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Katalin Német

Publications and source records attributed to Katalin Német.

7 recordsLinked to original sources
PubMed2005

The role of the human ABCG2 multidrug transporter and its variants in cancer therapy and toxicology.

The human multidrug resistance ABC transporters provide a protective function in our body against a large number of toxic compounds. These proteins, residing in the plasma membrane, perform an active, ATP-dependent extrusion of such xenobiotics. However, the same proteins are also used by the tumor cells to fight various anticancer agents. ABCG2 is an important member of the multidrug resistance proteins, an 'ABC half transporter', which functions as a homodimer in the cell membrane. In this review, we provide a basic overview of ABCG2 function in physiology and drug metabolism, but concentrate on the discussion of mutations and polymorphisms discovered in this protein. Interestingly, a single nucleotide mutation, changing amino acid 482 from arginine to threonine or glycine in ABCG2, results in a major increase in the catalytic activity and a wider drug recognition by this protein. Still, this mutation proved to be an in vitro artifact, produced only in heavily drug-selected cell lines. In contrast, at least two, but possibly more polymorphic variants of ABCG2 were found to be present in large human populations with different ethnic background. However, currently available experimental data regarding the cellular expression, localization and function of these ABCG2 variants are strongly contradictory. Since, the proteins produced by these variant alleles may differently modulate cancer treatment, general drug absorption and toxicity, may represent risk factors in fetal toxicity, or alter the differentiation of stem cells, their exact characterization is a major challenge in this field.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2005

Multidrug transporter ABCG2 prevents tumor cell death induced by the epidermal growth factor receptor inhibitor Iressa (ZD1839, Gefitinib).

Iressa (ZD1839, Gefitinib), used in clinics to treat non-small cell lung cancer patients, is a tyrosine kinase receptor inhibitor that leads to specific decoupling of epidermal growth factor receptor (EGFR) signaling. Recent data indicate that Iressa is especially effective in tumors with certain EGFR mutations; however, a subset of these tumors does not respond to Iressa. In addition, certain populations have an elevated risk of side effects during Iressa treatment. The human ABCG2 (BCRP/MXR/ABCP) transporter causes cancer drug resistance by actively extruding a variety of cytotoxic drugs, and it functions physiologically to protect our tissues from xenobiotics. Importantly, ABCG2 modifies absorption, distribution, and toxicity of several pharmacologic agents. Previously, we showed that ABCG2 displays a high-affinity interaction with several tyrosine kinase receptor inhibitors, including Iressa. Here, we show that the expression of ABCG2, but not its nonfunctional mutant, protects the EGFR signaling-dependent A431 tumor cells from death on exposure to Iressa. This protection is reversed by the ABCG2-specific inhibitor, Ko143. These data, reinforced with cell biology and biochemical experiments, strongly suggest that ABCG2 can actively pump Iressa. Therefore, variable expression and polymorphisms of ABCG2 may significantly modify the antitumor effect as well as the absorption and tissue distribution of Iressa.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Function-dependent conformational changes of the ABCG2 multidrug transporter modify its interaction with a monoclonal antibody on the cell surface.

The human ABCG2 protein is an important primary active transporter for hydrophobic compounds in several cell types, and its overexpression causes multidrug resistance in tumors. A monoclonal antibody (5D3) recognizes this protein on the cell surface. In ABCG2-expressing cells 5D3 antibody showed a saturable labeling and inhibited ABCG2 transport and ATPase function. However, at low antibody concentrations 5D3 binding to intact cells depended on the actual conformation of the ABCG2 protein. ATP depletion or the addition of the ABCG2 inhibitor Ko143 significantly increased, whereas the vanadate-induced arrest of ABCG2 strongly decreased 5D3 binding. The binding of the 5D3 antibody to a non-functional ABCG2 catalytic center mutant (K86M) in intact cells was not affected by the addition of vanadate but still increased with the addition of Ko143. In isolated membrane fragments the ligand modulation of 5D3 binding to ABCG2 could be analyzed in detail. In this case 5D3 binding was maximum in the presence of ATP, ADP, or Ko143, whereas the non-hydrolysable ATP analog, adenosine 5'-(beta,gamma-imido)triphosphate (AMP-PNP), and nucleotide trapping by vanadate decreased antibody binding. In membranes expressing the ABCG2-K86M mutant, ATP, ADP, and AMP-PNP decreased, whereas Ko143 increased 5D3 binding. Based on these data we suggest that the 5D3 antibody can be used as a sensitive tool to reveal intramolecular changes, reflecting ATP binding, the formation of a catalytic intermediate, or substrate inhibition within the transport cycle of the ABCG2 protein.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

ABCG2 -- a transporter for all seasons.

The human ABCG2 (ABCP/MXR/BCRP) protein is a recently recognized ABC half-transporter, which forms homodimers in the plasma membrane and actively extrudes a wide variety of chemically unrelated compounds from the cells. This protein protects our cells and tissues against various xenobiotics, with a crucial role in the intestine, liver, placenta, and the blood-brain barrier. Moreover, ABCG2 seems to have a key function in stem cell protection/regulation, and also in hypoxic defense mechanisms. Widely occurring single nucleotide polymorphisms in ABCG2 may affect absorption and distribution, altering the effectiveness and toxicity of drugs in large populations. At the clinics, overexpression of ABCG2 in tumor cells confers cancer multidrug resistance to a variety of newly developed anticancer agents. On the other hand, specific substrate mutants of ABCG2 are advocated for use as selectable markers in stem-cell based gene therapy.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter.

Tyrosine kinase inhibitors (TKIs) are promising new agents for specific inhibition of malignant cell growth and metastasis formation. Because most of the TKIs have to reach an intracellular target, specific membrane transporters may significantly modulate their effectiveness. In addition, the hydrophobic TKIs may interact with so-called multidrug transporters and thus alter the cellular distribution of unrelated pharmacological agents. In the present work, we show that certain TKIs, already in the clinical phase of drug development, directly interact with the ABCG2 multidrug transporter protein with a high affinity. We found that in several in vitro assay systems, STI-571 (Gleevec; imatinib mesylate), ZD1839 (Iressa; gefitinib), and N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (EKI-785) interacted with ABCG2 at submicromolar concentrations, whereas other multidrug transporters, human multidrug resistance protein (P-glycoprotein, ABCB1) and human multidrug resistance protein 1 (ABCC1), showed much lower reactivity toward these agents. Low concentrations of the TKIs examined selectively modulated ABCG2-ATPase activity, inhibited ABCG2-dependent active drug extrusion, and significantly affected drug resistance patterns in cells expressing ABCG2. Our results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the clinical treatment of cancer patients. These data also raise the possibility that an extrusion of TKIs by multidrug transporters, e.g., ABCG2, may be involved in tumor cell TKI resistance.

Adenosine Triphosphatases↗
PubMed2003

The inducibility of TNF-alpha production is different in the granulocytic and monocytic differentiated forms of wild type and CGD-mutant PLB-985 cells.

Chronic granulomatous disease is an inherited disorder associated with a defect in phagocytic cell oxidative metabolism resulting in ineffective microbicidal activity. Consequently, patients with chronic granulomatous disease suffer from recurrent infections. Published data show that besides the failure to produce superoxide and its derivatives, other functional problems can also be found in chronic granulomatous disease-mutant cells. Since in innate immune responses other mediators, such as cytokines, also play an important role, we hypothesized that there may be a disturbance in cytokine production by chronic granulomatous disease-mutant cells as well. To prove this hypothesis, the production of tumour necrosis factor-alpha, an important proinflammatory cytokine, was determined by enzyme-linked immunosorbent assay in wild-type and chronic granulomatous disease-mutant myelomonoblastic PLB-985 cells in their immature, granulocytic and monocytic/macrophage differentiated forms. Tumour necrosis factor-alpha production was induced with N-formyl-L-methionyl-L-leucyl-L-phenylalanine (100 nmol/L), lipopolysaccharide (10 micro g/mL), opsonized zymosan (100 micro g/mL) or phorbol 12-myristate 13-acetate (100 nmol/L) for 24 h. We could demonstrate that: (i) there were marked differences in tumour necrosis factor-alpha production only in the differentiated forms of both wild-type and chronic granulomatous disease-mutant cells, while there were no differences in the case of their immature counterparts; (ii) only chronic granulomatous disease-mutant cells retained sensitivity to phorbol 12-myristate 13-acetate both in their granulocytic and monocytic forms, although phorbol 12-myristate 13-acetate responsiveness was a characteristic of both types of immature cells; (iii) the granulocytic form of wild-type cells produced tumour necrosis factor-alpha after opsonized zymosan stimulation, but such a response was not observed in cells originating from the chronic granulomatous disease-mutant cell line; (iv) with the monocytic forms, significantly higher tumour necrosis factor-alpha production could be induced by lipopolysaccharide in the wild-type cells than in the chronic granulomatous disease-mutant cells, although there was no difference in their lipopolysaccharide receptor CD14 expression. In summary, these data show an altered inducibility of tumour necrosis factor-alpha production by chronic granulomatous disease-mutant cells. Our observations suggest a further defect in differentiated chronic granulomatous disease-mutant cells in addition to the known defect in reduced nicotinamide adenine dinucleotide phosphate oxidase, which may contribute to the development of susceptibility to infections in people with chronic granulomatous disease.

Cell Differentiation↗