Redox Control of Multidrug Resistance and Its Possible Modulation by Antioxidants

Figure 1

Inherited and acquired multiple drug resistance. (a) In the inherited multiple drug resistance (MDR), chronic exposure of normal cells to low levels of unknown xenobiotics (XB) or/and endobiotics (EB) takes place. It causes upregulation of ATP-binding cassette transporters such as P-glycoprotein (P-gp), MDR proteins (MDRs), and multiple xenobiotic resistance (MXR) without induction by anticancer drugs. Single nucleotide polymorphisms of phase I and II metabolic enzymes and efflux transporters often accompany inherited MDR and they could also be a causative reason for the resistance. Reactive oxygen species-mediated modulation of xenobiotics/drug metabolism is similar to that in the acquired drug resistance. This cellular pattern seems to be associated with high risk of tumour transformation. ROS: reactive oxygen species; MDR: multiple drug resistance transporters; MXR: multiple xenobiotic resistance transporters; P-gp: P-glycoprotein; CYP: cytochrome P450; HO1: hemeoxygenase-1; SOD: superoxide dismutase; CAT: catalase; GPx: glutathione peroxidase; PI3K: phosphatidylinositol-3 kinase; AhR: aromatic hydrocarbon receptor; NF-κB: nuclear factor kappa B; AP-1: activator protein 1; NR: nuclear receptor; Nrf2: nuclear factor erythroid-derived 2-related factor 2; ARE: antioxidant responsive elements. (b) In the acquired MDR, chemotherapeutics induce redox-dependent MDR expression and activity in tumour cells. Chemotherapeutics activate also aromatic hydrocarbon receptor- (AhR-) driven and ROS-regulated expression of transcriptional factors (nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1)) which initiate inflammatory response. Reactive oxygen species (ROS) mediate activation of phosphoinositol-3 kinase upstream of inflammatory cytokine transcription and synthesis. ROS and AhR-associated stimulation of Nrf2 followed by antioxidant responsive element of DNA motif causes upregulation of protective, antioxidant, and detoxifying systems, such as antioxidant phase I and II enzymes.

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