Cellular and Molecular Mechanisms of Multiple Drug Resistance (MDR)

Dear Colleagues,

In the course of evolution, living organisms have developed multiple mechanisms of response to harmful chemicals present in the environment. These substances may attack genes (via modification, mutation and degradation of DNA), proteins, phospholipids, sugars and other intracellular components (via sets of modification reactions including radical oxidation). Toxic attack of these substances leads to cell death in the case of lethal concentration. Sub-lethal concentrations of such substances may induce cell adaptation to toxic stress, which will lead to decreased cellular sensitivity and tolerance. Under permanent sublethal toxic pressure cells are able to respond via activation of diverse well-defined cell defensive pathways. Activation of cell defense pathways subsequently leads to an increase in cells' tolerance often resulting in resistance to different chemicals with principally diverse structures and mechanisms of action. Almost all cell types are able to respond this way. The development of drug resistance represents a real obstacle in antimicrobial and anticancer treatment. The above-described decrease in cells' sensitivity to various unrelated drugs is known as multidrug resistance (MDR). Xenobiotic detoxification involves a step-by-step mechanism (detoxification phase I–III). The first step is the conversion of the hydrophobic nature of molecules (which allows the molecule to be easily transported through the cell membrane) to metabolic intermediates that are more water-soluble. The transforming enzymes alter compounds by oxidation, reduction or hydrolysis, to make them either more readily excretable or less pharmacologically active. These reactions are mediated by the versatile cytochrome P450 (CYP) enzymes and the more selective flavin-containing monooxygenases, and monoamine oxidases. Altered compounds are subject to conjugation enzymes in the process of glucuronidation, acetylation, sulfation, glutathione conjugation, acetylation, aminoacyl conjugation or methylation by conjugating enzymes of phase II detoxification. These processes are adjusting the toxic compounds as substrates for the membrane transporters (predominantly from the ABC and MFS family) that ensure their transport out of the cell. These membrane transporters are known as systems of phase III of detoxification.

In addition to drug modification/elimination under phases I–III of cell detoxification, tolerance/resistance of cells against toxic compounds could be influenced by alteration in ER stress development, cell death progression, DNA repair, epigenetics regulation and others. Parallel to these mechanisms, the balance in prooxidation/antioxidation status of cells represents another important feature responsible for the capability of cells to enter the process of death.

We are looking forward to your contributions to this Special Issue.

Dr. Petra Olejníková
Dr. Lucia Bírošová
Prof. Dr. Albert Breier
Prof. Dr. Helena Bujdáková
Guest Editors

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• multidrug resistance (MDR)
• detoxification
• cellular drug modification/elimination
• ER stress
• cell death
• DNA repair
• epigenetics regulation