Targeting Glucose Metabolism in Cancer Cells as an Approach to Overcoming Drug Resistance

Abstract

The "Warburg effect" consists of a metabolic shift in energy production from oxidative phosphorylation to glycolysis. The continuous activation of glycolysis in cancer cells causes rapid energy production and an increase in lactate, leading to the acidification of the tumour microenvironment, chemo- and radioresistance, as well as poor patient survival. Nevertheless, the mitochondrial metabolism can be also involved in aggressive cancer characteristics. The metabolic differences between cancer and normal tissues can be considered the Achilles heel of cancer, offering a strategy for new therapies. One of the main causes of treatment resistance consists of the increased expression of efflux pumps, and multidrug resistance (MDR) proteins, which are able to export chemotherapeutics out of the cell. Cells expressing MDR proteins require ATP to mediate the efflux of their drug substrates. Thus, inhibition of the main energy-producing pathways in cancer cells, not only induces cancer cell death per se, but also overcomes multidrug resistance. Given that most anticancer drugs do not have the ability to distinguish normal cells from cancer cells, a number of drug delivery systems have been developed. These nanodrug delivery systems provide flexible and effective methods to overcome MDR by facilitating cellular uptake, increasing drug accumulation, reducing drug efflux, improving targeted drug delivery, co-administering synergistic agents, and increasing the half-life of drugs in circulation.

Keywords: Warburg effect; glycolysis; nanoparticles; resistance; tumor metabolism; tumor microenvironment.

Figure 1

Glucose metabolism in mammalian cells. Illustrative scheme of glycolysis, TCA cycle, and the electron transport chain (red). Glucose from the blood stream is uptaken by the cells, converted into G6P by HK and posteriorly in pyruvate. In the absence of oxygen, pyruvate is converted into lactate, whereas in the presence of oxygen, the pyruvate is completely oxidized into Acetyl-CoA, which enters the mitochondrial TCA cycle. The generated NADH are then fed the OXPHOS-producing ATP (blue). The PPP (green) synthetizes the ribose-5-phosphate, which is needed for nucleic acid synthesis, and NADPH. The excess glucose is used to synthetize glycogen, via glycogenesis (purple). Created by the Authors with BioRender.com. ATP: adenosine triphosphate; G6P: glucose-6-phosphate; HK: hexokinase; NADH: nicotinamide adenine dinucleotide; NADPH: nicotinamide adenine dinucleotide phosphate; OXPHOS: oxidative phosphorylation; PPP: pentose phosphate pathway; TCA cycle: tricarboxylic acid cycle.

Figure 2

Schematic representation of the main differences between aerobic glycolysis (“Warburg effect”) in proliferative tissue and OXPHOS and anaerobic glycolysis in differentiated tissues. In the presence of O₂, differentiated tissues (no proliferating) metabolize glucose to pyruvate via glycolysis and subsequently completely oxidize pyruvate to CO₂ in the mitochondria (OXPHOS). At low levels of O₂, pyruvate is partially oxidized by glycolysis, generating lactate (anaerobic glycolysis). The generation of lactate results in minimal ATP production when compared with OXPHOS. In contrast, cancer/proliferative cells predominantly produce energy through an increased rate of glycolysis, followed by a reduction of pyruvate into lactate in the cytosol, resulting in a high production of lactic acid. Created by the Authors with BioRender.com. ATP: adenosine triphosphate; OXPHOS: oxidative phosphorylation.

Figure 3

Mechanisms of chemotherapeutic drug resistance in cancer cells. This resistance may be due to intrinsic mechanisms or due to acquired mechanisms, such as the ones listed in the figure.

Figure 4

A simplified schematic diagram of ABC transporter overexpression leading to drug resistance in cancer cells. The ABC proteins (green) reduce intracellular drug concentration by actively transporting ABC substrate drugs (blue circles) out of the cancer cell, which leads to the MDR phenotype. Created by the Authors with BioRender.com. ABC: ATP-binding cassette; MDR: multidrug resistance.

Figure 5

Metabolic alterations underlying the development of cancer cell drug resistance. Glycolysis upregulation is associated with ATP production and ABC transporter activity, leading to the reduced sensitivity of cells to chemotherapeutic agents. In addition, the low pH of TME, promoted by lactate accumulation and transported out of the cell by MCTs, reduces the therapeutic agent. Created by the Authors with BioRender.com. ABC: ATP-binding cassette; ATP: adenosine triphosphate; MCTs: monocarboxylate transporters; TME: tumor microenvironment.

Figure 6

Metabolic modulation as an approach to overcome drug resistance. Glucose and glutamine metabolism, in tumor cells, supply vital components for the high requirements of both glycolysis and OXPHOS. The different compounds (IAA and 2DG) are glycolytic inhibitors. DCA inhibits PDK, reactivating PDH, and switching the metabolism from glycolysis towards OXPHOS. CCP is an uncoupler that inhibits ATP synthesis. The depletion of cancer cell energy probably leads to the inactivation of the pumps’ ABC transporters. Created by the Authors with BioRender.com. 2DG: 2-deoxyglucose; ABC: ATP-binding transporter; ATP: adenosine triphosphate; CCP: Carbonyl Cyanide m-chlorophenyl Hydrazone; DCA: dichloroacetate; IAA: iodoacetate; OXPHOS: oxidative phosphorylation; PDH: pyruvate dehydrogenase.

Figure 7

Schematic representation of nanoparticles as a drug delivery vehicle into cancer cells. The drug can be dissolved, entrapped, encapsulated, or attached to a nanoparticle matrix in order to promote therapeutic absorption, particularly in oncology. Once inside the cell, the nanoparticle is degraded through intracellular signals in order to release the drug. Created by the Authors with BioRender.com.