The Warburg effect and drug resistance

Abstract

The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumour cells, tumourigenesis and the microenvironment of tumours. More recently, studies have begun to reveal how the Warburg effect could influence drug efficacy and how our understanding of tumour energetics could be exploited to improve drug development. In particular, evidence is emerging demonstrating how better modelling of the tumour metabolic microenvironment could lead to a better prediction of drug efficacy and the identification of new combination strategies. This review will provide details of the current understanding of the complex interplay between glucose metabolism and pharmacology and discuss opportunities for utilizing the Warburg effect in future drug development.

ENO2 Promotes Cell Proliferation, Glycolysis, and Glucocorticoid-Resistance in Acute Lymphoblastic Leukemia

“…The phenomenon of aerobic glycolysis, termed the Warburg effect [21-23], involves an increased glycolysis rate due to the up-regulation of several genes involved in glycolysis or glucose uptake [24, 25]. In the present study, Akt has been implicated in the regulation of glucose uptake and has been shown to induce the expression of glycolysis-related genes, including GLUT-1, LDHα, and PKM2.…”

Extracellular matrix protein Reelin promotes myeloma progression by facilitating tumor cell proliferation and glycolysis

“…Accumulating studies have shown that chemoresistance is closely associated with enhanced glucose metabolism in a variety of cancer types, including myeloma49. Defective mitochondrial ATP production, elevated aerobic glycolysis, and enhanced HIF1α-mediated signaling are major characteristics of these drug-resistant tumor cells5051.…”

Metabolic reprogramming in the tumour microenvironment: a hallmark shared by cancer cells and T lymphocytes

“…Lactate extrusion may not merely be a mechanism of waste clearance, but maintains glycolytic rate and promotes tumour progression and metastasis . The resulting acidic extracellular microenvironment promotes epithelial‐to‐mesenchymal transition in cancer cells, contributes to drug resistance, and impairs immunological cell signalling . The dependence of cancer cells on fermentation and extrusion of lactate suggests an additional reason for aerobic glycolysis: rapid, albeit inefficient, ATP generation supports demand for membrane transporter activity to regulate nutrient flux and pH homeostasis …”