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

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 O2 consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O2 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.

Protective effects of short-term dietary restriction in surgical stress and chemotherapy

“…48 h of water-only fasting sensitizes intracranial and subcutaneous glioma models to radio-and chemotherapy (Safdie et al, 2012), an effect not observed by dietary protein restriction alone (Brandhorst et al, 2013). PF alone or in combination with oxaliplatin reduces the progression of CT26 colorectal tumors by down-regulating aerobic glycolysis and glutaminolysis, and increasing oxidative phosphorylation in the mitochondrial electron transport chain which results in reduced ATP production, increased oxidative stress, and apoptosis (Bianchi et al, 2015). In murine 4T1 breast cancer cells, PF increases the phosphorylation of the pro-proliferative but stress-sensitizing Akt and S6 kinases, and increases oxidative stress, caspase-3 cleavage, DNA damage, and apoptosis (Lee et al, 2012).…”

Glibenclamide Mimics Metabolic Effects of Metformin in H9c2 Cells

“…The activity assay of the four redox complexes was measured on 50 µg of total protein homogenate [16]. Complex I (NADH-ubiquinone oxidoreductase) was assayed following the reduction of ferricyanide at 420 nm.…”

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…In a murine CT26 colon cancer model, STF decreased both glycolysis and glutaminolysis while shifting metabolism towards the mitochondria, which resulted in enhanced mtROS production and ATP depletion [86]. Marini et al [87] confirmed these findings, showing that STF in vitro enhanced the oxygen consumption rate and increased the complex I and IV activity in murine CT26 colon and 4T1 breast cancer cells, leading to a subsequent boost in mtROS production.…”

“…Studies using FDG-PET imaging [25,80] or microdialysis measurements [81] have shown that a KD can downregulate the glycolytic tumor metabolism in some patients. A decrease in tumor lactate production has also been observed in mice kept on a KD [82,83] and in cultured cancer cells treated with ketone bodies [84,85] or fasting-mimicking conditions [86,87]. The decreased tumor lactate concentrations after a few days on a KD in head-and-neck cancer patients measured by Schroeder et al [81] are of particular interest, as tumor lactate concentrations have been directly linked to radioresistance in a variety of xenografted head-and-neck tumors that were irradiated using a clinically relevant schedule of 30 fractions over 6 weeks [88,89].…”

“…Similarly, Lee et al [92] measured increased oxidative stress under in vitro fasting conditions in 4T1 cells, which they associated with the increased superoxide levels and the synergistic responses they observed when allografted tumors were treated with combined fasting and cyclophosphamide. Synergistic effects between fasting and chemotherapy were also observed in murine B16 melanoma and GL26 glioma allografts, human breast cancer and ovarian cancer xenografts (all treated with doxorubicin [92]), pancreatic cancer xenografts treated with gemcitabine [93], CT26 colorectal allografts treated with oxaliplatin [86], and murine fibrosarcoma allografts treated with mitoxantrone or oxaliplatin [94] (table 1). Furthermore, Morscher et al [95] revealed synergistic effects between a KD and metronomic chemotherapy with cyclophosphamide in 2 neuroblastoma xenograft models.…”