Glycolytic Inhibition Alters Anaplastic Thyroid Carcinoma Tumor Metabolism and Improves Response to Conventional Chemotherapy and Radiation

Sandulache, Vlad C.; Skinner, Heath D.; Wang, Yuan; Chen, Yunyun; Dodge, Cristina T.; Ow, Thomas J.; Bankson, James A.; Myers, Jeffrey N.; Lai, Stephen Y.

doi:10.1158/1535-7163.mct-12-0041

Cited by 59 publications

(84 citation statements)

References 27 publications

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“…Tumor metabolism was challenged using 2DG (31) (N=9), external radiation therapy (32) (N=7), or conditional gene expression (19) (N=3); controls were tested prior to or without perturbation (N=33) or administered a negative control (N=3). All three kinetic models fit these datasets (N=55) reasonably well, as summarized in Figure 3.…”

Section: Resultsmentioning

confidence: 99%

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

et al. 2015

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Hyperpolarized [1-13C]-pyruvate has shown tremendous promise as an agent for imaging tumor metabolism with unprecedented sensitivity and specificity. Imaging hyperpolarized substrates by magnetic resonance is unlike traditional MRI because signals are highly transient and their spatial distribution varies continuously over their observable lifetime. Therefore, new imaging approaches are needed to ensure optimal measurement under these circumstances. Constrained reconstruction algorithms can integrate prior information, including biophysical models of the substrate/target interaction, to reduce the amount of data that is required for image analysis and reconstruction. In this study, we show that metabolic MRI with hyperpolarized pyruvate is biased by tumor perfusion, and present a new pharmacokinetic model for hyperpolarized substrates that accounts for these effects. The suitability of this model is confirmed by statistical comparison to alternates using data from 55 dynamic spectroscopic measurements in normal animals and murine models of anaplastic thyroid cancer, glioblastoma, and triple-negative breast cancer. The kinetic model was then integrated into a constrained reconstruction algorithm and feasibility was tested using significantly under-sampled imaging data from tumor-bearing animals. Compared to naïve image reconstruction, this approach requires far fewer signal-depleting excitations and focuses analysis and reconstruction on new information that is uniquely available from hyperpolarized pyruvate and its metabolites, thus improving the reproducibility and accuracy of metabolic imaging measurements.

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Section: Resultsmentioning

confidence: 99%

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

et al. 2015

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“…Thus, it is reasonable to assume that the increased ROS levels induced by oxamate synergistically enhanced the DNA damage effect and toxicity of irradiation in NPC cells. Other studies also found that glycolysis inhibitors increased radiosensitivity in cancer cells (33)(34)(35). Sharma et al (34) reported that non-coordinated expression of antioxidant enzymes was another essential factor that led to selective radiosensitization in malignant cells, in addition to redox status.…”

Section: Discussionmentioning

confidence: 96%

Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells

et al. 2013

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Abstract. An elevated rate of glucose consumption and the dependency on aerobic glycolysis for ATP generation have long been observed in cancer cells, a phenomenon known as the Warburg effect. The altered energy metabolism in cancer cells provides an attractive opportunity for developing novel cancer therapeutic strategies. Lactate dehydrogenase (LDH), which catalyzes the transformation of pyruvate to lactate, plays a vital role in the process of glycolysis. It has been reported that the level of LDH-A expression is increased both in head and neck cancer cells and in the blood serum of nasopharyngeal carcinoma (NPC) patients, and is associated with poor prognosis. However, the effect of LDH-A inhibition on NPC cells remains unknown. Here, in the present study, we found that oxamate, a classical inhibitor of LDH-A, suppressed cell proliferation in a dose-and time-dependent manner both in CNE-1 and CNE-2 cells, two NPC cancer cell lines. LDH inhibition by oxamate induced G 2 /M cell cycle arrest via downregulation of the CDK1/cyclin B1 pathway and promoted apoptosis through enhancement of mitochondrial ROS generation. N-acetylcysteine, a specific scavenger of ROS, significantly blocked the growth inhibition effect induced by oxamate. We also identified that oxamate increased sensitivity to ionizing radiation in the two NPC cancer cell lines. Furthermore, we verified similar results in tumor xenograft models. Collectively, these results suggest that LDH-A may serve as a promising therapeutic target for NPC treatment.

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“…HNSCC cell lines containing TP53 constructs have been previously described by our group and were obtained for the experiments detailed here within the last 4 months. (6, 7)…”

Section: Methodsmentioning

confidence: 99%

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

Sandulache

Chen

Skinner

et al. 2015

Molecular Cancer Therapeutics

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Ionizing radiation is the primary non-surgical treatment modality for solid tumors. Its effectiveness is impacted by temporal constraints such as fractionation, hypoxia and development of radioresistant clones. Biomarkers of acute radiation response are essential to developing more effective clinical algorithms. We hypothesized that acute perturbations in tumor lactate levels act as a surrogate marker of radiation response. In vitro experiments were carried out using validated human derived cell lines from 3 histologies: anaplastic thyroid carcinoma (ATC), head and neck squamous cell carcinoma (HNSCC) and papillary thyroid carcinoma (PTC). Cellular metabolic activity was measured using standard biochemical assays. In vivo validation was performed using both an orthotopic and a flank derivative of a previously established ATC xenograft murine model. Irradiation of cells and tumors triggered a rapid, dose-dependent, transient decrease in lactate levels which was reversed by free radical scavengers. Acute lactate perturbations following irradiation could identify hypoxic conditions and correlated with hypoxia-induced radioresistance. Mutant TP53 cells and cells in which p53 activity was abrogated (shRNA) demonstrated a blunted lactate response to irradiation, consistent with a radioresistant phenotype. Lactate measurements therefore rapidly detected both induced (i.e. hypoxia) and intrinsic (i.e. mutTP53 driven) radioresistance. We conclude that lactate is a quantitative biomarker of acute genotoxic stress, with a temporal resolution which can inform clinical decision-making. Combined with the spatial resolution of newly developed metabolic imaging platforms, this biomarker could lead to the development of truly individualized treatment strategies.

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Glycolytic Inhibition Alters Anaplastic Thyroid Carcinoma Tumor Metabolism and Improves Response to Conventional Chemotherapy and Radiation

Cited by 59 publications

References 27 publications

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

Kinetic Modeling and Constrained Reconstruction of Hyperpolarized [1-13C]-Pyruvate Offers Improved Metabolic Imaging of Tumors

Inhibition of LDH-A by oxamate induces G2/M arrest, apoptosis and increases radiosensitivity in nasopharyngeal carcinoma cells

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

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