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2-Deoxy-d-Glucose Can Complement Doxorubicin and Sorafenib to Suppress the Growth of Papillary Thyroid Carcinoma Cells.

Wang SY, Wei YH, Shieh DB, Lin LL, Cheng SP, Wang PW, Chuang JH - PLoS ONE (2015)

Bottom Line: Doxorubicin and sorafenib are the drugs of choice for treating advanced thyroid cancer but both induce adverse effects.However, dose-dependent reduction in cell viability, intracellular ATP depletion, and extracellular l-lactate production were observed after 2-DG treatment.These results demonstrate that the therapeutic effects of low combined doses of 2-DG and doxorubicin or sorafenib are similar to those of high doses of doxorubicin or sorafenib alone in PTC cell lines regardless of the BRAFV600E mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan; Graduate Institute of Clinical Medical Sciences, Chang-Gung University, College of Medicine, Kaohsiung, Taiwan.

ABSTRACT
Tumor cells display a shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. A subset of papillary thyroid carcinoma (PTC) is refractory to surgery and radioactive iodine ablation. Doxorubicin and sorafenib are the drugs of choice for treating advanced thyroid cancer but both induce adverse effects. In this study, we assessed the anti-cancer activity of 2-deoxy-d-glucose (2-DG) alone and in combination with doxorubicin or sorafenib in PTC cell lines with (BCPAP) and without (CG3) the BRAFV600E mutation. BCPAP cells were more glycolytic than CG3 cells, as evidenced by their higher extracellular l-lactate production, lower intracellular ATP level, lower oxygen consumption rate (OCR), and lower ratio of OCR/extracellular acidification rate. However, dose-dependent reduction in cell viability, intracellular ATP depletion, and extracellular l-lactate production were observed after 2-DG treatment. Regression analysis showed that cell growth in both cell lines was dependent on ATP generation. 2-DG increased the chemosensitivity of BCPAP and CG3 cell lines to doxorubicin and sorafenib. These results demonstrate that the therapeutic effects of low combined doses of 2-DG and doxorubicin or sorafenib are similar to those of high doses of doxorubicin or sorafenib alone in PTC cell lines regardless of the BRAFV600E mutation.

No MeSH data available.


Related in: MedlinePlus

Effects of doxorubicin on the viability of PTC cells treated or not with 2-DG.(A, B) BCPAP and CG3 cells cultured in medium supplemented with 10% fetal bovine serum were treated for 48 h with different concentrations of doxorubicin in the presence or absence of 2-DG. Post-treatment, cell viability was measured using a WST-1 assay. (C, D) Colony formation in BCPAP and CG3 cells treated for 48 h with 1 mM 2-DG, 0.5 μM doxorubicin, or both. The medium was replaced with fresh medium for 3–5 days to check for colony formation. *p < 0.05, **p < 0.001, compared to the controls (t test); panels A, B: ##p < 0.001, 2-way ANOVA; C, D: ##p < 0.001, compared to 2-DG plus doxorubicin treatment (t test). Data are presented as means± standard deviation (SD).
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pone.0130959.g004: Effects of doxorubicin on the viability of PTC cells treated or not with 2-DG.(A, B) BCPAP and CG3 cells cultured in medium supplemented with 10% fetal bovine serum were treated for 48 h with different concentrations of doxorubicin in the presence or absence of 2-DG. Post-treatment, cell viability was measured using a WST-1 assay. (C, D) Colony formation in BCPAP and CG3 cells treated for 48 h with 1 mM 2-DG, 0.5 μM doxorubicin, or both. The medium was replaced with fresh medium for 3–5 days to check for colony formation. *p < 0.05, **p < 0.001, compared to the controls (t test); panels A, B: ##p < 0.001, 2-way ANOVA; C, D: ##p < 0.001, compared to 2-DG plus doxorubicin treatment (t test). Data are presented as means± standard deviation (SD).

Mentions: The growth of the PTC cell lines treated with doxorubicin alone for 48 h was only mildly inhibited and in both cell viability was still > 60% at the concentration of 0.5 μM (Fig 4A and 4B). The IC50 of doxorubicin alone in CG3 cells was 2.2 times higher than that in BCPAP cells. To determine whether 2-DG increased the cytotoxic activity of doxorubicin, the cells were treated with 2-DG (0.0625 mM or 0.25 mM) plus doxorubicin at various concentrations. The IC50 of doxorubicin plus 2-DG was significantly lower in BCPAP cells and in CG3 cells treated with doxorubicin alone: 0.51 ± 0.09 μM and 1.12 ± 0.22 μM, respectively. The IC50 of doxorubicin plus 0.0625 mM 2-DG was 0.35 ± 0.05 μM (69% of the IC50 of doxorubicin alone) in BCPAP cells and 0.60 ± 0.12 μM (53%) in CG3 cells. The IC50 of doxorubicin plus 0.25 mM 2-DG was 0.16 ± 0.03 μM (31%) in BCPAP cells and 0.26 ± 0.04 μM (23%) in CG3 cells (Fig 4A and 4B). For both BCPAP and CG3 cells, colony formation was significantly lower in cells treated with doxorubicin plus 2-DG than in the controls or in cells treated with either 2-DG or doxorubicin alone (Fig 4C and 4D).


2-Deoxy-d-Glucose Can Complement Doxorubicin and Sorafenib to Suppress the Growth of Papillary Thyroid Carcinoma Cells.

Wang SY, Wei YH, Shieh DB, Lin LL, Cheng SP, Wang PW, Chuang JH - PLoS ONE (2015)

Effects of doxorubicin on the viability of PTC cells treated or not with 2-DG.(A, B) BCPAP and CG3 cells cultured in medium supplemented with 10% fetal bovine serum were treated for 48 h with different concentrations of doxorubicin in the presence or absence of 2-DG. Post-treatment, cell viability was measured using a WST-1 assay. (C, D) Colony formation in BCPAP and CG3 cells treated for 48 h with 1 mM 2-DG, 0.5 μM doxorubicin, or both. The medium was replaced with fresh medium for 3–5 days to check for colony formation. *p < 0.05, **p < 0.001, compared to the controls (t test); panels A, B: ##p < 0.001, 2-way ANOVA; C, D: ##p < 0.001, compared to 2-DG plus doxorubicin treatment (t test). Data are presented as means± standard deviation (SD).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4489888&req=5

pone.0130959.g004: Effects of doxorubicin on the viability of PTC cells treated or not with 2-DG.(A, B) BCPAP and CG3 cells cultured in medium supplemented with 10% fetal bovine serum were treated for 48 h with different concentrations of doxorubicin in the presence or absence of 2-DG. Post-treatment, cell viability was measured using a WST-1 assay. (C, D) Colony formation in BCPAP and CG3 cells treated for 48 h with 1 mM 2-DG, 0.5 μM doxorubicin, or both. The medium was replaced with fresh medium for 3–5 days to check for colony formation. *p < 0.05, **p < 0.001, compared to the controls (t test); panels A, B: ##p < 0.001, 2-way ANOVA; C, D: ##p < 0.001, compared to 2-DG plus doxorubicin treatment (t test). Data are presented as means± standard deviation (SD).
Mentions: The growth of the PTC cell lines treated with doxorubicin alone for 48 h was only mildly inhibited and in both cell viability was still > 60% at the concentration of 0.5 μM (Fig 4A and 4B). The IC50 of doxorubicin alone in CG3 cells was 2.2 times higher than that in BCPAP cells. To determine whether 2-DG increased the cytotoxic activity of doxorubicin, the cells were treated with 2-DG (0.0625 mM or 0.25 mM) plus doxorubicin at various concentrations. The IC50 of doxorubicin plus 2-DG was significantly lower in BCPAP cells and in CG3 cells treated with doxorubicin alone: 0.51 ± 0.09 μM and 1.12 ± 0.22 μM, respectively. The IC50 of doxorubicin plus 0.0625 mM 2-DG was 0.35 ± 0.05 μM (69% of the IC50 of doxorubicin alone) in BCPAP cells and 0.60 ± 0.12 μM (53%) in CG3 cells. The IC50 of doxorubicin plus 0.25 mM 2-DG was 0.16 ± 0.03 μM (31%) in BCPAP cells and 0.26 ± 0.04 μM (23%) in CG3 cells (Fig 4A and 4B). For both BCPAP and CG3 cells, colony formation was significantly lower in cells treated with doxorubicin plus 2-DG than in the controls or in cells treated with either 2-DG or doxorubicin alone (Fig 4C and 4D).

Bottom Line: Doxorubicin and sorafenib are the drugs of choice for treating advanced thyroid cancer but both induce adverse effects.However, dose-dependent reduction in cell viability, intracellular ATP depletion, and extracellular l-lactate production were observed after 2-DG treatment.These results demonstrate that the therapeutic effects of low combined doses of 2-DG and doxorubicin or sorafenib are similar to those of high doses of doxorubicin or sorafenib alone in PTC cell lines regardless of the BRAFV600E mutation.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan; Graduate Institute of Clinical Medical Sciences, Chang-Gung University, College of Medicine, Kaohsiung, Taiwan.

ABSTRACT
Tumor cells display a shift in energy metabolism from oxidative phosphorylation to aerobic glycolysis. A subset of papillary thyroid carcinoma (PTC) is refractory to surgery and radioactive iodine ablation. Doxorubicin and sorafenib are the drugs of choice for treating advanced thyroid cancer but both induce adverse effects. In this study, we assessed the anti-cancer activity of 2-deoxy-d-glucose (2-DG) alone and in combination with doxorubicin or sorafenib in PTC cell lines with (BCPAP) and without (CG3) the BRAFV600E mutation. BCPAP cells were more glycolytic than CG3 cells, as evidenced by their higher extracellular l-lactate production, lower intracellular ATP level, lower oxygen consumption rate (OCR), and lower ratio of OCR/extracellular acidification rate. However, dose-dependent reduction in cell viability, intracellular ATP depletion, and extracellular l-lactate production were observed after 2-DG treatment. Regression analysis showed that cell growth in both cell lines was dependent on ATP generation. 2-DG increased the chemosensitivity of BCPAP and CG3 cell lines to doxorubicin and sorafenib. These results demonstrate that the therapeutic effects of low combined doses of 2-DG and doxorubicin or sorafenib are similar to those of high doses of doxorubicin or sorafenib alone in PTC cell lines regardless of the BRAFV600E mutation.

No MeSH data available.


Related in: MedlinePlus