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.

Keywords: cancer; drug resistance; metabolic adaptation; reactive oxygen species.

Figure 1

Interplay between reactive oxygen species (ROS) and the central carbon metabolism. ROS impact cellular metabolism through regulating key enzymes in glycolysis pathway/TCA cycle as well as redox signaling pathways; reciprocally, energy metabolic pathways especially PPP balance ROS homeostasis in cancer cells. PPP, pentose phosphate pathway; HK, hexokinase; PFK1, phosphofructokinase 1; PDK1, pyruvate dehydrogenase kinase; G6PD, glucose 6-phosphate dehydrogenase; Aco, aconitase; αKGDH, Alpha ketoglutarate dehydrogenase; IDH, isocitrate dehydrogenase; ME1, malic enzyme 1.

Figure 2

Metabolic deregulations lead to drug resistance. The metabolic shift favors cancer cell proliferation and survival in response to therapy via upregulation of DNA repair, increase of prosurvival signaling and autophagy, activation of drug efflux pumps, and neutralization of ROS.