007

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Keywords

  • HIF inhibitors
  • Hypoxia-inducible factor
  • Pyruvate dehydrogenase kinase
  • Tumor metabolism

ASJC Scopus subject areas

  • General

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