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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

In vivo effect of fasting cycles in combination with chemotherapy on tumor glucose consumption and cancer growthCT26 cells were subcutaneously inoculated in the fat pad of BALB/c mice (200.000 cells/mouse). Five days after tumor cell inoculum, the mice were either fasted or maintained on the ad lib standard diet for 48 hours and treated with Oxaliplatin (OXP) (10 mg/Kg). After 1 week, the treatment was repeated. All mice were imaged after the first and the second cycle of therapy by a dedicated micro-PET system. Panel A shows the Patlak-map of a representative mouse for each group after the first cycle of treatment. Panel B shows the Patlak-map of a representative mouse for each group after the second cycle of treatment. Red arrows indicate the tumor mass. Panel C shows the cancer average glucose consumption expressed as nMol x min−1 x gr−1. Panel D shows the tumor volume expressed as mean value ± SD. Groups of experiments include: control (black), STS (green), OXP (light blue), and STS+OXP (red). Panel E shows the total cancer glucose consumption expressed as nMol x min−1.
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Figure 1: In vivo effect of fasting cycles in combination with chemotherapy on tumor glucose consumption and cancer growthCT26 cells were subcutaneously inoculated in the fat pad of BALB/c mice (200.000 cells/mouse). Five days after tumor cell inoculum, the mice were either fasted or maintained on the ad lib standard diet for 48 hours and treated with Oxaliplatin (OXP) (10 mg/Kg). After 1 week, the treatment was repeated. All mice were imaged after the first and the second cycle of therapy by a dedicated micro-PET system. Panel A shows the Patlak-map of a representative mouse for each group after the first cycle of treatment. Panel B shows the Patlak-map of a representative mouse for each group after the second cycle of treatment. Red arrows indicate the tumor mass. Panel C shows the cancer average glucose consumption expressed as nMol x min−1 x gr−1. Panel D shows the tumor volume expressed as mean value ± SD. Groups of experiments include: control (black), STS (green), OXP (light blue), and STS+OXP (red). Panel E shows the total cancer glucose consumption expressed as nMol x min−1.

Mentions: We investigated the effect of STS +/− chemotherapy on glucose metabolism in CT26 colon carcinoma cells in mice by micro-PET analyses. As previously described [16, 17], 48-hour of STS induced a significant body weight loss and serum glucose reduction. Analysis of tracer uptake by the tumor showed a differential response to the treatments (Figure 1A-C). After the first cycle, STS was as effective as oxaliplatin (OXP) in reducing the average tumor glucose consumption (Figure 1C). However, the lowest values were achieved by STS+OXP (Figure 1A-C). Monitoring of tumor progression during multiple cycles revealed that average tumor metabolism was inhibited similarly by the first and second STS treatments (Figure 1C). Chemotherapy induced only a transient reduction of the lesion metabolic rate after its first application. By contrast, average glucose consumption remained significantly lower in STS+OXP-treated mice (Figure 1C).


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)

In vivo effect of fasting cycles in combination with chemotherapy on tumor glucose consumption and cancer growthCT26 cells were subcutaneously inoculated in the fat pad of BALB/c mice (200.000 cells/mouse). Five days after tumor cell inoculum, the mice were either fasted or maintained on the ad lib standard diet for 48 hours and treated with Oxaliplatin (OXP) (10 mg/Kg). After 1 week, the treatment was repeated. All mice were imaged after the first and the second cycle of therapy by a dedicated micro-PET system. Panel A shows the Patlak-map of a representative mouse for each group after the first cycle of treatment. Panel B shows the Patlak-map of a representative mouse for each group after the second cycle of treatment. Red arrows indicate the tumor mass. Panel C shows the cancer average glucose consumption expressed as nMol x min−1 x gr−1. Panel D shows the tumor volume expressed as mean value ± SD. Groups of experiments include: control (black), STS (green), OXP (light blue), and STS+OXP (red). Panel E shows the total cancer glucose consumption expressed as nMol x min−1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: In vivo effect of fasting cycles in combination with chemotherapy on tumor glucose consumption and cancer growthCT26 cells were subcutaneously inoculated in the fat pad of BALB/c mice (200.000 cells/mouse). Five days after tumor cell inoculum, the mice were either fasted or maintained on the ad lib standard diet for 48 hours and treated with Oxaliplatin (OXP) (10 mg/Kg). After 1 week, the treatment was repeated. All mice were imaged after the first and the second cycle of therapy by a dedicated micro-PET system. Panel A shows the Patlak-map of a representative mouse for each group after the first cycle of treatment. Panel B shows the Patlak-map of a representative mouse for each group after the second cycle of treatment. Red arrows indicate the tumor mass. Panel C shows the cancer average glucose consumption expressed as nMol x min−1 x gr−1. Panel D shows the tumor volume expressed as mean value ± SD. Groups of experiments include: control (black), STS (green), OXP (light blue), and STS+OXP (red). Panel E shows the total cancer glucose consumption expressed as nMol x min−1.
Mentions: We investigated the effect of STS +/− chemotherapy on glucose metabolism in CT26 colon carcinoma cells in mice by micro-PET analyses. As previously described [16, 17], 48-hour of STS induced a significant body weight loss and serum glucose reduction. Analysis of tracer uptake by the tumor showed a differential response to the treatments (Figure 1A-C). After the first cycle, STS was as effective as oxaliplatin (OXP) in reducing the average tumor glucose consumption (Figure 1C). However, the lowest values were achieved by STS+OXP (Figure 1A-C). Monitoring of tumor progression during multiple cycles revealed that average tumor metabolism was inhibited similarly by the first and second STS treatments (Figure 1C). Chemotherapy induced only a transient reduction of the lesion metabolic rate after its first application. By contrast, average glucose consumption remained significantly lower in STS+OXP-treated mice (Figure 1C).

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