Therapeutic Implication of Oxidative Stress Regulators in Drug-Resistant Cancers

Abstract

Although initial clinical responses to current standard chemotherapies are often dramatic, a significant number of cancer patients develop drug resistance after a certain period of treatment. Recently, drugs targeting redox homeostasis have emerged as an appealing strategy to antagonize drug resistance in cancer treatment. Redox homeostasis refers to the overall balance between oxidative stress producing and eliminating systems. Generally, drug-resistant cancer cells have high oxidative stress due to the high level of reactive oxygen species (ROS) induced by chemotherapeutic drugs. Consequently, the ROS elimination systems, which are majorly composed of different types of reductases, remain active in order to counter the ROS-induced cell death. Thus, the ROS regulators that adjust the redox homeostasis hold potential in killing drug-resistant cancer cells and sensitizing both conventional chemotherapeutics and targeted therapies. In this chapter, we discussed some important players/proteins in regulating oxidative stress, including respiratory chain complexes in mitochondria and the major organelles that generate ROS; NADPH oxidases (NOXs); glutathione-related proteins such as gamma-glutamylcysteine synthetase (γ-GCS), glutathione peroxidase (GPx), glutathione S-transferases (GST), and glutamate/cystine antiporter solute carrier family 7 member 11 (SLC7A11); and antioxidant proteins thioredoxin reductases (TrxR), superoxide dismutase (SOD), peroxiredoxins (Prxs), and others. These oxidative stress-related proteins are usually dysregulated and/or upregulated in drug-resistant cancer cells; accordingly, their disturbance by varied drugs or silence by si/shRNA may lead to re-sensitization of certain chemotherapeutics, suggesting that they could be druggable targets. Small-molecule drugs in regulating these proteins, particularly those under clinical trials, and their mechanisms are the focus of this chapter.KeywordsDrug resistanceRedox homeostasisOxidative stress regulatorsSensitizing agents