Abstract
The metabolic features of tumor cells diverge from those of normal cells. Otto Warburg was the first to observe that cancer cells dramatically increase their glucose consumption to generate ATP. He also claimed that cancer cells do not have functional mitochondria or oxidative phosphorylation (OXPHOS) but simply rely on glycolysis to provide ATP to the cell, even in the presence of oxygen (aerobic glycolysis). Several studies have revisited this observation and demonstrated that most cancer cells contain metabolically efficient mitochondria. Indeed, to sustain high proliferation rates, cancer cells require functional mitochondria to provide ATP and intermediate metabolites, such as citrate and cofactors, for anabolic reactions. This difference in metabolism between normal and tumors cells causes the latter to be more sensitive to agents that can disrupt energy homeostasis. In this review, we focus on energy disruptors, such as biguanides, 2-deoxyglucose and 5-aminoimidazole-4-carboxamide ribonucleotide, that interfere with the main metabolic pathways of the cells, OXPHOS, glycolysis and glutamine metabolism. We discuss the preclinical data and the mechanisms of action of these disruptors at the cellular and molecular levels. Finally, we consider whether these drugs can reasonably contribute to the antitumoral therapeutic arsenal in the future.
Highlights
Cancer cells are characterized by uncontrolled and rapid proliferation
In the presence of oxygen, glucose is converted via glycolysis into pyruvate, which is transported to the mitochondria to be transformed into acetyl-CoA by pyruvate dehydrogenase for integration into the tricarboxylic acid cycle (TCA)
Encouraging results concerning a small number of patients have in isolated cancer cells, the use of these agents as monotherapy is recently been published
Summary
Cancer cells are characterized by uncontrolled and rapid proliferation. Deregulation of the cell division machinery requires metabolic adjustments to provide macromolecules and energy to fuel cell growth and division. The tumor suppressor LKB1 is required to phosphorylate AMPK in response to biguanides.[12] The following question could be asked: if metformin action requires LKB1 to activate AMPK, and AMPK inhibits mTORC1, what a mechanism by which glutamine provides carbon to the TCA cycle via glutamate and α-ketoglutarate, by metformin further attenuates proliferation. Increasing glutamine metabolism rescues the antiproliferative effects of metformin.[32] Together, these studies demonstrate that cancer cells activate compensatory pathways to counteract the metabolic chaos induced by metformin. These studies demonstrate that cancer cells activate compensatory pathways to counteract the metabolic chaos induced by metformin Targeting these adaptations will improve the effect of biguanides and avoid resistance. Was confirmed in several other cancer models, including pancreas, breast and ovary.[35,36,37] Interestingly, Sancho et al have shown that
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
