Rolul proteinelor din familia ABC în rezistența la medicamente antitumorale

Introduction

Resistance to antitumor treatment – including multidrug resistance – represents a major obstacle in the success of oncological treatment, being characterized by the ability of tumor cells to survive after exposure to a wide range of cytostatic drugs.

One of the major mechanisms of this phenomenon is the overexpression of the ABC (ATP-binding cassette) family proteins.

These proteins function as transmembrane pumps that use the energy derived from ATP hydrolysis to actively eliminate cytostatic agents from inside the cell, resulting in the reduction of intracellular drug concentration.

Materials and method

An analysis was conducted on the articles published on the PubMed, Google Scholar and HINARI platforms. The analyzed literature is written exclusively in English, in the form of literature reviews and clinical studies. The search for studies was carried out using the keywords: “ABC proteins”, “antitumor resistance”, “multidrug resistance”, “antitumor drugs” and “resistance in oncology”.

The objective of the study consists of the selection, analysis and systematization of the current literature regarding ABC family proteins and their role in reduced chemotherapeutic response in oncology.

The ABC (ATP-binding cassette) family

The ABC family represents an important group of transmembrane proteins, which transport a wide range of substrates across the cell membrane via primary active transport, meaning with the direct consumption of ATP energy.

The proteins from this given family are essential for normal cell physiology and are involved in fundamental processes such as nutrient homeostasis, detoxification and the immune response⁽¹⁾.

One of their most important roles is protection against toxins and xenobiotics. The most well-known protein in the ABC family, involved in this given process, is called P-glycoprotein. It actively pumps substances of different genesis from the intracellular space to the extracellular one. It is most abundantly expressed at the level of various barriers and filters of the human body: the blood-brain barrier, intestine, liver and placenta⁽²⁾.

These proteins have an important role in lipid metabolism (including steroid transport) by modulating the exchange of cholesterol and phospholipids between plasma lipoproteins, thus influencing the atherogenesis process. Likewise, the proteins from this given family participate in the process of bile formation through the transport of phosphatidylcholine and bile acid salts into the bile canaliculi. The ABCG5 and ABCG8 proteins have an important role in the excretion of plant sterols in the intestine^(1-3).

Some proteins from the ABC family act as channels and receptors: CFTR, an important transporter for Cl- ions, is also called ABCC7, and the sulfonylurea receptors, which modulate K+ efflux from the cell, are called ABCC8/SUR1 and ABCC9/SUR2^(1,2).

Representatives of the ABC family have also been found in many membrane-bound intracellular organelles, such as peroxisomes, mitochondria and lysosomes. This entire wide range of localizations and functions in the human cell only underlines the importance of ABC proteins^(1,2).

Structurally, each representative of the family must have a minimum of four basic domains: two transmembrane domains (are responsible for forming the substrate translocation pathway across the membrane) and two nucleotide-binding domains (they are responsible for binding and hydrolyzing ATP to provide energy). In nature, seven types of ABC transporters are known from a structural point of view. Mammals possess only types IV and V.

Type IV or type I exporter includes the ABCB, ABCC and ABCD subfamilies. All four domains are fused into one polypeptide chain, which is incorporated into the membrane^(1,2).

Type V or type II exporters include the ABCA and ABCG subfamilies. A single polypeptide contains only one transmembrane domain and one nucleotide-binding domain. Two polypeptides, either identical (homodimers) or different (heterodimers), assemble into a unique, complex and functional structure that is then incorporated into the cell membrane (Figure 1)^(1,2).

The role of ABC family in antitumor resistance

The proteins from the ABC family represent one of the most critical factors in the development of resistance to antitumor drugs, especially in multidrug resistance. This resistance can be natural, present from the outset of treatment, and acquired, which appeared after the exposure of the cells to cytostatic agents. The mechanisms through which ABC proteins mediate resistance to antitumor drugs are the following:

1. Active efflux from the level of the plasma membrane. The proteins from the ABC family recognize the drugs that have penetrated into the cell and actively pump them from the cytosol into the extracellular environment. Some substrates can be taken up for excretion right from the lipid layer, before penetrating into the cell. Each representative of the family can recognize a wide range of drugs – tens or possibly even hundreds of drugs from different pharmacological groups, including the antitumor ones^(4,5,7).

2. Intracellular sequestration in organelles. Proteins such as ABCC3, ABCB9, ABCD4 and ABCC1 have been detected on the membrane of lysosomes and intracellular vesicles, which prevents the migration of the drug towards its target and, consequently, prevents the occurrence of the effect^(4,5).

3. Genetic mechanisms. The amount of ABC pumps on the membrane of tumor cells is controlled by genetic mechanisms. Therefore, the changes that will cause the increased expression of the proteins will lead to increased transmembrane excretion. The increase in expression can be caused by phenomena such as: promoter capture (translocation of an active promoter upstream of an ABC gene), regulation by micro-RNAs (the levels of some RNAs, like miR-326 and miR-297 are inversely proportional to the expression level of some ABC pumps) or activation by nuclear receptors (some drugs, such as paclitaxel, can activate nuclear receptors, modifying the expression level of ABC proteins)^(4-6).

4. Co-expression of transporters. It was mentioned before that a pump from the ABC family can recognize and excrete tens or possibly hundreds of drugs from different pharmacological groups, including antitumor ones. At the same time, a cell, even a normal one, expresses many different ABC proteins, which can summarily cover a very large range of different drugs. In leukemias, it has been observed that the prognosis is worse the more types of pumps the tumor cells express⁽⁶⁾.

In Table 1, there are represented three proteins that are most often associated with resistance to antitumor drugs: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1). From the total number of neoplasms, in which the overexpression of the given proteins is found, and from the number of antitumor drugs that are excreted through the pumps, conclusions can be drawn about their importance in the resistance to antitumor drugs.

In Figure 2 (A) is represented the result of the analysis of 211 studies, of which 168 are in vitro studies, 43 are clinical studies, and 53 used both the in vitro and the clinical approach. From this figure we can draw conclusions regarding the number of studies that highlight multidrug resistance caused by the ABC family proteins, in malignant neoplasms. Most cases report resistance associated with ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP). Resistance associated with other representatives of the family is also encountered, but more rarely, a fact that underlines the clinical importance of the three previously mentioned proteins.

In Figure 2 (B) is schematically represented the total amount of antitumor drugs that each of the 20 main representatives of the ABC family can eliminate. It can be observed that ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) are, also, leaders among all the 20 representatives. The ABCC2, ABCC3, ABCC4, ABCC5 and ABCC10 proteins can eliminate a significant number of antitumor drugs (over 10), a fact that confirms the importance of studying them in oncological patients, besides the three main representatives.

Conclusions

The in-depth understanding of the efflux mechanisms mediated by ABC proteins is essential in modern clinical oncology, as it enables explaining and potentially preventing therapeutic failure. Knowledge of the tumor resistance profile supports a rational and personalized approach to chemotherapy⁽⁸⁾. The administration of cytostatic agents that are substrates of overexpressed ABC transporters may result in reduced therapeutic efficacy and unnecessary systemic toxicity. Therefore, the management of multidrug resistance requires molecular profiling and strategic selection of treatment, in order to optimize clinical outcomes and improve patient response.

This work is permanently accessible online free of charge and published under the CC-BY.

Corresponding author: Ina Pogonea E-mail: ina.pogonea@usmf.md

Conflict of interests: none declared.

Financial support: none declared.