A number of dietary polyphenols with redox properties (resveratrol, quercetin, curcumin, etc.), indoles, tryptophane metabolites, bilirubin, and oxidised products of lipid metabolism have been suggested as nontoxic ligands-activators or ligandsinhibitors of AhR expression by competitive and noncompetitive pathways [181, 182]. If ligands-activators of AhR are regarded as potential anti-inflammatory agents [181?84], redox-active ligands able to suppress AhR expression/ functions could be candidates for MDR reversals. For example, 7-ketocholesterol, a major dietary oxysterol, may actually strongly inhibit AhR activation [185]. Alphanaphthoflavone is considered as a classical AhR antagonist blocking activation of XRE-containing reporter gene and Cyp1 upregulation in hepatoma cells [186]. However, alphanaphthoflavone is also a partial agonist of AhR and acts as a competitive inhibitor exclusively in the presence of another agonist. Recently, more selective pure ligands-antagonists of AhR have been developed such as 2-methyl-2H-pyrazole-3carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide, 3 methoxy-4 -nitroflavone, 3 ,4 -dimethoxyflavone, and 6,2 , 4 -trimethoxyflavone. These were able to block the induction of Cyp1A1-dependent ethoxyresorufin O-deethylase (EROD) activity [187?90]. They all belong to redox-active flavones and after proper clinical Necrostatin-1 site studies on safety and efficacy could be feasible for combinatory anticancer therapy to combat MDR. Among a number of plant polyphenols used for topical application, exclusively the phenylpropanoid verbascoside and flavonoid quercetin proved to be strong inhibitors ofOxidative Medicine and Cellular Longevity UV- or FICZ-upregulated AhR-Cyp1A1-Cyp1B1 axis in human keratinocytes [184], AG-490 web suggesting their potency as topical MDR suppressors/reversals.4. ConclusionsThe multiple pleiotropic interactions of redox-active molecules so far demonstrated on the molecular pathways controlling cellular MDR, from xenobiotic cellular uptake inhibition to the modulation of phase I/II enzyme detoxification, to the inhibition of Toll-like receptor activation and/or AhR expression and function, provide a consistent rationale for the necessity of more intense and systematic research efforts in the field of anti-/prooxidant adjuvants for anticancer chemotherapy, to attempt clinically effective MDR inhibition with tolerable toxicity. The design and implementation of more selected and targeted clinical studies centred on redox-active candidate MDR-interfering molecules will possibly contribute to overcoming the presently dominating clinical practice, which confers a constantly growing interest in redox modulators and antioxidants as a mere palliative against the potent cytotoxicity of conventional and biologic anticancer drugs.AbbreviationsATP-binding cassette Aryl hydrocarbon receptor Protein kinase B Activator protein 1 Antioxidant response element Apoptosis regulator Bcl-2 Breast cancer resistance protein Catalase Catechol-O-methyl transferase Cytochrome P450 Extensive Metabolisers FADD-like IL-1beta-converting enzyme inhibitory protein GPx: Glutathione peroxidase GSH/GSSG: Reduced glutathione/oxidised glutathione GST: Glutathione-S-transferase JNK1: c-Jun N-terminal kinase 1 Keap 1: Kelch-like ECH-associated protein 1 MDR: Multiple drug resistance MMP: Matrix metalloproteinase mTOR: Mammalian target of rapamycin MXR: Multiple xenobiotic resistance NADPH: Nicotinamide dinucleotide phosphate, reduced form NAT: N-Acetyl t.A number of dietary polyphenols with redox properties (resveratrol, quercetin, curcumin, etc.), indoles, tryptophane metabolites, bilirubin, and oxidised products of lipid metabolism have been suggested as nontoxic ligands-activators or ligandsinhibitors of AhR expression by competitive and noncompetitive pathways [181, 182]. If ligands-activators of AhR are regarded as potential anti-inflammatory agents [181?84], redox-active ligands able to suppress AhR expression/ functions could be candidates for MDR reversals. For example, 7-ketocholesterol, a major dietary oxysterol, may actually strongly inhibit AhR activation [185]. Alphanaphthoflavone is considered as a classical AhR antagonist blocking activation of XRE-containing reporter gene and Cyp1 upregulation in hepatoma cells [186]. However, alphanaphthoflavone is also a partial agonist of AhR and acts as a competitive inhibitor exclusively in the presence of another agonist. Recently, more selective pure ligands-antagonists of AhR have been developed such as 2-methyl-2H-pyrazole-3carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide, 3 methoxy-4 -nitroflavone, 3 ,4 -dimethoxyflavone, and 6,2 , 4 -trimethoxyflavone. These were able to block the induction of Cyp1A1-dependent ethoxyresorufin O-deethylase (EROD) activity [187?90]. They all belong to redox-active flavones and after proper clinical studies on safety and efficacy could be feasible for combinatory anticancer therapy to combat MDR. Among a number of plant polyphenols used for topical application, exclusively the phenylpropanoid verbascoside and flavonoid quercetin proved to be strong inhibitors ofOxidative Medicine and Cellular Longevity UV- or FICZ-upregulated AhR-Cyp1A1-Cyp1B1 axis in human keratinocytes [184], suggesting their potency as topical MDR suppressors/reversals.4. ConclusionsThe multiple pleiotropic interactions of redox-active molecules so far demonstrated on the molecular pathways controlling cellular MDR, from xenobiotic cellular uptake inhibition to the modulation of phase I/II enzyme detoxification, to the inhibition of Toll-like receptor activation and/or AhR expression and function, provide a consistent rationale for the necessity of more intense and systematic research efforts in the field of anti-/prooxidant adjuvants for anticancer chemotherapy, to attempt clinically effective MDR inhibition with tolerable toxicity. The design and implementation of more selected and targeted clinical studies centred on redox-active candidate MDR-interfering molecules will possibly contribute to overcoming the presently dominating clinical practice, which confers a constantly growing interest in redox modulators and antioxidants as a mere palliative against the potent cytotoxicity of conventional and biologic anticancer drugs.AbbreviationsATP-binding cassette Aryl hydrocarbon receptor Protein kinase B Activator protein 1 Antioxidant response element Apoptosis regulator Bcl-2 Breast cancer resistance protein Catalase Catechol-O-methyl transferase Cytochrome P450 Extensive Metabolisers FADD-like IL-1beta-converting enzyme inhibitory protein GPx: Glutathione peroxidase GSH/GSSG: Reduced glutathione/oxidised glutathione GST: Glutathione-S-transferase JNK1: c-Jun N-terminal kinase 1 Keap 1: Kelch-like ECH-associated protein 1 MDR: Multiple drug resistance MMP: Matrix metalloproteinase mTOR: Mammalian target of rapamycin MXR: Multiple xenobiotic resistance NADPH: Nicotinamide dinucleotide phosphate, reduced form NAT: N-Acetyl t.