Redox Potential of Antioxidants in Cancer Progression and Prevention

Abstract

The benevolent and detrimental effects of antioxidants are much debated in clinical trials and cancer research. Several antioxidant enzymes and molecules are overexpressed in oxidative stress conditions that can damage cellular proteins, lipids, and DNA. Natural antioxidants remove excess free radical intermediates by reducing hydrogen donors or quenching singlet oxygen and delaying oxidative reactions in actively growing cancer cells. These reducing agents have the potential to hinder cancer progression only when administered at the right proportions along with chemo-/radiotherapies. Antioxidants and enzymes affect signal transduction and energy metabolism pathways for the maintenance of cellular redox status. A decline in antioxidant capacity arising from genetic mutations may increase the mitochondrial flux of free radicals resulting in misfiring of cellular signalling pathways. Often, a metabolic reprogramming arising from these mutations in metabolic enzymes leads to the overproduction of so called 'oncometabolites' in a state of 'pseudohypoxia'. This can inactivate several of the intracellular molecules involved in epigenetic and redox regulations, thereby increasing oxidative stress giving rise to growth advantages for cancerous cells. Undeniably, these are cell-type and Reactive Oxygen Species (ROS) specific, which is manifested as changes in the enzyme activation, differences in gene expression, cellular functions as well as cell death mechanisms. Photodynamic therapy (PDT) using light-activated photosensitizing molecules that can regulate cellular redox balance in accordance with the changes in endogenous ROS production is a solution for many of these challenges in cancer therapy.

Keywords: antioxidants; cancer; redox potential.

Figure 1

Redox potential of antioxidants: In healthy cells, oxide free radicals generated from mitochondria and cell membrane NADPH Oxidases (NOX) are detoxified by the endogenous antioxidants, catalases (CAT), Glutathione Peroxidases (GPx) and Superoxide Dismutases (SOD). A constitutively low level of Reactive Oxygen Species (ROS) stimulate Protein Kinases (PK) B/C for maintaining cellular homeostasis while, higher levels can result in the change in mitochondrial membrane potential leading to apoptosis or cell death. Cancer cells have higher levels of oxidative stress as compared to the normal cells allowing them to activate several signaling pathways and transcription factors. Any imbalances in the redox-sensitive signaling pathways, Mitogen Activated Protein Kinases (MAPK) and PK B/C may result in the tumor growth. The Ras-Raf-MEK-ERK pathway (also known as the MAPK/ERK pathway) is the signaling cascade from cell membrane receptor complex to the nucleus. During excessive oxidative stress, Apoptosis Signal-regulating Kinase 1 (Ask1) induces apoptosis by activating c-Jun N-terminal Kinases (JNK) and p38 MAPK pathways. It may also lead to the inactivation and proteolytic degradation of PK molecules leading to the initiation of apoptosis or cell death signaling. The redox regulation of cellular oxidative stress is achieved either by activation or repression of the antioxidant genes through several transcription factors, acting individually or in combination. Objects in RED show the pathways activated directly by oxides radicals and the objects in GREEN indicate pathways regulating the cellular antioxidant mechanisms. Abbreviations: cAMP, cyclic Adenosine Monophosphate; ATP, Adenosine Triphosphate; ERK, Extracellular Signal-regulated Kinases; O₂, oxygen.

Figure 2

Metabolic regulation of antioxidants: Highly proliferative cancer cells rely on glycolysis to meet its exceedingly high energy demands. Activation of Hypoxia inducible factor-1 (Hif-1) cause the suppression of Pyruvate Dehydrogenase (PDH) resulting in the opening up of glucose transporters and increase in the flux of glucose in glycolytic cycle. During hypoxia, Hif-1 switches cell gene expressions from glycolysis to production and utilization of lactates (Warburg effect). The oncometabolites, fumerate and succinate may act on Hif-1 for inducing a ‘pseudohypoxic’ response. Besides, mutations in p53 attenuate TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) causing a lack of inhibition on the Glucose-6-Phosphate Dehydrogenase (G6PD) enzyme activity leading to the increase in the metabolic flux through glycolytic and Pentose Phosphate Pathway (PPP). The D-2-hydroxyglutarate (D2HG) and the L-2-hydroxyglutarate (L2HG) are enantiomers of the metabolite 2-HG arising from the mutations in the Isocitrate Dehydrogenase 1/2/3 (IDH1/2/3). Eventually, these changes may cause altered metabolic flux responsible for the initiation of neoplasms. Thick solid lines indicate strong and dotted lines indicate weak flux of metabolites. Abbreviations: HK, Hexokinase; G-6-P, Glucose-6-Phosphate; LDH, Lactic Dehydrogenase.