The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of substrates including amino acids, lipids, inorganic ions, peptides, saccharides, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but also are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. The typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. Defects in 14 of these transporters cause 13 genetic diseases (cystic fibrosis, Stargardt disease, adrenoleukodystrophy, Tangier disease, etc.). Mutations in three genes affect lipid levels expressively. Mutations in ABCA1 cause severe HDL deficiency syndromes called Tangier disease and familial high-density lipoprotein deficiency, which are characterized by a severe deficiency or absence of high-density lipoprotein in the plasma. Two other ABCG transporters, ABCG5 and ABCG8, mutations of which cause sitosterolemia, have been identified. The affected individuals absorb and retain plant sterols, as well as shellfish sterols.

• MeSH
• ABC transportéry chemie   klasifikace   genetika   metabolismus   MeSH
• adenosintrifosfát metabolismus   MeSH
• energetický metabolismus genetika   MeSH
• hydrolýza MeSH
• lidé MeSH
• metabolismus lipidů * MeSH
• vrozené poruchy metabolismu genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• ABC transportéry MeSH
• adenosintrifosfát MeSH

Targeting mutations that trigger acute myeloid leukaemia (AML) has emerged as a refined therapeutic approach in recent years. Enasidenib (Idhifa) is the first selective inhibitor of mutated forms of isocitrate dehydrogenase 2 (IDH2) approved against relapsed/refractory AML. In addition to its use as monotherapy, a combination trial of enasidenib with standard intensive induction therapy (daunorubicin + cytarabine) is being evaluated. This study aimed to decipher enasidenib off-target molecular mechanisms involved in anthracycline resistance, such as reduction by carbonyl reducing enzymes (CREs) and drug efflux by ATP-binding cassette (ABC) transporters. We analysed the effect of enasidenib on daunorubicin (Daun) reduction by several recombinant CREs and different human cell lines expressing aldo-keto reductase 1C3 (AKR1C3) exogenously (HCT116) or endogenously (A549 and KG1a). Additionally, A431 cell models overexpressing ABCB1, ABCG2, or ABCC1 were employed to evaluate enasidenib modulation of Daun efflux. Furthermore, the potential synergism of enasidenib over Daun cytotoxicity was quantified amongst all the cell models. Enasidenib selectively inhibited AKR1C3-mediated inactivation of Daun in vitro and in cell lines expressing AKR1C3, as well as its extrusion by ABCB1, ABCG2, and ABCC1 transporters, thus synergizing Daun cytotoxicity to overcome resistance. This work provides in vitro evidence on enasidenib-mediated targeting of the anthracycline resistance actors AKR1C3 and ABC transporters under clinically achievable concentrations. Our findings may encourage its combination with intensive chemotherapy and even suggest that the effectiveness of enasidenib as monotherapy against AML could lie beyond the targeting of mIDH2.

• Klíčová slova
• ABC transporters, AKR1C3, AML, Enasidenib, IDH inhibitor,
• MeSH
• ABC transportéry metabolismus   MeSH
• adenosintrifosfát MeSH
• akutní myeloidní leukemie * farmakoterapie   genetika   MeSH
• antracykliny MeSH
• cytarabin terapeutické užití   MeSH
• daunomycin * farmakologie   MeSH
• isocitrátdehydrogenasa genetika   metabolismus   terapeutické užití   MeSH
• lidé MeSH
• protinádorová antibiotika terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• adenosintrifosfát MeSH
• antracykliny MeSH
• cytarabin MeSH
• daunomycin * MeSH
• enasidenib MeSH Prohlížeč
• isocitrátdehydrogenasa MeSH
• protinádorová antibiotika MeSH

Adenosine triphosphate-binding cassette proteins constitute a large family of active transporters through extracellular and intracellular membranes. Increased drug efflux based on adenosine triphosphate-binding cassette protein activity is related to the development of cancer cell chemoresistance. Several articles have focused on adenosine triphosphate-binding cassette gene expression profiles (signatures), based on the expression of all 49 human adenosine triphosphate-binding cassette genes, in individual tumor types and reported connections to established clinicopathological features. The aim of this study was to test our theory about the existence of adenosine triphosphate-binding cassette gene expression profiles common to multiple types of tumors, which may modify tumor progression and provide clinically relevant information. Such general adenosine triphosphate-binding cassette profiles could constitute a new attribute of carcinogenesis. Our combined cohort consisted of tissues from 151 cancer patients-breast, colorectal, and pancreatic carcinomas. Standard protocols for RNA isolation and quantitative real-time polymerase chain reaction were followed. Gene expression data from individual tumor types as well as a merged tumor dataset were analyzed by bioinformatics tools. Several general adenosine triphosphate-binding cassette profiles, with differences in gene functions, were established and shown to have significant relations to clinicopathological features such as tumor size, histological grade, or clinical stage. Genes ABCC7, A3, A8, A12, and C8 prevailed among the most upregulated or downregulated ones. In conclusion, the results supported our theory about general adenosine triphosphate-binding cassette gene expression profiles and their importance for cancer on clinical as well as research levels. The presence of ABCC7 (official symbol CFTR) among the genes with key roles in the profiles supports the emerging evidence about its crucial role in various cancers. Graphical abstract.

• Klíčová slova
• Adenosine triphosphate–binding cassette, adenosine triphosphate–binding cassette transporters, bioinformatics, cancer, gene expression, profile,
• MeSH
• ABC transportéry biosyntéza   genetika   MeSH
• karcinogeneze * MeSH
• kolorektální nádory genetika   patologie   MeSH
• lidé MeSH
• nádory prsu genetika   patologie   MeSH
• nádory slinivky břišní genetika   patologie   MeSH
• protein CFTR biosyntéza   genetika   MeSH
• receptory sulfonylurey biosyntéza   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• transkriptom genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCA12 protein, human MeSH Prohlížeč
• ABCA3 protein, human MeSH Prohlížeč
• ABCA8 protein, human MeSH Prohlížeč
• ABCC8 protein, human MeSH Prohlížeč
• CFTR protein, human MeSH Prohlížeč
• protein CFTR MeSH
• receptory sulfonylurey MeSH

Brassinosteroids are steroidal phytohormones that regulate plant development and physiology, including adaptation to environmental stresses. Brassinosteroids are synthesized in the cell interior but bind receptors at the cell surface, necessitating a yet to be identified export mechanism. Here, we show that a member of the ATP-binding cassette (ABC) transporter superfamily, ABCB19, functions as a brassinosteroid exporter. We present its structure in both the substrate-unbound and the brassinosteroid-bound states. Bioactive brassinosteroids are potent activators of ABCB19 ATP hydrolysis activity, and transport assays showed that ABCB19 transports brassinosteroids. In Arabidopsis thaliana, ABCB19 and its close homolog, ABCB1, positively regulate brassinosteroid responses. Our results uncover an elusive export mechanism for bioactive brassinosteroids that is tightly coordinated with brassinosteroid signaling.

• MeSH
• ABC transportéry * chemie   genetika   metabolismus   MeSH
• adenosintrifosfát metabolismus   MeSH
• Arabidopsis * genetika   metabolismus   MeSH
• brassinosteroidy * metabolismus   MeSH
• konformace proteinů MeSH
• kyseliny indoloctové metabolismus   MeSH
• proteiny huseníčku * chemie   genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry * MeSH
• ABCB19 protein, Arabidopsis MeSH Prohlížeč
• adenosintrifosfát MeSH
• brassinosteroidy * MeSH
• kyseliny indoloctové MeSH
• proteiny huseníčku * MeSH

Brassinosteroids (BRs) are steroidal phytohormones indispensable for plant growth, development, and responses to environmental stresses. The export of bioactive BRs to the apoplast is essential for BR signaling initiation, which requires binding of a BR molecule to the extracellular domains of the plasma membrane-localized receptor complex. We have previously shown that the Arabidopsis thaliana ATP-binding cassette (ABC) transporter ABCB19 functions as a BR exporter and, together with its close homolog ABCB1, positively regulates BR signaling. Here, we demonstrate that ABCB1 is another BR transporter. The ATP hydrolysis activity of ABCB1 can be stimulated by bioactive BRs, and its transport activity was confirmed in proteoliposomes and protoplasts. Structures of ABCB1 were determined in substrate-unbound (apo), brassinolide (BL)-bound, and ATP plus BL-bound states. In the BL-bound structure, BL is bound to the hydrophobic cavity formed by the transmembrane domain and triggers local conformational changes. Together, our data provide additional insights into ABC transporter-mediated BR export.

• Klíčová slova
• ABCB1, Arabidopsis, brassinosteroids, signaling, structure, transport,
• MeSH
• ABC transportéry * metabolismus   chemie   genetika   MeSH
• adenosintrifosfát metabolismus   MeSH
• Arabidopsis * metabolismus   genetika   MeSH
• biologický transport MeSH
• brassinosteroidy * metabolismus   MeSH
• proteiny huseníčku * metabolismus   chemie   genetika   MeSH
• steroidy heterocyklické metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABC transportéry * MeSH
• adenosintrifosfát MeSH
• brassinolide MeSH Prohlížeč
• brassinosteroidy * MeSH
• proteiny huseníčku * MeSH
• steroidy heterocyklické MeSH

1. Purine cyclin-dependent kinase inhibitors have recently been recognised as promising candidates for the treatment of various cancers. While pharmacodynamic properties of these compounds are relatively well understood, their pharmacokinetics including possible interactions with placental transport systems have not been characterised to date. 2. In this study, we investigated transplacental passage of olomoucine II and purvalanol A in rat focusing on possible role of p-glycoprotein (ABCB1), breast cancer resistance protein (ABCG2) and/or multidrug resistance-associated proteins (ABCCs). Employing the in situ method of dually perfused rat term placenta, we demonstrate transplacental passage of both olomoucine II and purvalanol A against the concentration gradient in foetus-to-mother direction. Using several ATP-binding cassette (ABC) drug transporter inhibitors, we confirm the participation of ABCB1, ABCG2 and ABCCs transporters in the placental passage of olomoucine II, but not purvalanol A. 3. Transplacental passage of olomoucine II and purvalanol A from mother to foetus is significantly reduced by active transporters, restricting thereby foetal exposure and providing protection against harmful effects of these xenobiotics. Importantly, we demonstrate that in spite of their considerable structural similarity, the two molecules utilise distinct placental transport systems. These facts should be kept in mind when introducing these prospective anticancer candidates and/or their analogues into the clinical area.

• Klíčová slova
• Cyclin-dependent kinase inhibitors, drug efflux transporters, olomoucine II, placental pharmacokinetics, purvalanol A,
• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry metabolismus   MeSH
• adenosintrifosfát chemie   MeSH
• aktivní transport MeSH
• krysa rodu Rattus MeSH
• matka - expozice noxám MeSH
• P-glykoproteiny metabolismus   MeSH
• placenta účinky léků   metabolismus   MeSH
• potkani Wistar MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům metabolismus   MeSH
• puriny aplikace a dávkování   farmakokinetika   MeSH
• roskovitin MeSH
• těhotenství u zvířat MeSH
• těhotenství MeSH
• trofoblasty účinky léků   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• xenobiotika chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 6-((3-chloro)anilino)-2-(isopropyl-2-hydroxyethylamino)-9-isopropylpurine MeSH Prohlížeč
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry MeSH
• Abcg2 protein, rat MeSH Prohlížeč
• adenosintrifosfát MeSH
• multidrug resistance protein 3 MeSH Prohlížeč
• olomoucine II MeSH Prohlížeč
• P-glykoproteiny MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH
• puriny MeSH
• roskovitin MeSH
• xenobiotika MeSH

The ATP-independent chaperone SurA protects unfolded outer membrane proteins (OMPs) from aggregation in the periplasm of Gram-negative bacteria, and delivers them to the β-barrel assembly machinery (BAM) for folding into the outer membrane (OM). Precisely how SurA recognises and binds its different OMP clients remains unclear. Escherichia coli SurA comprises three domains: a core and two PPIase domains (P1 and P2). Here, by combining methyl-TROSY NMR, single-molecule Förster resonance energy transfer (smFRET), and bioinformatics analyses we show that SurA client binding is mediated by two binding hotspots in the core and P1 domains. These interactions are driven by aromatic-rich motifs in the client proteins, leading to SurA core/P1 domain rearrangements and expansion of clients from collapsed, non-native states. We demonstrate that the core domain is key to OMP expansion by SurA, and uncover a role for SurA PPIase domains in limiting the extent of expansion. The results reveal insights into SurA-OMP recognition and the mechanism of activation for an ATP-independent chaperone, and suggest a route to targeting the functions of a chaperone key to bacterial virulence and OM integrity.

• MeSH
• ABC transportéry metabolismus   chemie   genetika   MeSH
• adenosintrifosfát metabolismus   MeSH
• Escherichia coli * metabolismus   genetika   MeSH
• molekulární chaperony * metabolismus   MeSH
• molekulární modely MeSH
• peptidylprolylisomerasa * metabolismus   genetika   MeSH
• proteinové domény MeSH
• proteiny vnější bakteriální membrány metabolismus   genetika   chemie   MeSH
• proteiny z Escherichia coli * metabolismus   genetika   chemie   MeSH
• rezonanční přenos fluorescenční energie MeSH
• sbalování proteinů MeSH
• transportní proteiny * metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• adenosintrifosfát MeSH
• molekulární chaperony * MeSH
• peptidylprolylisomerasa * MeSH
• proteiny vnější bakteriální membrány MeSH
• proteiny z Escherichia coli * MeSH
• SurA protein, E coli MeSH Prohlížeč
• transportní proteiny * MeSH

Ritonavir (RIT) is a widely used antiviral drug that acts as an HIV protease inhibitor with emerging potential in anticancer therapies. RIT causes inhibition of P-glycoprotein, which plays an important role in multidrug resistance (MDR) in cancer cells when overexpressed. Moreover, RIT causes mitochondrial dysfunction, leading to decreased ATP production and reduction of caveolin I expression, which can affect cell migration and tumor progression. To increase its direct antitumor activity, decrease severe side effects induced by the use of free RIT and improve its pharmacokinetics, ritonavir 5-methyl-4-oxohexanoate (RTV) was synthesized and conjugated to a tumor-targeted polymer carrier based on a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. Here we demonstrated that polymer-bound RTV enhanced the internalization of polymer-RTV conjugates, differing in RTV content from 4 to 15 wt%, in HeLa cancer cells compared with polymer without RTV. The most efficient influx and internalization properties were determined for the polymer conjugate bearing 11 wt% of RTV. This conjugate was internalized by cells using both caveolin- and clathrin-dependent endocytic pathways in contrast to the RTV-free polymer, which was preferentially internalized only by clathrin-mediated endocytosis. Moreover, we found the co-localization of the RTV-conjugate with mitochondria and a significant decrease of ATP production in treated cells. Thus, the impact on mitochondrial mechanism can influence the function of ATP-dependent P-glycoprotein and also the cell viability of MDR cancer cells. Overall, this study demonstrated that the polymer-RTV conjugate is a promising polymer-based nanotherapeutic, suitable for antitumor combination therapy with other anticancer drugs and a potential mitochondrial drug delivery system.

• Klíčová slova
• Anticancer therapy, Cell penetration compound, Drug delivery, HPMA, Mitochondrial drug delivery, Multidrug resistance, Polymer-based nanotherapeutic, Ritonavir,
• MeSH
• adenosintrifosfát biosyntéza   MeSH
• chemorezistence účinky léků   MeSH
• endocytóza účinky léků   MeSH
• HeLa buňky MeSH
• kaveolin 1 biosyntéza   genetika   MeSH
• klathrin farmakologie   MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• methakryláty chemie   MeSH
• nanostruktury chemie   MeSH
• P-glykoprotein účinky léků   metabolismus   MeSH
• polymery MeSH
• protinádorové látky aplikace a dávkování   chemie   MeSH
• ritonavir aplikace a dávkování   analogy a deriváty   chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosintrifosfát MeSH
• hydroxypropyl methacrylate MeSH Prohlížeč
• kaveolin 1 MeSH
• klathrin MeSH
• methakryláty MeSH
• P-glykoprotein MeSH
• polymery MeSH
• protinádorové látky MeSH
• ritonavir MeSH

The effect of alcohols on cell membrane proteins has originally been assumed to be mediated by their primary action on membrane lipid matrix. Many studies carried out later on both animal and yeast cells have revealed that ethanol and other alcohols inhibit the functions of various membrane channels, receptors and solute transport proteins, and a direct interaction of alcohols with these membrane proteins has been proposed. Using our fluorescence diS-C3 (3) diagnostic assay for multidrug-resistance pump inhibitors in a set of isogenic yeast Pdr5p and Snq2p mutants, we found that n-alcohols (from ethanol to hexanol) variously affect the activity of both pumps. Beginning with propanol, these alcohols have an inhibitory effect that increases with increasing length of the alcohol acyl chain. While ethanol does not exert any inhibitory effect at any of the concentration used (up to 3%), hexanol exerts a strong inhibition at 0.1%. The alcohol-induced inhibition of MDR pumps was detected even in cells whose membrane functional and structural integrity were not compromised. This supports a notion that the inhibitory action does not necessarily involve only changes in the lipid matrix of the membrane but may entail a direct interaction of the alcohols with the pump proteins.

• Klíčová slova
• alcohols, fluorescent probe diS-C3(3), membrane potential, pump inhibitor, yeast MDR pump,
• MeSH
• ABC transportéry antagonisté a inhibitory   genetika   metabolismus   MeSH
• adenosintrifosfát metabolismus   MeSH
• alkoholy farmakologie   MeSH
• fungální léková rezistence genetika   MeSH
• ionty metabolismus   MeSH
• mikrobiální testy citlivosti MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• Saccharomyces cerevisiae - proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• Saccharomyces cerevisiae účinky léků   genetika   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• adenosintrifosfát MeSH
• alkoholy MeSH
• ionty MeSH
• PDR5 protein, S cerevisiae MeSH Prohlížeč
• Saccharomyces cerevisiae - proteiny MeSH
• SNQ2 protein, S cerevisiae MeSH Prohlížeč

Multidrug resistance (MDR) represents one of the major concerns in cancer therapy as it may cause reduced efficacy of chemotherapeutic drugs due to the overexpression of ABC transporters, particularly P-glycoprotein (P-gp). This study explores the potential of novel amphiphilic diblock (DB) copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide]-based copolymers (PHPMA) and poly(propylene oxide) (PPO) to overcome MDR mechanisms. The DB copolymers and their doxorubicin (Dox) conjugates significantly increased Dox accumulation in P-gp positive cells, markedly sensitizing them to Dox cytotoxic activity. The underlying mechanisms included depletion of intracellular ATP with subsequent inhibition of P-gp mediated drug efflux, an altered mitochondrial membrane potential, and increased ROS production. Moreover, the DB-Dox conjugates inhibited tumor growth in vivo more effectively compared to the corresponding PHPMA-based drug delivery system. Copolymers with additionally loaded PPO in the micelle core demonstrated superior efficacy in terms of P-gp inhibition, ATP depletion, and chemosensitizing effect in vitro, as well as antitumor activity in vivo. DB copolymers effectively depleted ATP levels both in vitro and in vivo using patient-derived xenograft (PDX) models, underscoring their capacity to enhance the effectiveness of standard chemotherapy and translational potential.

• Klíčová slova
• Diblock copolymers, Drug delivery system, HPMA copolymer, Intracellular ATP depletion, Multidrug resistance, P-glycoprotein inhibition, PPO, Sensitization to chemotherapy,
• MeSH
• adenosintrifosfát metabolismus   MeSH
• chemorezistence účinky léků   MeSH
• doxorubicin * aplikace a dávkování   chemie   terapeutické užití   MeSH
• lidé MeSH
• methakryláty chemie   MeSH
• micely MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• nosiče léků * chemie   MeSH
• P-glykoprotein * metabolismus   MeSH
• polymery chemie   MeSH
• polypropyleny * chemie   MeSH
• propylenglykoly * chemie   aplikace a dávkování   MeSH
• protinádorová antibiotika * aplikace a dávkování   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosintrifosfát MeSH
• doxorubicin * MeSH
• methakryláty MeSH
• micely MeSH
• nosiče léků * MeSH
• P-glykoprotein * MeSH
• polymery MeSH
• polypropylene glycol MeSH Prohlížeč
• polypropyleny * MeSH
• propylenglykoly * MeSH
• protinádorová antibiotika * MeSH