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Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors.
BMC Cancer 2017; 17(1):418BC

Abstract

BACKGROUND

A high rate of glycolysis leading to elevated lactate content has been linked to poor clinical outcomes in patients with head and neck and cervical cancer treated with radiotherapy. Although the biological explanation for this relationship between lactate and treatment response remains unclear, there is a continued interest in evaluating strategies of targeting metabolism to enhance the effectiveness of radiotherapy. The goal of this study was to investigate the effect of metabolic-targeting through HIF-1α inhibition and the associated changes in glycolysis, oxygen consumption and response on the efficacy of high-dose single-fraction radiotherapy (HD-SFRT).

METHODS

HIF-1α wild-type and HIF-1α knockdown FaDu and ME180 xenograft tumors were grown in the hind leg of mice that were placed in an environmental chamber and exposed to different oxygen conditions (air-breathing and hypoxia). Ex vivo bioluminescence microscopy was used to measure lactate and ATP levels and the hypoxic fraction was measured using EF5 immunohistochemical staining. The oxygen consumption rate (OCR) in each cell line in response to in vitro hypoxia was measured using an extracellular flux analyzer. Tumor growth delay in vivo was measured following HD-SFRT irradiation of 20 Gy.

RESULTS

Targeting HIF-1α reduced lactate content, and increased both oxygen consumption and hypoxic fraction in these tumors after exposure to short-term continuous hypoxia. Tumors with intact HIF-1α subjected to HD-SFRT immediately following hypoxia exposure were less responsive to treatment than tumors without functional HIF-1α, and tumors irradiated under air breathing conditions regardless of HIF-1α status.

CONCLUSIONS

Blocking the HIF1 response during transient hypoxic stress increased hypoxia, reduced lactate levels and enhanced response to HD-SFRT. This strategy of combining hypofractionated radiotherapy with metabolic reprogramming to inhibit anaerobic metabolism may increase the efficacy of HD-SFRT through increased oxygen consumption and complementary killing of radiosensitive and hypoxic, radioresistant cells.

Authors+Show Affiliations

Department of Radiation Oncology, Sunnybrook Health Sciences Centre and Odette Cancer Centre, Toronto, Canada. Department of Radiation Oncology, University of Toronto, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Radiation Oncology, University of Toronto, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada.Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Department of Radiation Oncology, University of Toronto, Toronto, Canada. Department of Medical Biophysics, University of Toronto, Toronto, Canada.Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada. Mike.Milosevic@rmp.uhn.ca. Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. Mike.Milosevic@rmp.uhn.ca. Department of Radiation Oncology, University of Toronto, Toronto, Canada. Mike.Milosevic@rmp.uhn.ca.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28619042

Citation

Leung, Eric, et al. "Metabolic Targeting of HIF-dependent Glycolysis Reduces Lactate, Increases Oxygen Consumption and Enhances Response to High-dose Single-fraction Radiotherapy in Hypoxic Solid Tumors." BMC Cancer, vol. 17, no. 1, 2017, p. 418.
Leung E, Cairns RA, Chaudary N, et al. Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors. BMC Cancer. 2017;17(1):418.
Leung, E., Cairns, R. A., Chaudary, N., Vellanki, R. N., Kalliomaki, T., Moriyama, E. H., ... Milosevic, M. (2017). Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors. BMC Cancer, 17(1), p. 418. doi:10.1186/s12885-017-3402-6.
Leung E, et al. Metabolic Targeting of HIF-dependent Glycolysis Reduces Lactate, Increases Oxygen Consumption and Enhances Response to High-dose Single-fraction Radiotherapy in Hypoxic Solid Tumors. BMC Cancer. 2017 Jun 15;17(1):418. PubMed PMID: 28619042.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Metabolic targeting of HIF-dependent glycolysis reduces lactate, increases oxygen consumption and enhances response to high-dose single-fraction radiotherapy in hypoxic solid tumors. AU - Leung,Eric, AU - Cairns,Rob A, AU - Chaudary,Naz, AU - Vellanki,Ravi N, AU - Kalliomaki,Tuula, AU - Moriyama,Eduardo H, AU - Mujcic,Hilda, AU - Wilson,Brian C, AU - Wouters,Bradly G, AU - Hill,Richard, AU - Milosevic,Michael, Y1 - 2017/06/15/ PY - 2016/07/04/received PY - 2017/06/02/accepted PY - 2017/6/17/entrez PY - 2017/6/18/pubmed PY - 2018/3/27/medline KW - Glycolysis KW - Hif-1α KW - High-dose single-fraction radiation KW - Hypoxia KW - Lactate KW - Metabolism KW - Radiation response SP - 418 EP - 418 JF - BMC cancer JO - BMC Cancer VL - 17 IS - 1 N2 - BACKGROUND: A high rate of glycolysis leading to elevated lactate content has been linked to poor clinical outcomes in patients with head and neck and cervical cancer treated with radiotherapy. Although the biological explanation for this relationship between lactate and treatment response remains unclear, there is a continued interest in evaluating strategies of targeting metabolism to enhance the effectiveness of radiotherapy. The goal of this study was to investigate the effect of metabolic-targeting through HIF-1α inhibition and the associated changes in glycolysis, oxygen consumption and response on the efficacy of high-dose single-fraction radiotherapy (HD-SFRT). METHODS: HIF-1α wild-type and HIF-1α knockdown FaDu and ME180 xenograft tumors were grown in the hind leg of mice that were placed in an environmental chamber and exposed to different oxygen conditions (air-breathing and hypoxia). Ex vivo bioluminescence microscopy was used to measure lactate and ATP levels and the hypoxic fraction was measured using EF5 immunohistochemical staining. The oxygen consumption rate (OCR) in each cell line in response to in vitro hypoxia was measured using an extracellular flux analyzer. Tumor growth delay in vivo was measured following HD-SFRT irradiation of 20 Gy. RESULTS: Targeting HIF-1α reduced lactate content, and increased both oxygen consumption and hypoxic fraction in these tumors after exposure to short-term continuous hypoxia. Tumors with intact HIF-1α subjected to HD-SFRT immediately following hypoxia exposure were less responsive to treatment than tumors without functional HIF-1α, and tumors irradiated under air breathing conditions regardless of HIF-1α status. CONCLUSIONS: Blocking the HIF1 response during transient hypoxic stress increased hypoxia, reduced lactate levels and enhanced response to HD-SFRT. This strategy of combining hypofractionated radiotherapy with metabolic reprogramming to inhibit anaerobic metabolism may increase the efficacy of HD-SFRT through increased oxygen consumption and complementary killing of radiosensitive and hypoxic, radioresistant cells. SN - 1471-2407 UR - https://www.unboundmedicine.com/medline/citation/28619042/Metabolic_targeting_of_HIF_dependent_glycolysis_reduces_lactate_increases_oxygen_consumption_and_enhances_response_to_high_dose_single_fraction_radiotherapy_in_hypoxic_solid_tumors_ L2 - https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3402-6 DB - PRIME DP - Unbound Medicine ER -