Methyl pyruvate protects a normal lung fibroblast cell line from irinotecan-induced cell death: Potential use as adjunctive to chemotherapy

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.

LPS induces inflammatory chemokines via TLR-4 signalling and enhances the Warburg Effect in THP-1 cells

“…We have previously shown that exogenous pyruvate kills breast, lung and ovarian cancer cell lines but promotes the survival of a normal fibroblast cell line. Furthermore, exogenous pyruvate protects the normal cell line from genotoxic stress caused by irinotecan [5]. Since monocytes are often exposed to stress caused by infectious agents, we investigated the response of THP-1 cells to LPS in order to understand the effect of superimposing infection on a cancerous monocyte.…”

“…Previously, we have shown that the reversal of the Warburg Effect in some cancer cell lines by the introduction of exogenous pyruvate is sufficient to kill them. In contrast, this strategy promotes survival in a normal cell line even when exogenous pyruvate is combined with a genotoxic agent suggesting that exogenous pyruvate can be used as an adjunctive to protect normal cells during chemotherapy [5].…”

Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment

“…To determine whether energy stress could be a possible mechanism of cell death, flow cytometry with DRAQ7 labelling was carried out with samples treated for 48 h with either DMSO, or nelfinavir and mefloquine combination in the presence or absence of methyl pyruvate ( Figure 5 D). Methyl pyruvate can alleviate energy stress when supplemented to cells, as it is a direct substrate of the citric acid cycle to produce energy by oxidative phosphorylation [ 26 ]. Methyl pyruvate partially rescued nelfinavir and mefloquine induced cell death when supplemented to the Tsc2 −/− MEFs (causing a 40% rescue of cell death).…”

Sodium pyruvate pre‐treatment prevents cell death due to localised, damaging mechanical strains in the context of pressure ulcers

“…For example, NaPy has been shown to minimise deficits following traumatic myocardial infraction in pigs and reduce cortical contusion injury and hypoxic‐ischemic damage in rat brains . In addition, NaPy has improved rat renal function after glycerol‐induced renal failure and has been proposed as an adjunct treatment to protect fibroblast cell lines from chemotherapy‐induced death . Physiological NaPy levels in human blood are low, 0.090 to 0.12 mM, and abnormal levels of NaPy in blood serum and extracellular spaces are often an indicator of disease .…”