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To better understand the energetic status of proliferating cells, we have measured the intracellular pH (pHi) and concentrations of key metabolites, such as adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP) in normal and cancer cells, extracted from fresh human colon tissues. Cells were sorted by elutriation and segregated in different phases of the cell cycle (G0/G1/S/G2/M) in order to study their redox (NAD, NADP) and bioenergetic (ATP, pHi) status. Our results show that the average ATP concentration over the cell cycle is higher and the pHi is globally more acidic in normal proliferating cells. The NAD+/NADH and NADP+/NADPH redox ratios are, respectively, five times and ten times higher in cancer cells compared to the normal cell population. These energetic differences in normal and cancer cells may explain the well-described mechanisms behind the Warburg effect. Oscillations in ATP concentration, pHi, NAD+/NADH, and NADP+/NADPH ratios over one cell cycle are reported and the hypothesis addressed. We also investigated the mitochondrial membrane potential (MMP) of human and mice normal and cancer cell lines. A drastic decrease of the MMP is reported in cancer cell lines compared to their normal counterparts. Altogether, these results strongly support the high throughput aerobic glycolysis, or Warburg effect, observed in cancer cells.

In the recent years, cancer research succeeded with sensitive detection methods, targeted drug delivery systems, and the identification of a large set of genes differently expressed. However, although most therapies are still based on antimitotic agents, which are causing wide secondary effects, there is an increasing interest for metabolic therapies that can minimize side effects. In the early 20th century, Otto Warburg revealed that cancer cells rely on the cytoplasmic fermentation of glucose to lactic acid for energy synthesis (called \"Warburg effect\"). Our investigations aim to reverse this effect in reprogramming cancer cells' metabolism. In this work, we present a metabolic therapy specifically targeting the activity of specific enzymes of central carbon metabolism, combining the METABLOC bitherapeutic drugs combination (Alpha Lipoic Acid and Hydroxycitrate) to Metformin and Diclofenac, for treating tumors implanted in mice. Furthermore, a dynamic metabolic model describing central carbon metabolism as well as fluxes targeted by the drugs allowed to simulate tumors progression in both treated and non-treated mice, in addition to draw hypotheses on the effects of the drugs on tumor cells metabolism. Our model predicts metabolic therapies-induced reversed Warburg effect on tumor cells.