Abstract
The Warburg Effect, characterized by increased rate of glycolysis even under normoxic conditions, is one of the hallmarks of cancer. Relatively lower oxidative phosphorylation (OXPHOS) is also a characteristic feature in cancer cells. We hypothesized that interference with this phenomenon, by introducing exogenous pyruvate, would upset this cancer phenotype and boost the energy requirements of normal cells. We find that methyl pyruvate protects irinotecan-treated normal lung fibroblast cell line (MRC-5) probably by turning off the p53/p21 axis of the apoptotic pathways. When the MRC-5 fibroblasts recover in drug-free medium, the intrinsic apoptotic pathway is also turned off and the cells survive with no discernible exponential growth during the observation period. In contrast, the mere introduction of exogenous pyruvate kills the lung cancer cell line (A549). Although, functional p53 is important in the drug-induced cancer cell death, it is probably not essential because cancer cell lines with mutated p53 also die albeit less efficiently. We conclude that methyl pyruvate may preferentially kill cancer cells and protect normal cells during chemotherapy.
Highlights
Metabolic reprogramming, known as the Warburg Effect, is one of the hallmarks of cancer [1]
In aqueous solutions, pyruvate is rapidly converted to parapyruvate (which inhibits the tricarboxylic acid cycle (TCA)) or to pyruvate hydrate [22,23,24]. Favorable pharmacokinetic properties such as membrane permeability further make methyl pyruvate a better substrate for the TCA compared to pyruvate [25]
Our findings indicate that methyl pyruvate protects MRC-5 fibroblasts from irinotecaninduced cell death by turning off the p53/p21 axis since the downstream p21 is downregulated upon treatment by the drug combination and undetectable during the recovery period
Summary
Known as the Warburg Effect, is one of the hallmarks of cancer [1]. Otto Warburg discovered that cancer cells undergo metabolic reprogramming with concomitant increase in glucose uptake. They utilize the glycolytic pathway to metabolize glucose even in normoxic conditions [2]. This phenomenon led to opportunities for drug discovery and development. Otto Warburg noticed that while normal and tumour cells could undergo glycolysis in the presence of oxygen, normal cells died and cancer cells continued to thrive. It is likely that by enhanced glycolysis cancer cells do not invest primarily in ATP production but to anabolic processes such as lipid synthesis and de novo nucleic acid synthesis
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