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

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 microenviron...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-05, Vol.104 (22), p.9445-9450
Main Authors: Cairns, Rob A, Papandreou, Ioanna, Sutphin, Patrick D, Denko, Nicholas C
Format: Article
Language:English
Subjects:
3-Phosphoinositide-Dependent Protein Kinases
Animals
Antineoplastics
Biological Sciences
Blood
Cell Line, Tumor
Cell lines
Cellular metabolism
Chemotherapy
Cytotoxins
Enzyme Activation
Humans
Hypoxia
Hypoxia - metabolism
Hypoxia - pathology
Hypoxia-Inducible Factor 1 - metabolism
Kinases
Metabolism
Mice
Neoplasms - drug therapy
Neoplasms - metabolism
Neoplasms - pathology
Oxygen
Oxygen - metabolism
Oxygen consumption
Protein Serine-Threonine Kinases - metabolism
Tumor cell line
Tumors
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0611662104