Metabolic Reprogramming During Multidrug Resistance in Leukemias

Abstract

Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR) phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.

The roles of glucose metabolic reprogramming in chemo- and radio-resistance

“…With the increasing research understanding on the resistance of chemo- and radiotherapy, the researchers have pointed out that cancer stem cells, tumor microenvironment, autophagy, and exosomes are all closely related to tumor chemo- and radio-resistance. In fact, recent reports have shown that chemo- and radio-resistance acquisition is coupled to deregulate glucose metabolism and glycolysis [35]. Signaling pathways related to chemo-radiotherapy resistance are abnormally activated or inactivated during metabolic stress, such as Wnt, PI3K/AKT, Notch, NF-κB, MAPK [36–41].…”

Glycolysis-induced drug resistance in tumors—A response to danger signals?

“…These precursors are required for rapidly proliferating tumor cells [9] . Second, the rate of glycolysis is much faster than that of OXPHOS [10 , 11] . This may be particularly advantageous in situations where a sudden increase of energy demand occurs, like in tumor cells undergoing an epithelial-mesenchymal transition (EMT) [12 , 13] .…”

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

“…These connections are especially interesting given the rapidly growing evidence that RB1 is needed for cells to maintain a normal metabolic balance, and that the loss of RB1 leads to reprogramming of specific pathways [70][71][72] . Metabolic adaptations are thought to enhance the ability of cancer cells to sustain the metabolic intermediates for cell survival during multidrug resistance 73,74 . Our results outline a clinically feasible scenario to use RB1 as a biomarker to stratify the TNBC patients for targeted therapy.…”