title: Redox Control of Multidrug Resistance and Its Possible Modulation by Antioxidants.
abstract: Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic enzymes with a temporal redox-regulated axis. This results in rapid metabolic transformation and elimination of a toxin. This metabolic axis is tightly interconnected with the inducible Nrf2-linked pathway, a key switch-on mechanism for upregulation of endogenous antioxidant enzymes and detoxifying systems. As a result, chemotherapeutics and cytotoxic by-products of their metabolism (ROS, hydroperoxides, and aldehydes) are inactivated and MDR occurs. On the other hand, tumour cells are capable of mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells. The multiple redox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) or inhibitors of inducible antioxidant defence as a novel approach to diminish MDR. Pitfalls and progress in this direction are discussed.
authors.affiliation: Department of Nutrition and Dietetics, Faculty of Health Sciences, Sanko University, İncili Pınar, Gazi Muhtar Paşa Bulvarı, Sehitkamil, 27090 Gaziantep, Turkey.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Cort
authors.affiliation: Department of Biochemistry, Akdeniz University Medical Faculty, Campus, Dumlupınar Street, 07070 Antalya, Turkey.
authors.forename: Tomris
authors.initials: T
authors.lastname: Ozben
authors.affiliation: Department of Physiology and Pharmacology "Vittorio Erspamer", La Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
authors.affiliation: Evidence-Based Well-Being (EB-WB) Ltd., 31 Alt-Stralau, 10245 Berlin, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Luca
authors.affiliation: Centre of Innovative Biotechnological Investigations Nanolab, 197 Vernadskogo Prospekt, Moscow 119571, Russia.
authors.forename: Liudmila
authors.identifier: 0000-0003-3887-8866
authors.initials: L
authors.lastname: Korkina
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000447:Aldehydes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007249:Inflammation; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D015398:Signal Transduction; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000447:Aldehydes; D000970:Antineoplastic Agents; D000975:Antioxidants; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C495635:NFE2L2 protein, human; C095122:multidrug resistance protein 3