Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Abstract

Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation.

Keywords: chemoresistance; drug resistance; metabolic regulation; metabolic reprogramming; reversal of chemoresistance.

Figure 1

Mechanisms of acquired tumor drug resistance. Some of the reasons for acquired drug resistance are common to many drugs, and others may be drug-specific or pathway-specific. They are all related to the expression and function of specific genes. The pathway-specific mechanisms usually involve the restoration of the tumor-driving signaling pathway.

Figure 2

Proposed metabolic mechanisms of drug resistance. The development of drug resistance involves several aspects of metabolism, including the enhancement of glucose and glutamine uptake; active glutaminolysis, glycolysis, pentose phosphate pathway, and fatty acid oxidation; polyamine production; and adaptive mitochondrial reprogramming. NADPH, reduced form of nicotinamide adenine dinucleotide phosphate.

Figure 3

Targeting several key enzymes or proteins (green ellipses) are potential to re-sensitize the resistant tumor cells to chemotherapeutic agents (purple font). Targets marked with green ellipses involve multiple metabolic pathways, including glutaminolysis, transport and glycolysis of glucose, pentose phosphate pathway, fatty acid oxidation, pyruvate dehydrogenation, and production of polyamine. The drugs that can be metabolically regulated are highlighted with purple font. 6PGD, 6-phosphogluconate dehydrogenase; CDDP, cisplatin; CoA, coenzyme A; CPT, carnitine palmitoyltransferase; ENO, enolase; G6PDH, glucose-6-phosphate dehydrogenase; GLS, glutaminase; GLUT1, glucose transporter protein 1; LDHA, lactate dehydrogenase A; ODC, ornithine decarboxylase; PDK, pyruvate dehydrogenase kinase.