Depolarization of cell membranes in the formation of drug resistance

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Depolarization of cell membranes in the formation of drug resistance

Voroshylova Natalia Mikhailivna

Candidate of Biological Sciences, Major Researcher

SI "O.S. Kolomiychenko Institute of Otolarynglology, NAMSU” Kyiv, Ukraine

Kizim Yaroslav Volodymyrovych

PhD, Junior Researcher

SI "O.S. Kolomiychenko Institute of Otolarynglology, NAMSU” Kyiv, Ukraine

Verevka Serhij Viktorovych

Doctor of Biological Sciences, Professor, Head of the Department of Biochemistry

SI "O.S. Kolomiychenko Institute of Otolarynglology, NAMSU” Kyiv, Ukraine

Summary

Correlation of the properties of biofilms of microorganisms and malignant tumors indicates the existence of a certain analogy between them, which allows us to explain the essential circumstances of the formation of drug resistance. Intercellular substance plays a significant role in the functioning of both types of cell groups. Both types are characterized by the formation and local accumulation of structurally damaged proteins and peptides. The regularity of their interaction with membrane's phospholipid bilayer creates prerequisites for the formation of f- structured inclusions that are characterized by electrical conductivity. This leads to membrane depolarization and, as a result, to disruption of its barrier function. An increase in the permeability of the membrane contributes to the entry of external genetic material, the formation of mutated forms and the development of drug resistance. drug resistance cancer biofilm

Keywords: drug resistance, cancer, biofilms, cell membranes.

The formation of drug resistance is an acute medical and social problem that complicates, or makes impossible, effective therapy of a wide range of diseases. The basis of this process is the ability of cells of pathogenic microorganisms and malignant neoplasms to accelerate mutation with the acquisition of increased resistance to the action of drugs [1,2]. There are certain analogies between biofilms of microorganisms and tumors of malignant neoplasms [3]. Intercellular substance plays an important role in both systems. Both the stroma of malignant tumors and the intercellular polymeric substance of biofilms are multicomponent and highly organized structures [4,5]. This gives both cellular systems the ability to widely adapt to changes in environmental conditions.Intercellular substances of both types include proteins, lipids, carbohydrates and nucleic acids. They perform various functions and provide a sharp increase in the resistance of the cells themselves both to the action of the immune system and to a number of adverse factors [5,6]. The formation and development of biofilms is accompanied by the formation of significant amounts of cell decay products that could not adapt to the influence of adverse environmental factors. However, biofilms are two to three orders of magnitude more resistant to antibiotics than unicellular planktonic forms [7]. The extracellular polymeric substance of biofilms effectively absorbs and accumulates various toxins. This dramatically reduces the number of toxic molecules that can reach the intracellular space. Extracellular DNA (eDNA) plays a similar protective function.Extracellular DNA is one of the types of remnants of dead cells and participates in adhesive interactions at the early stages of biofilm formation [8,9]. However, it is able to bind toxins and antibiotics [6,10]. As is known, the bactericidal effect of most antibiotics is due to their ability to interact with the nucleic acids of bacterial cells. Most chemotherapeutic cytostatic drugs also work according to the same principle. The presence of dechromatized DNA of dead cells in the stroma creates prerequisites for similar sorption. However, its role is probably not limited to this. It is known that the cells of malignant neoplasms are characterized by wide genetic diversity even within the limits of one tumor [11,12]. Horizontal transfer of genes between different types of microorganisms within the same biofilm has also been known for a long time [13,14]. Therefore, the question arises about the causes of this kind of genetic plasticity. The answer, or at least a reasonable explanation, can be obtained thanks to correlation with information about the properties of cell membranes and the laws of their interaction with destabilized proteins and peptides.

As is known, the formation and development of biofilms is accompanied by the formation of significant amounts of cell decay products that could not adapt to the influence of adverse environmental factors [6]. An integral circumstance of the malignant process is the formation and accumulation of various components of endogenous intoxication [15]. Under normal circumstances, such metabolites are removed from the circulation, however, due to their local accumulation, they can significantly affect the functioning of adjacent cells.Among the latter, the leading place belongs to structurally damaged proteins and their fragments, which have undergone structural destabilization due to non-functional proteolysis and a number of parametabolic processes [16,17]. It is known that structurally destabilized proteins and peptides are prone to the formation of beta-structured fibrils that are a kind of energy bottom of confirmation states of destabilized proteins.Such aggregates are present both as part of the stroma of malignant tumors and as part of the intercellular polymeric substance [4,18]. In the case of biofilms, these fibrils play an important role in the formation and maintenance of the structure of the intercellular association. However, an equally important role belongs to the aggregates that were formed by the interaction of destabilized proteins with the outer membranes of cells (Fig. 1).

Fig. 1. A simplified scheme of the structure formation of a destabilized protein molecule under the influence of a phospholipid bilayer [19].

This interaction includes the sorption of the peptide chain on the surface of the membrane, its alpha-spiralization, the embedding of the formed spiral into the double phospholipid layer, the association of similar inclusions with each other and their rearrangement into beta-folded structures [18,19]. Such interactions underlie various pathological processes, in particular, amyloidoses of the central nervous system [20]. Such inclusions tend to associate both with each other and with integral proteins of the cell membrane, which disrupts the functioning of the latter. A typical example of such an effect is type 2 diabetes, in which the loading of cell membranes with protein aggregates causes the dysfunction of insulin receptors [21]. However, beta-structured protein aggregates have another property that remains underestimated in relation to their influence on the properties of cell membranes. They are electrically conductive [22-24]. What follows from this?

According to existing concepts, cell membranes are highly organized multidomain structures, the components of which ensure the membrane performs a long list of functions (Fig. 2)

Fig.2. One of the schemes, reflecting modern views on the membrane structure. Rather densely located integral proteins are presented next to the heterogeneous lipid component. Glycan components (above) are protruding on the cell surface, while polymer rods (below) illustrate the cytoskeleton elements, conjugated with the membrane [25].

These include participation in the processes of adhesion, endocytosis, immune response, action potential generation, apoptosis, and many others. However, the most important function of cell membranes is the barrier function. It not only limits the volume of the cell, but also ensures the selectivity of the exchange of substances with the surrounding environment, which includes, in particular, the prevention of the entry of unwanted substances into the cell [26]. An integral circumstance of the normal functioning of the membrane is the asymmetry of its structure and the presence of an electrostatic field gradient between the outer and inner phospholipid layers. Support of this gradient is provided by numerous cell systems. When the cell dies, this gradient disappears, and the permeability of the outer membrane increases sharply [27,28]. It is obvious that the shunting of the phospholipid bilayer by electrically conductive inclusions cannot fail to affect the barrier function of the membranes. Given the high level of structuredness, it is not about the complete destruction of the electrostatic gradient, but only a partial, zonal one. It is known that both cells of malignant tumors and microorganisms in the composition of biofilms intensively absorb nano-sized particles of the most diverse nature.In this regard, they are sharply different from cells of healthy tissues and from microorganisms in a free planktonic form. Absorbed nanoparticles have an extremely negative effect on the functioning of cells [29]. This determines the undiminished interest in studies of the effect of nanoparticles both on malignant neoplasms and on biofilms of malignant microorganisms (more than 30 thousand and more than 8 thousand citations in the PubMed database, respectively). In the context of the given material, these properties of nanoparticles are nothing more than direct experimental evidence of a dramatic increase in the permeability of the outer membranes of the corresponding cells [30]. The presence of dechromatized DNA of dead cells in the intercellular substance ensures the non-functional transfer of genetic material and, as a result, the formation of mutated forms with their subsequent selection [14, 31, 32]. In this regard, a very telling example is the development of antibiotic resistance of biofilms that have previously been intoxicated by heavy metal ions [33].

The above considerations testify in favor of the previously expressed assumption about the necessity of the death of a significant part of the cells of biofilms and malignant neoplasms for their functioning. The products of the decay of dead cells become a necessary component for the survival of the cellular society as a whole, the growth of its resistance to the action of adverse factors, in particular, for the formation of drug resistance.

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