title: Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy.
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.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Cairns
authors.forename: Ioanna
authors.initials: I
authors.lastname: Papandreou
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Sutphin
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Denko
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051793:Hypoxia-Inducible Factor 1; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D010100:Oxygen