![]() ![]() ![]() Singlet oxygen is the first excited state of the dioxygen molecule and is part of the ROS species generated during the OXPHOS process. In perspective of this study, we propose that the cancer metabolic phenotype or Warburg effect could be relieved by the controlled generation of mitochondrial singlet oxygen ( 1O 2). ![]() We specially focused on the involvement of mitochondria regarding the metabolic adaptation of cancer cells to escape from apoptosis and promote, in some way, cancer recurrence ( 12). Here, we bring an overview of the common therapeutic approaches such as chemotherapy to circumvent tumor progression and limits thereof. However, many more recent studies have demonstrated the integrity of mitochondria in cancer cells ( 10, 11). Warburg showed that cancer cells in culture have higher rates of glucose consumption and lactate secretion compared to normal cells and hypothesized mitochondrial dysfunction to explain this glycolytic phenotype. As far as cancer cells are concerned, they favor the glycolysis pathway for energy production, even in oxygenated environment, referred as aerobic glycolysis or “Warburg effect” named after the German physician and biochemist Otto Heinrich Warburg who first reported this observation ( 7– 9). Under hypoxic conditions, they produce only 2 molecules of ATP through glycolysis and release 2 molecules of lactic acid. In presence of oxygen, healthy cells use glucose to produce about 30 molecules of mitochondrial oxidative phosphorylation ATP. Transposed to game theory, the metabolism of healthy cells and cancer cells are distinguished by the way they produce energy in the form of ATP. This competition is similar to game theory as introduced by John von Neumann ( 5) then applied to biology by John Maynard Smith ( 6). In this way, competition arises between cancer cells and somatic cells for access to nutrients, specially to glucose, and oxygen. The other common point between cancer cells and pathogenic organisms is their dependence on metabolism of healthy cells and the irrigation of nutrients by the blood system to ensure their replication ( 4). Every day tens thousands of cancer cells are formed but are also soon eliminated by the immune system ( 3). Human body is made up of 10,000–100,000 billion cells. These living organisms use oxygen as oxidizing agents to retrieve energy from reduced compounds ( 2). Nowadays, the atmosphere of Earth is composed of 21% oxygen and used by most organisms for respiration (animals, plants, and many prokaryotes). Oxygen is “the molecule that made the world” stated Lane in his seminal book ( 1). We therefore propose that cancer cells mitochondrial singlet oxygen ( 1O 2) dynamics may be an efficient target for metabolic therapy development. Our conclusion, while integrating literature, is that mitochondrial activity and, in particular, the activity of cytochrome c oxidase, complex IV of the ETC, plays a fundamental role in the effectiveness or non-effectiveness of chemotherapy, immunotherapy and probably radiotherapy treatments. Indeed, the idea that cancer is a metabolic disease with mitochondria as the central site of the pathology is now emerging, and we provide here a review supporting this “novel” hypothesis re-actualizing past century Otto Warburg's thoughts. Conventional cancer treatments such as chemotherapy, which mainly focus on disrupting the cell division process, have shown being effective in the attenuation of various cancers but also showing significant limits as well as serious sides effects. However, its dysfunction is now also seen as the most probable cause of one of the biggest scourges in human health, cancer. The occurrence of mitochondrial respiration has allowed evolution toward more complex and advanced life forms. 2Assistance Publique des Hôpitaux de Paris, Paris, France.1Research Laboratory in Applied Metabolic Engineering, Department of Chemical Engineering, Polytechnique Montréal, Montréal, QC, Canada.Jorgelindo da Veiga Moreira 1 * †, Laurent Schwartz 2 and Mario Jolicoeur 1 ![]()
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