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.

The cancer metabolic reprogramming and immune response

“…It is now clear that the high utilization rate of glutamine in many immune cells is related to the functional activity of immune cells, such as cell proliferation, antigen presentation, synthesis and secretion of cytokines, production of NO and peroxide, phagocytosis, etc. These functions are all indirectly or directly dependent on NADPH reserves [78]. Moreover, glutamine has a high utilization rate in macrophages, and neutrophils.…”

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

“…The glucometabolic reprogramming that occurs in many cancer cells, and in other diseased cells as well [ 1 , 2 ], shifts ATP production away from the mitochondria and into the cytosol; this can occur even when ample oxygen is available and is referred to as aerobic glycolysis or the Warburg effect [ 3 , 4 ]. This change permits cancer cells to rapidly proliferate since it is accompanied by the upregulation of the pentose phosphate pathway (also known as the phosphogluconate pathway or the hexose monophosphate shunt) which provides abundant amounts of ribose-5-phosphate, a necessary constituent that supports nucleotide production [ 5 , 6 ]. Under these conditions, amino acids are also more rapidly converted to proteins [ 7 , 8 ].…”

Lipid Metabolism and Resistance to Anticancer Treatment

“…Cancer cells need to reprogram their metabolism to produce enough ATP and intermediates for macromolecular biosynthesis, to meet requirements of intense cell proliferation. Changes in cellular metabolism not only result in tumor progression, but also contribute to aggressiveness features such as invasion, metastasis and cancer cell resistance to treatments [ 2 , 3 , 4 ]. In addition, cancer cells can use different metabolic programs depending on the environment.…”