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Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.

Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, Emionite L, Lavarello C, Amaro A, Petretto A, Pfeffer U, Sambuceti G, Pistoia V, Raffaghello L, Longo VD - Oncotarget (2015)

Bottom Line: STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models.The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis.Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.

ABSTRACT
Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

No MeSH data available.


Related in: MedlinePlus

Effects of STS in combination with chemotherapy on viability and glucose uptake by colon carcinoma cellsTumor cells were cultured in with either low glucose (0.5 g/l) and 1% serum (in vitro STS) or the standard glucose levels (1.0 g/l) and 10% serum (control) for 48 hours. Then, cells were incubated with 40 μM oxaliplatin (OXP) for 24 hours. Panel A shows cell viability of different mouse and human colon carcinoma cell lines (CT26, HCT 116 and HT-29) as determined by Trypan Blue Assay. Panel B shows 18F-Fluorodeoxyglucose (FDG) uptake by different colon carcinoma cells (CT26, HCT 116 and HT-29). Tumor cells were incubated with FDG at 37 KBq/ml for 60 minutes. FDG retention was measured as the ratio between bound and total radioactivity. Data are expressed as percentage of viable cells ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05; **: P<0.01; ***: P<0.001.
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Figure 2: Effects of STS in combination with chemotherapy on viability and glucose uptake by colon carcinoma cellsTumor cells were cultured in with either low glucose (0.5 g/l) and 1% serum (in vitro STS) or the standard glucose levels (1.0 g/l) and 10% serum (control) for 48 hours. Then, cells were incubated with 40 μM oxaliplatin (OXP) for 24 hours. Panel A shows cell viability of different mouse and human colon carcinoma cell lines (CT26, HCT 116 and HT-29) as determined by Trypan Blue Assay. Panel B shows 18F-Fluorodeoxyglucose (FDG) uptake by different colon carcinoma cells (CT26, HCT 116 and HT-29). Tumor cells were incubated with FDG at 37 KBq/ml for 60 minutes. FDG retention was measured as the ratio between bound and total radioactivity. Data are expressed as percentage of viable cells ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05; **: P<0.01; ***: P<0.001.

Mentions: We investigated the in vitro effects of STS on a panel of colon carcinoma cell lines grown under normal or conditions mimicking starvation [17] for 48 hours. One day after STS, the cells were treated with OXP. STS and OXP showed additive cytotoxic effects in all the cell lines tested (Figure 2A). FDG uptake paralleled viability response since it was reduced by a similar degree by each single stressor, although the greatest impairment occurred in response to STS+OXP (Figure 2B). These results confirm the in vivo results and support the use of the in vitro paradigm to model the effects of STS in mice.


Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.

Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, Emionite L, Lavarello C, Amaro A, Petretto A, Pfeffer U, Sambuceti G, Pistoia V, Raffaghello L, Longo VD - Oncotarget (2015)

Effects of STS in combination with chemotherapy on viability and glucose uptake by colon carcinoma cellsTumor cells were cultured in with either low glucose (0.5 g/l) and 1% serum (in vitro STS) or the standard glucose levels (1.0 g/l) and 10% serum (control) for 48 hours. Then, cells were incubated with 40 μM oxaliplatin (OXP) for 24 hours. Panel A shows cell viability of different mouse and human colon carcinoma cell lines (CT26, HCT 116 and HT-29) as determined by Trypan Blue Assay. Panel B shows 18F-Fluorodeoxyglucose (FDG) uptake by different colon carcinoma cells (CT26, HCT 116 and HT-29). Tumor cells were incubated with FDG at 37 KBq/ml for 60 minutes. FDG retention was measured as the ratio between bound and total radioactivity. Data are expressed as percentage of viable cells ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05; **: P<0.01; ***: P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494906&req=5

Figure 2: Effects of STS in combination with chemotherapy on viability and glucose uptake by colon carcinoma cellsTumor cells were cultured in with either low glucose (0.5 g/l) and 1% serum (in vitro STS) or the standard glucose levels (1.0 g/l) and 10% serum (control) for 48 hours. Then, cells were incubated with 40 μM oxaliplatin (OXP) for 24 hours. Panel A shows cell viability of different mouse and human colon carcinoma cell lines (CT26, HCT 116 and HT-29) as determined by Trypan Blue Assay. Panel B shows 18F-Fluorodeoxyglucose (FDG) uptake by different colon carcinoma cells (CT26, HCT 116 and HT-29). Tumor cells were incubated with FDG at 37 KBq/ml for 60 minutes. FDG retention was measured as the ratio between bound and total radioactivity. Data are expressed as percentage of viable cells ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05; **: P<0.01; ***: P<0.001.
Mentions: We investigated the in vitro effects of STS on a panel of colon carcinoma cell lines grown under normal or conditions mimicking starvation [17] for 48 hours. One day after STS, the cells were treated with OXP. STS and OXP showed additive cytotoxic effects in all the cell lines tested (Figure 2A). FDG uptake paralleled viability response since it was reduced by a similar degree by each single stressor, although the greatest impairment occurred in response to STS+OXP (Figure 2B). These results confirm the in vivo results and support the use of the in vitro paradigm to model the effects of STS in mice.

Bottom Line: STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models.The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis.Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.

ABSTRACT
Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

No MeSH data available.


Related in: MedlinePlus