Reactive Oxygen Species, Metabolic Plasticity, and Drug Resistance in Cancer

Abstract

The metabolic abnormality observed in tumors is characterized by the dependence of cancer cells on glycolysis for their energy requirements. Cancer cells also exhibit a high level of reactive oxygen species (ROS), largely due to the alteration of cellular bioenergetics. A highly coordinated interplay between tumor energetics and ROS generates a powerful phenotype that provides the tumor cells with proliferative, antiapoptotic, and overall aggressive characteristics. In this review article, we summarize the literature on how ROS impacts energy metabolism by regulating key metabolic enzymes and how metabolic pathways e.g., glycolysis, PPP, and the TCA cycle reciprocally affect the generation and maintenance of ROS homeostasis. Lastly, we discuss how metabolic adaptation in cancer influences the tumor’s response to chemotherapeutic drugs. Though attempts of targeting tumor energetics have shown promising preclinical outcomes, the clinical benefits are yet to be fully achieved. A better understanding of the interaction between metabolic abnormalities and involvement of ROS under the chemo-induced stress will help develop new strategies and personalized approaches to improve the therapeutic efficiency in cancer patients.

Oxidative Pentose Phosphate Pathway Enzyme 6-Phosphogluconate Dehydrogenase Plays a Key Role in Breast Cancer Metabolism

“…In addition, we aimed to investigate the relation between p53 activation and PPP, since p53 has several vital functions in cellular metabolism, among which are cell cycle regulation, apoptosis induction, regulation of glycolysis and PPP, and cellular senescence [ 29 , 30 , 31 ]. Because of the high reliance of breast cancer cells on PPP and their dependence on ROS detoxification to manage oxidative stress and maintain their survival [ 11 , 22 , 32 ], we targeted 6PGD in MCF7. MCF7 is an estrogen and progesterone receptor (ER and PR, respectively) positive, and a human epidermal growth factor receptor 2 (HER2) negative cell line [ 33 ].…”

Oxidative Stress and DNA Damage in Chronic Disease and Environmental Studies

“…The review by Bhardwaj et al [ 8 ] addressed the study of abnormal energy metabolism in cancer cells that show a dependence on glycolysis, a cytoplasmic pathway that generates ATP, rather than on mitochondrial oxidative phosphorylation in the presence of oxygen for their energy requirement. In tumors, energy metabolic alterations are associated with the high production of ROS levels, which need to be kept under certain limits by increasing the action of the glycolysis pathway, the pentose phosphate pathway and the tricarboxylic acid cycle in order to maintain redox homeostasis and to prevent ROS-mediated cancer cell death.…”

Protopine/Gemcitabine Combination Induces Cytotoxic or Cytoprotective Effects in Cell Type-Specific and Dose-Dependent Manner on Human Cancer and Normal Cells

“…On the whole, these results indicate that PRO exhibits pro-oxidant or antioxidant properties, depending on dose and cell type [ 26 , 49 ]. Recent evidence demonstrates that prolonged chemotherapy reduces the overall cellular ROS in cancer, and this reduction may contribute to the mechanism of drug resistance [ 50 , 51 ], including that of PDAC to GEM [ 52 ]. For these reasons, to avoid chemoresistance, the use of compounds able to overcome the antioxidant mechanisms and to promote high levels of ROS represents one promising therapeutic strategy to induce cancer cell death and inhibit cancer progression [ 53 , 54 , 55 ].…”

“…Notably, PRO/GEM treatments caused both intracellular and mitochondrial ROS increase in HDFs (up to 350.7 ± 12.2%) without causing viability decline. Because normal cells produce less ROS than cancer cells and have efficient antioxidant systems [ 50 ], it is possible that an antioxidant response is activated in HDFs following the ROS induction due to PRO/GEM combinations. Further experiments will be necessary to confirm the oxidative stress resistance of these cells.…”