Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Abstract

Inhibition of metabolic features which distinguish cancer cells from their non-malignant counterparts is a promising approach to cancer treatment. Energy support for drug extrusion in multidrug resistance (MDR) is a potential target for metabolic inhibition. Two major sources of ATP-based metabolic energy are partial (glycolysis) and complete (mitochondrial oxidative phosphorylation) oxidation of metabolic fuels. In cancer cells, the balance between them tends to be shifted toward glycolysis; this shift is considered to be characteristic of the cancer metabolic phenotype. Numerous earlier studies, conducted with cells cultured in a monolayer (2-D model), suggested inhibition of glycolytic ATP production as an efficient tool to suppress MDR in cancer cells. Yet, more recent work challenged the appropriateness of the 2-D model for such studies and suggested that a more clinically relevant approach would utilize a more advanced cellular model such as a 3-D model. Here, we show that the transition from the 2-D model (cultured monolayer) to a 3-D model (cultured spheroids) introduces essential changes into the concept of energetic suppression of MDR. The 3-D cell organization leads to the formation of a discrete cell subpopulation (not formed in the 2-D model) with elevated MDR transport capacity. This subpopulation has a specific metabolic phenotype (mixed glycolytic/oxidative MDR support) different from that of cells cultured in the 2-D model. Finally, the shift to the oxidative phenotype becomes greater when the spheroids are grown under conditions of lactic acidosis that are typical for solid tumors. The potential clinical significance of these findings is discussed.

Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles

“…For this reason, glycolysis inhibition has attracted significant interest as a possible way to sensitize cancer cells to chemotherapy. Indeed, several studies in different cancer models have demonstrated an efficient suppression of MDR by glycolytic inhibitors823244445. Moreover, during the course of this work another study has suggested the possibility of an accelerated process of glycolysis in MDR cells to increase their energy supply46.…”

Electrical impedance tomography for real-time and label-free cellular viability assays of 3D tumour spheroids

“…where ε * c is the complex permittivity of the cytoplasm, ε * m is the complex permittivity of the cell membrane and 3 , in which r is the outer radius of the cell and d m is the thickness of the membrane.…”

“…There is currently a need to move away from traditional twodimensional (2D) cell culture towards cell culture systems that better mimic the behaviour of cells growing in the natural environment. 1,2 For instance, three-dimensional (3D) tumour cells are considered to have higher radio-and chemo-resistance than cancer cells cultured at 2D because of the 3D cellcell and cell-matrix interactions, 3,4 which is pointed out as one of the most important reasons for the low success rate in anticancer drug discovery and development. 5 Because 3D spheroid culture models are closer to an in vivo like morphology, they can better reflect the biological mechanisms of cell migration, differentiation and viability.…”

Apoptosis and cell cycle arrest of hepatocellular carcinoma spheroids treated by an alternating electric field

“…Cancer cells cultured in a 3D environment can proliferate into multicellular spheroids, called tumor spheroids or cell colonies. Because cells cultured in a 3D environment exhibited greater drug resistance then cells in a monolayer, greater accuracy of the prediction of clinical efficacy can be obtained during drug development . This culture technique has become a standard assay to study the development of early tumors and the cytotoxic effects of drugs on tumors …”