Redox-Mediated Mechanism of Chemoresistance in Cancer Cells

Abstract

Cellular reactive oxygen species (ROS) status is stabilized by a balance of ROS generation and elimination called redox homeostasis. ROS is increased by activation of endoplasmic reticulum stress, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family members and adenosine triphosphate (ATP) synthesis of mitochondria. Increased ROS is detoxified by superoxide dismutase, catalase, and peroxiredoxins. ROS has a role as a secondary messenger in signal transduction. Cancer cells induce fluctuations of redox homeostasis by variation of ROS regulated machinery, leading to increased tumorigenesis and chemoresistance. Redox-mediated mechanisms of chemoresistance include endoplasmic reticulum stress-mediated autophagy, increased cell cycle progression, and increased conversion to metastasis or cancer stem-like cells. This review discusses changes of the redox state in tumorigenesis and redox-mediated mechanisms involved in tolerance to chemotherapeutic drugs in cancer.

Keywords: 5-Fluorouracil; antioxidant proteins; chemoresistance; oxaliplatin; reactive oxygen species.

Figure 1

Redox homeostasis between generation and elimination of reactive oxygen species (ROS). ROS production is regulated by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) in membranes, the electron transport chain (ETC) of the adenosine triphosphate (ATP) synthesis process in mitochondria, and the protein synthesis process in endoplasmic reticulum (ER) during O₂ consumption. Alternative levels of ROS induce DNA damage or transcription factors (TFs)-mediated gene expression in the nucleus. The superoxide anion (O₂•⁻) produced intracellularly is neutralized to hydrogen peroxide (H₂O₂) by the superoxide dismutase (SOD) family. H₂O₂ are detoxified to H₂O by catalase and peroxiredoxin (Prx). ROS regulate cellular processes such as proliferation, apoptosis, chemoresistance, and differentiation through a variety of signaling pathways.

Figure 2

Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates redox-homeostasis and chemoresistance in cells. Nrf2 induces antioxidant proteins such as superoxide dismutase (SOD), catalase (CAT), peroxiredoxin (Prx), glutathione reductase (GR), thioredoxin reductase (TR), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO). Multidrug resistance protein 1 (MRP1) and breast cancer resistance protein/ATP-binding cassette subfamily G member 2 (BCRP/ABCG2) are related with drug transport and are upregulated by activation of Nrf2.

Figure 3

Redox homeostasis between generation and elimination of ROS. Cancer cells increase ROS-mediated apoptosis when exposed to chemotherapy treatments. Some cancer cells adapt to fluctuating ROS states through chemoresistance mechanisms. Activation of autophagy by ER stress gets rid of damaged organelles and protein aggregation. Cell cycle activation by the ignored entrance of the G0 phase increases cell proliferation in cancers. Epithelial-mesenchymal transition (EMT) enhances migration to other organs for the escapement of damaging environments. Cancer stem-like cells (CSCs) increase the expression of drug metabolic enzymes/transporters for cell survival from drug-mediated apoptosis. The specific microenvironment, called the niche, of CSCs are protected from chemotherapy. These mechanisms lead to the birth of chemoresistant cancer cells.