Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy.
Radiotherapy, an important treatment modality in oncology, kills cells through induction of oxidative stress. However, malignant tumors vary in their response to irradiation as a consequence of resistance mechanisms taking place at the molecular level. It is important to understand these mechanisms of radioresistance, as counteracting them may improve the efficacy of radiotherapy. In this review, we describe how the hypoxia-inducible factor 1 (HIF-1) pathway has a profound effect on the response to radiotherapy. The main focus will be on HIF-1-controlled protection of the vasculature postirradiation and on HIF-1 regulation of glycolysis and the pentose phosphate pathway. This aberrant cellular metabolism increases the antioxidant capacity of tumors, thereby countering the oxidative stress caused by irradiation. From the results of translational studies and the first clinical phase I/II trials, it can be concluded that targeting HIF-1 and tumor glucose metabolism at several levels reduces the antioxidant capacity of tumors, affects the tumor microenvironment, and sensitizes various solid tumors to irradiation.
Department of Radiation Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Tineke W H
TW
Meijer
Johannes H A M
JH
Kaanders
Paul N
PN
Span
Johan
J
Bussink
D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D059016:Tumor Microenvironment
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D005947:Glucose