Non-nitro Radiation Sensitizers

Shenoy, Mohan; Singh, B. B.

doi:10.1080/09553008514551311

Cited by 21 publications

(6 citation statements)

References 92 publications

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“…2DG has also been shown to have anticancer effects and has been used safely in both animal models and humans 42-44. Rot, a naturally occurring plant toxin which works by inhibiting NAD + linked oxidation in complex I of the ETC, along with deguelin (a similar rotenoid) have been shown to have cancer chemo preventative activity 45-47.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells

Fath

Diers²,

Aykin-Burns³

et al. 2009

Cancer Biology & Therapy

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Section: Discussionmentioning

confidence: 99%

Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells

Fath

Diers²,

Aykin-Burns³

et al. 2009

Cancer Biology & Therapy

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“…Administration of 2DG to mice has been shown to be an effective way to inhibit glucose metabolism without causing toxicity until very high levels are achieved (LD 50 ≥2 g/kg body weight) [31] and to be tolerable in humans when administered up to 200 mg/kg [32]. Furthermore, for more than 20 years, 2DG treatment was known to sensitize tumor cells to the cytotoxic effects of ionizing radiation both in vitro and in vivo [10,20,33]. This has led to phase I/II clinical trials in humans testing 2DG as an adjuvant to radiation therapy [33].…”

Section: Discussionmentioning

confidence: 99%

“…The glucose analog, 2DG, is a clinically relevant inhibitor of glucose metabolism believed to mimic the effects of glucose deprivation [20][21][22]. Therefore, we hypothesized that applying 2DG and DOX and modulating intracellular thiol levels using BSO will inhibit critical aspects of thiol-mediated hydroperoxide metabolism.…”

Section: Introductionmentioning

confidence: 99%

2DG enhances the susceptibility of breast cancer cells to doxorubicin

Ahmad

Mustafa

et al. 2010

Open Life Sciences

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2DG causes cytotoxicity in cancer cells by disrupting thiol metabolism while Doxorubicin (DOX) induces cytotoxicity in tumor cells by generating reactive oxygen species (ROS). Here we examined the combined cytotoxic action of 2DG and DOX in rapidly dividing T47D breast cancer cells vs. slowly growing MCF-7 breast cancer cells. T47D cells exposed to the combination of 2DG/DOX significantly decreased cell survival compared to controls, while 2DG/DOX had no effect on MCF-7 cells. 2DG/DOX also disrupted the oxidant status of T47D treated cells, decreased intracellular total glutathione and increased glutathione disulfide (%GSSG) compared to MCF-7 cells. Lipid peroxidation increased in T47D cells treated with 2DG and/or DOX, but not in MCF-7 cells. T47D cells were significantly protected by NAC, indicating that the combined treatment exerts its action by increasing ROS production and disrupting antioxidant stores. When we inhibited glutathione synthesis with BSO, T47D cells became more sensitive to 2DG/DOX-induced cytotoxicity, but NAC significantly reversed this cytotoxic effect. Finally, 2DG/DOX, and BSO significantly increased the %GSSG in T47D cells, an effect which was also reversed by NAC. Our results suggest that exposure of rapidly dividing breast cancer cells to 2DG/DOX enhances cytotoxicity via oxidative stress and via disruptions to thiol metabolism.

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“…In the current studies, 2DG was used to mimic the effects of glucose deprivation in head and neck squamous cell carcinoma cells. 2DG is a clinically relevant analogue of glucose that competes with glucose for uptake and entry into glucose metabolic pathways (22,(32)(33)(34)(35). 2DG can therefore create a drug-induced state of glucose deprivation, although it does not completely inhibit the regeneration of NADPH from NADP + because it is a substrate for glucose-6-phosphate dehydrogenase (35).…”

Section: Discussionmentioning

confidence: 99%

“…Because the glucose analogue 2DG is a clinically relevant inhibitor of glucose metabolism believed to mimic the effects of glucose deprivation (21,22), we hypothesized that 2DG in combination with cisplatin may act to inhibit critical aspects of thiol-mediated hydroperoxide metabolism leading to increased steady-state levels of ROS and enhanced tumor cell killing via metabolic oxidative stress. The current experiments were designed to test the aforementioned hypothesis using human head and neck squamous cell carcinoma cells.…”

Section: Introductionmentioning

confidence: 99%

2-Deoxy-d-Glucose Combined with Cisplatin Enhances Cytotoxicity via Metabolic Oxidative Stress in Human Head and Neck Cancer Cells

Ahmad²,

et al. 2007

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Glucose deprivation has been hypothesized to cause cytotoxicity by inducing metabolic oxidative stress in human cancer cells. The current work tests the hypothesis that 2-deoxy-Dglucose (2DG) combined with cisplatin [cis-diamminedichloroplatinum(II)] can enhance cytotoxicity in human head and neck cancer cells (FaDu) by mechanisms involving oxidative stress. Exposure of FaDu cells to the combination of 2DG and cisplatin resulted in a significant decrease in cell survival when compared with 2DG or cisplatin alone. Treatment with 2DG and cisplatin also caused perturbations in parameters indicative of oxidative stress, including decreased intracellular total glutathione and increased percentage of glutathione disulfide. Simultaneous treatment with the thiol antioxidant N-acetylcysteine (NAC) inhibited parameters indicative of oxidative stress, as well as protected FaDu cells from the cytotoxic effects of cisplatin alone and the combination of 2DG and cisplatin. In addition, polyethylene glycol-conjugated antioxidant enzymes (PEG-superoxide dismutase and PEG-catalase) also protected FaDu cells from 2DG toxicity. An inhibitor of glutathione synthesis, L-buthionine-[S,R]-sulfoximine (BSO), sensitized FaDu cells to the cytotoxic effects of 2DG and cisplatin, and these effects were inhibited by NAC. Furthermore, the combination of 2DG, cisplatin, and BSO significantly increased the percentage of glutathione disulfide, which was also inhibited by NAC. These results support the hypothesis that exposure of human head and neck cancer cells to 2DG combined with cisplatin enhances cytotoxicity via metabolic oxidative stress. These findings provide a strong biochemical rationale for evaluating inhibitors of glucose and hydroperoxide metabolism in combination with cisplatin for the treatment of head and neck cancer. [Cancer Res 2007;67(7):3364-70]

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Non-nitro Radiation Sensitizers

Abstract: A review of the literature on radiosensitization reveals that at least some of the non-nitro compounds, such as metabolic inhibitors and membrane-active drugs, could be considered as potentially valuable radiosensitizers for possible use in future cancer radiotherapy.

Cited by 21 publications

References 92 publications

Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells

Mitochondrial electron transport chain blockers enhance 2-deoxy-D-glucose induced oxidative stress and cell killing in human colon carcinoma cells

2DG enhances the susceptibility of breast cancer cells to doxorubicin

2-Deoxy-d-Glucose Combined with Cisplatin Enhances Cytotoxicity via Metabolic Oxidative Stress in Human Head and Neck Cancer Cells

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