Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Shen, Han; Hau, Eric; Joshi, Swapna; Dilda, Pierre J.; McDonald, Kerrie L.

doi:10.1158/1535-7163.mct-15-0247

Cited by 93 publications

(89 citation statements)

References 49 publications

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“…Colony formation assays for the PDCLs were performed as previously described [26]. PDCLs were plated in triplicate in 6-well plates and incubated overnight.…”

Section: Methodsmentioning

confidence: 99%

Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma

Jue¹,

Nozue²,

Lester³

et al. 2017

J Transl Med

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BackgroundThe O 6-methylguanine methyltransferase (MGMT) gene is frequently unmethylated in patients with glioblastoma (GBM), rendering them non-responsive to the standard treatment regime of surgery followed by concurrent radiotherapy (RT) and temozolomide. Here, we investigate the efficacy of adding a PARP inhibitor, veliparib, to radiotherapy to treat MGMT unmethylated GBM.MethodsThe inhibition of PARP with veliparib (ABT-888), a potent and orally bioavailable inhibitor in combination with RT was tested on a panel of patient derived cell lines (PDCLs) and patient-derived xenografts (PDX) models generated from GBM patients with MGMT unmethylated tumors.ResultsThe combination of veliparib and RT inhibited colony formation in the majority of PDCLs tested. The PDCL, RN1 showed significantly reduced levels of the homologous repair protein, Mre11 and a heightened response to PARP inhibition measured by increased apoptosis and decreased colony formation. The oral administration of veliparib (12.5 mg/kg, twice daily for 5 days in a 28-day treatment cycle) in combination with whole brain RT (4 Gy) induced apoptosis (Tunel staining) and decreased cell proliferation (Ki67 staining) in a PDX of MGMT unmethylated GBM. Significantly longer survival times of the PDX treated with the combination treatment were recorded compared to RT only or veliparib only.ConclusionsOur results demonstrate preclinical efficacy of targeting PARP at multiple levels and provide a new approach for the treatment of MGMT unmethylated GBM.

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“…Colony formation assays for the PDCLs were performed as previously described [26]. PDCLs were plated in triplicate in 6-well plates and incubated overnight.…”

Section: Methodsmentioning

confidence: 99%

Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma

Jue¹,

Nozue²,

Lester³

et al. 2017

J Transl Med

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“…Recently, some studies revealed that elevated glycolysis of cancer cells will not only provide a growth advantage but also involves in resistance to chemotherapy and ionizing radiation resistance (15,16). High glycolytic states of tumor cells are known to correlate strongly with radioresistance (17–21). …”

Section: Introductionmentioning

confidence: 99%

2-Methoxyestradiol enhances radiosensitivity in radioresistant melanoma MDA-MB-435R cells by regulating glycolysis via HIF-1α/PDK1 axis

Zhao

Jiang

et al. 2017

International Journal of Oncology

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HIF-1α overexpression is associated with radio-resistance of various cancers. A radioresistant human melanoma cell model MDA-MB-435R (435R) was established by us previously. Compared with the parental cells MDA-MB-435 (435S), an elevated level of HIF-1α expression in 435R cells was demonstrated in our recent experiments. Therefore, in the current study, we sought to determine whether selective HIF-1α inhibitors could radiosensitize the 435R cells to X-ray, and to identify the potential mechanisms. Our data demonstrated that inhibition of HIF-1α with 2-methoxyestradiol (2-MeOE2) significantly enhanced radiosensitivity of 435R cells. 2-MeOE2 increased DNA damage and ratio of apoptosis cells induced by irradiation. Whereas, cell proliferation and the expression of pyruvate dehydrogenase kinase 1 (PDK1) were decreased after 2-MeOE2 treatment. The change of expression of GLUT1, LDHA and the cellular ATP level and extracellular lactate production indicates that 2-MeOE2 suppressed glycolytic state of 435R cells. In addition, the radioresistance, glycolytic state and cell proliferation of 435R cells were also decreased after inhibiting pyruvate dehydrogenase kinase 1 (PDK1) with dichloroacetate (DCA). DCA could also increase DNA damage and ratio of apoptotic cells induced by irradiation. These results also suggest that inhibition of HIF-1α with 2-MeOE2 sensitizes radioresistant melanoma cells 435R to X-ray irradiation through targeting the glycolysis that is regulated by PDK1. Selective inhibitors of HIF-1α and glycolysis are potential drugs to enhance radio sensitivity of melanoma cells.

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“…A number of studies has demonstrated that glycolysis is highly correlated with radioresistance [14, 15, 26–30]. Tumor cells undergoing glycolysis not only produce large number of ATP molecules, but they could also produce many macromolecules such as pyruvate, lactate, glutathione and NAD(P), all of which compose an intracellular redox buffer network to effectively scavenge ROS and reduce the efficacy of RT as a consequence.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulated evidence supports the notion that glycolysis is associated with drug resistance and radioresistance in cancer therapy [11–13]. In this vein, switching cancer cells from glycolysis to oxidative phosphorylation may increase tumor cell sensitivity to RT [14, 15]. Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), leads to the reactivation of pyruvate dehydrogenase (PDH) and shifts glucose metabolism from glycolysis to mitochondrial oxidation [16].…”

Section: Introductionmentioning

confidence: 99%

“…Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK), leads to the reactivation of pyruvate dehydrogenase (PDH) and shifts glucose metabolism from glycolysis to mitochondrial oxidation [16]. Preclinical trials on DCA have shown that DCA could enhance the radiosensitivity of several tumor types when combined with RT [14, 17, 18]. However, it has not been permitted for use as an anti-cancer drug in the clinic.…”

Section: Introductionmentioning

confidence: 99%

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Diisopropylamine dichloroacetate enhances radiosensitization in esophageal squamous cell carcinoma by increasing mitochondria-derived reactive oxygen species levels

et al. 2016

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Radiotherapy is generally applied in the treatment of esophageal squamous cell carcinoma (ESCC). However, the radioresistance of ESCC still remains an obstacle for the curative effect of this treatment. We hypothesized that diisopropylamine dichloroacetate (DADA), an inhibitor of pyruvate dehydrogenase kinase (PDK), might enhance radiosensitizationin resistant ESCC. The clonogenic survival assay revealed that DADA sensitized ESCC cells to radiotherapy in vitro; furthermore, the combination of DADA and radiotherapy increased the expression of γ-H2AX, which is a hallmark of DNA double-strand breaks. Arrest at G2/M phase as well as the induction of apoptosis of ESCC cells were also observed in the cells treated with the combination of DADA and radiotherapy. Notably, xenograft tumor growth was significantly suppressed in vivo by combined radiotherapy and DADA administration. It has been proven that glycolysis is highly correlated with radioresistance, which could be reversed by the shift from glycolysis to mitochondrial oxidation. In our present study, we found that DADA could modulate oxidative phosphorylation as well as increase the intracellular levels of reactive oxygen species (ROS). Collectively, we concluded that DADA-induced intracellular ROS accumulation was identified as the key factor of radiotherapy sensitization of ESCC.

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Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

Cited by 93 publications

References 49 publications

Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma

Veliparib in combination with radiotherapy for the treatment of MGMT unmethylated glioblastoma

2-Methoxyestradiol enhances radiosensitivity in radioresistant melanoma MDA-MB-435R cells by regulating glycolysis via HIF-1α/PDK1 axis

Diisopropylamine dichloroacetate enhances radiosensitization in esophageal squamous cell carcinoma by increasing mitochondria-derived reactive oxygen species levels

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