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1.
Molecules ; 28(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36677553

RESUMO

The discovery of the first ATP-binding cassette (ABC) transporter, whose overexpression in cancer cells is responsible for exporting anticancer drugs out of tumor cells, initiated enormous efforts to overcome tumor cell multidrug resistance (MDR) by inhibition of ABC-transporter. Because of its many physiological functions, diverse studies have been conducted on the mechanism, function and regulation of this important group of transmembrane transport proteins. In this review, we will focus on the structural aspects of this transporter superfamily. Since the resolution revolution of electron microscope, experimentally solved structures increased rapidly. A summary of the structures available and an overview of recent structure-based studies are provided. More specifically, the artificial intelligence (AI)-based predictions from AlphaFold-2 will be discussed.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Inteligência Artificial , Resistencia a Medicamentos Antineoplásicos , Resistência a Múltiplos Medicamentos , Antineoplásicos/química , Neoplasias/tratamento farmacológico
2.
Molecules ; 28(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36677732

RESUMO

Centaurea is a genus compromising over 250 herbaceous flowering species and is used traditionally to treat several ailments. Among the Egyptian Centaurea species, C. lipii was reported to be cytotoxic against multidrug-resistant cancer cells. In this context, we aimed to explore the metabolome of C. lipii and compare it to other members of the genus in pursuance of identifying its bioactive principles. An LC-MS/MS analysis approach synchronized with feature-based molecular networks was adopted to offer a holistic overview of the metabolome diversity of the Egyptian Centaurea species. The studied plants included C. alexandrina, C. calcitrapa, C. eryngioides, C. glomerata, C. lipii, C. pallescens, C. pumilio, and C. scoparia. Their constitutive metabolome showed diverse chemical classes such as cinnamic acids, sesquiterpene lactones, flavonoids, and lignans. Linking the recorded metabolome to the previously reported cytotoxicity identified sesquiterpene lactones as the major contributors to this activity. To confirm our findings, bioassay-guided fractionation of C. lipii was adopted and led to the isolation of the sesquiterpene lactone cynaropicrin with an IC50 of 1.817 µM against the CCRF-CEM leukemia cell line. The adopted methodology highlighted the uniqueness of the constitutive metabolome of C. lipii and determined the sesquiterpene lactones to be the responsible cytotoxic metabolites.


Assuntos
Antineoplásicos , Centaurea , Sesquiterpenos , Extratos Vegetais/química , Cromatografia Líquida , Resistência a Múltiplos Medicamentos , Egito , Resistencia a Medicamentos Antineoplásicos , Espectrometria de Massas em Tandem , Centaurea/química , Compostos Fitoquímicos/farmacologia , Sesquiterpenos/química , Lactonas/química
3.
J Infect Public Health ; 16(2): 266-271, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36621204

RESUMO

BACKGROUND: Neonatal sepsis has high incidence with significant mortality and morbidity rates in Pakistan. We investigated common etiological patterns of neonatal sepsis at a tertiary care setup. METHODS: 90 pus and blood, gram negative and gram positive bacterial isolates were analyzed for virulence and antibiotic resistance gene profiling using PCR and disc diffusion methods. RESULTS: Staphylococcus aureus showed strong association with neonatal sepsis (43 %) followed by Citrobacter freundii (21 %), Pseudomonas aeruginosa (13 %), Escherichia coli (15 %) and Salmonella enterica (8 %). Molecular typing of E. coli isolates depicted high prevalence of the virulent F and B2 phylogroups, with 4 hypervirulent phylogroup G isolates. 76.9 % S. aureus isolates showed presence of Luk-PV, encoding for Panton-valentine leucocidin (PVL) toxin with majority also carrying MecA gene and classified as methicillin resistant S. aureus (MRSA). ecpA, papC, fimH and traT virulence genes were detected in E. coli and Salmonella isolates. 47 % Citrobacter freundii isolates carried the shiga like toxin SltII B. Antimicrobial resistance profiling depicted common resistance to cephalosporins, beta lactams and fluoroquinolones. CONCLUSION: Presence of PVL carrying MRSA and multidrug resistant gram negative bacteria, all isolated from late onset sepsis neonates indicate a predominant nosocomial transmission pattern which may complicate management of the disease in NICU setups.


Assuntos
Infecção Hospitalar , Staphylococcus aureus Resistente à Meticilina , Sepse Neonatal , Infecções Estafilocócicas , Humanos , Recém-Nascido , Antibacterianos/farmacologia , Infecção Hospitalar/epidemiologia , Escherichia coli , Exotoxinas/genética , Leucocidinas/genética , Testes de Sensibilidade Microbiana , Paquistão/epidemiologia , Prevalência , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Centros de Atenção Terciária , Resistência a Múltiplos Medicamentos
4.
BMJ Open ; 13(1): e061836, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639214

RESUMO

OBJECTIVE: To identify the risk factors for multidrug resistant tuberculosis (MDR-TB) among patients with TB at selected MDR-TB treatment initiative centres, southern Ethiopia, 2021. DESIGN: An unmatched case-control study was employed. SETTING: Multidrug resistance treatment initiative centres in southern Ethiopia (Nigist Elen Mohamed Memorial Comprehensive Specialized Hospital and Butajira General Hospital). PARTICIPANTS: A total sample size of 392 (79 cases and 313 controls) were selected by the systematic sampling technique. Cases were all patients with TB with culture proven or line probe assay confirmed Mycobacterium tuberculosis resistant to at least both isoniazid and rifampicin and registered on second-line TB treatment. Controls were all patients with bacteriological (molecular) proven drug-susceptible TB strains and whose recent smear results were turned to negative and registered as cured. Both bivariate and multivariable logistic regression analysis was used to identify risk factors of MDR-TB infections. MAIN OUTCOME MEASURE: Identifying the risk factors for MDR-TB. RESULTS: A total of 392 participants (79 cases and 313 controls) were interviewed. Multivariable analysis showed that direct contact with known patients with TB (AOR =4.35; 95% CI: 1.45 to 9.81), history of previous TB treatment (AOR=2.51; 95% CI: 1.50 to 8.24), history of cigarette smoking (AOR=3.24; 95% CI :2.17 to 6.91) and living in rural area (AOR=4.71; 95% CI :3.13 to 9.58) were identified risk factors for MDR-TB infections. CONCLUSIONS: The study findings revealed that direct contact with known patients with TB, previous history of TB treatment, history of cigarette smoking and rural residence were potential risk factors for the occurrence of MDR-TB. In order to reduce the burden of drug resistance, strategies of controlling MDR-TB in the study area should emphasise on enhancing public health education and reducing treatment interruptions of patients with TB and drug-resistant TB.


Assuntos
Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Humanos , Antituberculosos/uso terapêutico , Antituberculosos/farmacologia , Estudos de Casos e Controles , Etiópia/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Fatores de Risco , Resistência a Múltiplos Medicamentos
5.
Cell Commun Signal ; 21(1): 9, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639771

RESUMO

BACKGROUND: Solute carrier family 7 member 2 (SLC7A2), a cationic amino acid transporter, is lowly expressed in ovarian and hepatocellular cancers, which is associated with their worse prognosis. However, its roles in the prognosis, drug resistance and immune infiltration in non-small-cell lung cancer (NSCLC) are unclear. METHODS: We chose SLC7A2 from RNA-Seq of paclitaxel/cisplatin-resistant A549 cells, then bioinformatics, cell lines construction, RT-qPCR, and CCK8 were performed to investigate SLC7A2 role. RESULT: We analyzed the 223 differentially expressed genes (DEGs) from RNA-Seq of paclitaxel/cisplatin-resistant A549 cells and found that SLC7A2 expression was down-regulated in NSCLC. Lower SLC7A2 expression was associated with worse recurrence-free survival (RFS) in NSCLC. SLC7A2 silencing enhanced the proliferation of NSCLC cells and their insensitivity to paclitaxel, cisplatin, and gemcitabine in vitro. Activation of AMPK has up-regulated SLC7A2 expression and enhanced the sensitivity of NSCLC cells to anti-tumor drugs, which could be attributed to E2F1's regulation. In addition, the levels of SLC7A2 expression were correlated to the numbers of infiltrated neutrophils, macrophages, dendritic cells and their marker genes, like CD86, HLA-DPA1 and ITGAM. CONCLUSIONS: SLC7A2 may act as a tumor suppressor to modulate drug sensitivity, immune infiltration and survival in NSCLC. Video abstract.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/farmacologia , Neoplasias Pulmonares/patologia , Resistência a Múltiplos Medicamentos , Paclitaxel/farmacologia , Sistemas de Transporte de Aminoácidos Básicos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica
6.
Sci Rep ; 13(1): 351, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611083

RESUMO

Nanosecond pulsed electric fields (nsPEF) have been shown to exert anticancer effects; however, little is known about the mechanisms triggered in cancer cells by nanosecond-length pulses, especially when low, sub-permeabilization voltage is used. In this study, three human pancreatic cancer cell lines were treated with nsPEF and molecular changes at the cellular level were analyzed. Further, we assessed the efficacy of paclitaxel chemotherapy following nsPEF treatment and correlated that with the changes in the expression of multi-drug resistance (MDR) proteins. Finally, we examined the influence of nsPEF on the adhesive properties of cancer cells as well as the formation and growth of pancreatic cancer spheroids. Cell line response differed with the application of a 200 ns, 100 pulses, 8 kV/cm, 10 kHz PEF treatment. PEF treatment led to (1) the release of microvesicles (MV) in EPP85-181RDB cells, (2) electropermeabilization in EPP85-181RNOV cells and (3) cell shrinkage in EPP85-181P cells. The release of MV's in EPP85-181RDB cells reduced the membrane content of P-gp and LRP, leading to a transient increase in vulnerability of the cells towards paclitaxel. In all cell lines we observed an initial reduction in size of the cancer spheroids after the nsPEF treatment. Cell line EPP85-181RNOV exhibited a permanent reduction in the spheroid size after nsPEF. We propose a mechanism in which the surface tension of the membrane, regulated by the organization of actin fibers, modulates the response of cancer cells towards nsPEF. When a membrane's surface tension remains low, we observed some cells form protrusions and release MVs containing MDR proteins. In contrast, when cell surface tension remains high, the cell membrane is being electroporated. The latter effect may be responsible for the reduced tumor growth following nsPEF treatment.


Assuntos
Resistência a Múltiplos Medicamentos , Neoplasias Pancreáticas , Humanos , Linhagem Celular , Membrana Celular/metabolismo , Eletroporação , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/metabolismo
7.
BMC Infect Dis ; 23(1): 11, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609225

RESUMO

BACKGROUND: The prevalence of resistant hospital infections in the intensive care unit (ICU) increases mortality and antibiotic resistance. COVID-19 pandemic may have unintended impact on nosocomial infections (NI) and the prevalence of resistant microorganism. METHODOLOGY: The present non-interventional study was performed by a pre and a post survey each lasting 8 months before (March-October 2019) and after (March-October 2020) the onset of COVID-19 pandemic in three ICU's, not allocated to COVID-19 patients, in Nemazee Hospital, Shiraz, Iran. The rates of the following nosocomial infections were compared at pre- and post-pandemic period: ventilator associated pneumonia (VAP), central line associated blood stream infection (CLABSI), catheter-associated urinary tract infections (CAUTI) and incidence of multiple drug resistance (MDR) pathogens. RESULTS: Pre-pandemic and pandemic incidence of VAP was 23.5 and 17.2 cases per 1000 device-days, respectively; an absolute decrease of 27%. The main reason for the decrease in the rate of VAP during the pandemic was a significant decrease in the rate of VAP caused by Acinetobacter baumannii; from 39 to 17% in total VAP episodes. The rate of VAP associated with other microorganisms remained relatively unchanged from 14.2 cases in pre-pandemic period to 14.3 cases per 1000 MV-days during the pandemic (P = 0.801). Pre-pandemic incidence of CLABSI was 7.3 cases and, in pandemic period, was 6.5 cases per 1000 device-days (IRR = 0.88, 95% CI 0.43-1.73, P = 0.703). Pre-pandemic incidence of CAUTI was 2 and in pandemic period, was 1.4 cases per 1000 device-days (IRR = 0.70, 95% CI 0.22-1.98, P = 0.469). CONCLUSION: The results of the present study showed a decrease in the incidence of VAP in critically ill non-COVID-19 patients during the pandemic compared to before the pandemic, especially regarding Acinetobacter baumannii.


Assuntos
Acinetobacter baumannii , COVID-19 , Infecções Relacionadas a Cateter , Infecção Hospitalar , Pneumonia Associada à Ventilação Mecânica , Infecções Urinárias , Humanos , Infecção Hospitalar/epidemiologia , Pandemias , Incidência , Estudos Prospectivos , COVID-19/epidemiologia , Infecções Relacionadas a Cateter/epidemiologia , Unidades de Terapia Intensiva , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Hospitais de Ensino , Infecções Urinárias/epidemiologia , Resistência a Múltiplos Medicamentos , Cateteres
8.
BMC Cancer ; 23(1): 24, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609245

RESUMO

BACKGROUND: P-glycoprotein (P-gp), a member of the ATP Binding Cassette B1 subfamily (ABCB1), confers resistance to clinically relevant anticancer drugs and targeted chemotherapeutics. However, paradoxically P-glycoprotein overexpressing drug resistant cells are "collaterally sensitive" to non-toxic drugs that stimulate its ATPase activity. METHODS: Cell viability assays were used to determine the effect of low concentrations of tamoxifen on the proliferation of multidrug resistant cells (CHORC5 and MDA-Doxo400), expressing P-gp, their parental cell lines (AuxB1 and MDA-MB-231) or P-gp-CRISPR knockout clones of AuxB1 and CHORC5 cells. Western blot analysis was used to estimate P-gp expression in different cell lines. Apoptosis of tamoxifen-induced cell death was estimated by flow cytometry using Annexin-V-FITC stained cells. Oxidative stress of tamoxifen treated cells was determined by measuring levels of reactive oxygen species and reduced thiols using cell-permeant 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) and 5,5-dithio-bis-(2-nitrobenzoic acid) DTNB, respectively. RESULTS: In this report, we show that P-gp-expressing drug resistant cells (CHORC5 and MDA-Doxo400) are collaterally sensitive to the anti-estrogen tamoxifen or its metabolite (4-hydroxy-tamoxifen). Moreover, P-gp-knockout clones of CHORC5 cells display complete reversal of collateral sensitivity to tamoxifen. Drug resistant cells exposed to low concentrations of tamoxifen show significant rise in reactive oxygen species, drop of reduced cellular thiols and increased apoptosis. Consistent with the latter, CHORC5 cells expressing high levels of human Bcl-2 (CHORC5-Bcl-2) show significant resistance to tamoxifen. In addition, the presence of the antioxidant N-acetylcysteine or P-gp ATPase inhibitor, PSC-833, reverse the collateral sensitivity of resistant cells to tamoxifen. By contrast, the presence of rotenone (specific inhibitor of mitochondria complex I) synergizes with tamoxifen. CONCLUSION: This study demonstrates the use of tamoxifen as collateral sensitivity drug that can preferentially target multidrug resistant cells expressing P-gp at clinically achievable concentrations. Given the widespread use of tamoxifen in the treatment of estrogen receptor-positive breast cancers, this property of tamoxifen may have clinical applications in treatment of P-gp-positive drug resistant breast tumors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Humanos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Estrogênio/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Tamoxifeno/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Adenosina Trifosfatases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular Tumoral
9.
Eur J Med Chem ; 248: 115070, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36628850

RESUMO

Human breast cancer resistance protein (BCRP), known also as ABCG2, plays a major role in multiple drug resistance (MDR) in tumor cells. Through this ABC transporter, cancer cells acquire the ability of resistance to structurally and functionally unrelated anticancer drugs. Nowadays, the design of ABCG2 inhibitors as potential agents to enhance the chemotherapy efficacy is an interesting strategy. In this context, we have used computer-aided drug design (CADD) based on available data of a large series of potent inhibitors from our groups as an approach in guiding the design of effective ABCG2 inhibitors. We report therein the results on the use of the FLAPpharm method to elucidate the pharmacophoric features of one of the ABCG2 binding sites involved in the regulation of the basal ATPase activity of the transporter. The predictivity of the model was evaluated by testing three predicted compounds which were found to induce high inhibitory activity of BCRP, in the nanomolar range for the best of them.


Assuntos
Antineoplásicos , Proteínas de Neoplasias , Humanos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Antineoplásicos/farmacologia , Antineoplásicos/química , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos
10.
Eur J Med Chem ; 248: 115092, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36645980

RESUMO

The co-administration of anticancer drugs and P-glycoprotein (P-gp) inhibitors was a treatment strategy to surmount multidrug resistance (MDR) in anticancer chemotherapy. In this study, novel phenylfuran-bisamide derivatives were designed as P-gp inhibitors based on target-based drug design, and 31 novel compounds were synthesized and screened on MCF-7/ADR cells. The result of bioassay revealed that compound y12d exhibited low cytotoxicity and promising MDR reversal activity (IC50 = 0.0320 µM, reversal fold = 1163.0), 3.64-fold better than third-generation P-gp inhibitor tariquidar (IC50 = 0.1165 µM, reversal fold = 319.3). The results of Western blot and rhodamine 123 accumulation verified that compound y12d exhibited excellent MDR reversal activity by inhibiting the efflux function of P-gp but not expression. Furthermore, molecular docking showed that compound y12d bound to target P-gp by forming the double H-bond interactions with residue Gln 725. These results suggest that compound y12d might be a potential MDR reveal agent acting as a P-gp inhibitor in clinical therapeutics, and provide insight into design strategy and skeleton optimization for the development of P-gp inhibitors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Doxorrubicina , Humanos , Células MCF-7 , Doxorrubicina/farmacologia , Simulação de Acoplamento Molecular , Resistencia a Medicamentos Antineoplásicos , Resistência a Múltiplos Medicamentos
11.
ACS Appl Mater Interfaces ; 15(1): 309-326, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36576435

RESUMO

Cancer multidrug resistance (MDR) is an important reason that results in chemotherapy failure. As a main mechanism of MDR, overexpressed P-glycoprotein (P-gp) utilizes adenosine triphosphate (ATP) to actively pump chemotherapy drugs out of cells. In addition, metabolic reprogramming of drug-resistant tumor cells (DRTCs) exacerbates the specific hypoxic microenvironment and promotes tumor metastasis and recurrence. Therefore, we propose a novel sonodynamic therapy (SDT) paradigm to induce energy metabolism disorder and drug resistance change of DRTCs. A US-controlled "Nanoenabled Energy Metabolism Jammer" (TL@HPN) is designed using perfluoropentane (PFP) adsorbing oxygen in the core, and a targeting peptide (CGNKRTR) is attached to the liposome as the delivery carrier shell to incorporate hematoporphyrin monomethyl ether (HMME) and paclitaxel (PTX). The TL@HPN with ultrasonic/photoacoustic imaging (PAI/USI) precisely controlled the release of drugs and oxygen after being triggered by ultrasound (US), which attenuated the hypoxic microenvironment. SDT boosted the reactive oxygen species (ROS) content in tumor tissues, preferentially inducing mitochondrial apoptosis and maximizing immunogenic cell death (ICD). Persistently elevated oxidative stress levels inhibited ATP production and downregulated P-gp expression by disrupting the redox balance and electron transfer of the respiratory chain. We varied the effect of TL@HPN combined with PD-1/PD-L1 to activate autoimmunity and inhibit tumor metastasis, providing a practical strategy for expanding the use of SDT-mediated tumor energy metabolism.


Assuntos
Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Resistência a Múltiplos Medicamentos , Espécies Reativas de Oxigênio/metabolismo , Oxigênio , Metabolismo Energético , Trifosfato de Adenosina/metabolismo , Linhagem Celular Tumoral , Microambiente Tumoral
12.
Toxicol Appl Pharmacol ; 459: 116344, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36526072

RESUMO

P-glycoprotein (P-gp, encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP/ABCG2) are efflux multidrug resistance (MDR) transporters localized at the syncytiotrophoblast barrier of the placenta and protect the conceptus from drug and toxin exposure throughout pregnancy. Infection is an important modulator of MDR expression and function. This review comprehensively examines the effect of infection on the MDR transporters, P-gp and BCRP in the placenta. Infection PAMPs such as bacterial lipopolysaccharide (LPS) and viral polyinosinic-polycytidylic acid (poly I:C) and single-stranded (ss)RNA, as well as infection with Zika virus (ZIKV), Plasmodium berghei ANKA (modeling malaria in pregnancy - MiP) and polymicrobial infection of intrauterine tissues (chorioamnionitis) all modulate placental P-gp and BCRP at the levels of mRNA, protein and or function; with specific responses varying according to gestational age, trophoblast type and species (human vs. mice). Furthermore, we describe the expression and localization profile of Toll-like receptor (TLR) proteins of the innate immune system at the maternal-fetal interface, aiming to better understand how infective agents modulate placental MDR. We also highlight important gaps in the field and propose future research directions. We conclude that alterations in placental MDR expression and function induced by infective agents may not only alter the intrauterine biodistribution of important MDR substrates such as drugs, toxins, hormones, cytokines, chemokines and waste metabolites, but also impact normal placentation and adversely affect pregnancy outcome and maternal/neonatal health.


Assuntos
Infecção por Zika virus , Zika virus , Gravidez , Feminino , Humanos , Camundongos , Animais , Placenta/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Distribuição Tecidual , Proteínas de Neoplasias/genética , Resistência a Múltiplos Medicamentos , Proteínas de Membrana Transportadoras/metabolismo
13.
Proc Natl Acad Sci U S A ; 120(1): e2213437120, 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36580587

RESUMO

ABCG2 is an ATP-binding cassette (ABC) transporter that extrudes a wide range of xenobiotics and drugs from the cell and contributes to multidrug resistance in cancer cells. Following our recent structural characterization of topotecan-bound ABCG2, here, we present cryo-EM structures of ABCG2 under turnover conditions in complex with a special modulator and slow substrate, tariquidar, in nanodiscs. The structures reveal that similar to topotecan, tariquidar induces two distinct ABCG2 conformations under turnover conditions (turnover-1 and turnover-2). µs-scale molecular dynamics simulations of drug-bound and apo ABCG2 in native-like lipid bilayers, in both topotecan- and tariquidar-bound states, characterize the ligand size as a major determinant of its binding stability. The simulations highlight direct lipid-drug interactions for the smaller topotecan, which exhibits a highly dynamic binding mode. In contrast, the larger tariquidar occupies most of the available volume in the binding pocket, thus leaving little space for lipids to enter the cavity and interact with it. Similarly, when simulating ABCG2 in the apo inward-open state, we also observe spontaneous penetration of phospholipids into the binding cavity. The captured phospholipid diffusion pathway into ABCG2 offers a putative general path to recruit any hydrophobic/amphiphilic substrates directly from the membrane. Our simulations also reveal that ABCG2 rejects cholesterol as a substrate, which is omnipresent in plasma membranes that contain ABCG2. At the same time, cholesterol is found to prohibit the penetration of phospholipids into ABCG2. These molecular findings have direct functional ramifications on ABCG2's function as a transporter.


Assuntos
Resistência a Múltiplos Medicamentos , Topotecan , Ligantes , Transportadores de Cassetes de Ligação de ATP/metabolismo , Fosfolipídeos , Colesterol , Resistencia a Medicamentos Antineoplásicos
14.
Gut Microbes ; 15(1): 2157698, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36524841

RESUMO

Non-caloric artificial sweeteners have been widely permitted as table sugar substitutes with high intensities of sweetness. They can pass through the intestinal tract without significant metabolization and frequently encounter the gut microbiome, which is composed of diverse bacterial species and is a pool of antibiotic resistance genes (ARGs). However, little is known about whether these sweeteners could accelerate the spread of ARGs in the gut microbiome. Here, we established an in vitro conjugation model by using Escherichia coli that carries chromosome-inserted Tn7 lacIq-pLpp-mCherry and plasmid-encoded gfpmut3b gene as the donor and murine fecal bacteria as the recipient. We found that four commonly used artificial sweeteners (saccharin, sucralose, aspartame, and acesulfame potassium) can increase reactive oxygen species (ROS) production and promote plasmid-mediated conjugative transfer to the gut microbiome. Cell sorting and 16S rRNA gene amplicon sequencing analysis of fecal samples reveal that the tested sweeteners can promote the broad-host-range plasmid permissiveness to both Gram-negative and Gram-positive gut bacteria. The increased plasmid permissiveness was also validated with a human pathogen Klebsiella pneumoniae. Collectively, our study demonstrates that non-caloric artificial sweeteners can induce oxidative stress and boost the plasmid-mediated conjugative transfer of ARGs among the gut microbiota and a human pathogen. Considering the soaring consumption of these sweeteners and the abundance of mobile ARGs in the human gut, our results highlight the necessity of performing a thorough risk assessment of antibiotic resistance associated with the usage of artificial sweeteners as food additives.


Assuntos
Microbioma Gastrointestinal , Camundongos , Humanos , Animais , Microbioma Gastrointestinal/genética , Edulcorantes/farmacologia , RNA Ribossômico 16S/genética , Plasmídeos/genética , Bactérias/genética , Escherichia coli/genética , Antibacterianos/farmacologia , Resistência a Múltiplos Medicamentos
15.
J Nat Prod ; 86(1): 131-137, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36538372

RESUMO

The first total syntheses of the orchid-derived natural products isoarundinin I (1), (±)-bleochrin F ((±)-2), (±)-blestanol K ((±)-3), and (±)-pleionol ((±)-4) from renewable starting materials are reported, along with the evaluation of their biological activities. The total syntheses were based on regioselective aromatic bromination reactions in combination with a key acid-promoted regioselective intramolecular cyclization. The biological results suggest that isoarundinin I (1), (±)-blestanol K ((±)-3), and (±)-pleionol ((±)-4) have the potential to inhibit the growth of both sensitive and multidrug-resistant cancer cells.


Assuntos
Produtos Biológicos , Produtos Biológicos/química , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ciclização , Halogenação , Estereoisomerismo
16.
Drug Resist Updat ; 66: 100906, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36565657

RESUMO

It was well known that P-glycoprotein (P-gp/ABCB1) is a master regulator of multidrug resistance (MDR) in cancers. However, the clinical benefit from blocking this pathway remains inconclusive, which motivates a paradigm shift towards alternative strategies for enhancing drug influx. Using a patient-derived organoid (PDO)-based drug screening platform, we report that the combined use of chemotherapy and CCT251545 (CCT) displays robust synergistic effect against PDOs and reduces proliferation of MDR cancer cells in vitro, and results in regression of xenograft tumors, reductions in metastatic dissemination and recurrence rate in vivo. The synergistic activity mediated by CCT can be mainly attributed to the intense uptake of chemotherapeutic agents into the cells, accompanied by alterations in cell phenotypes defined as a mesenchymal epithelial transformation (MET). Mechanistically, analysis of the transcriptome coupled with validation in cellular and animal models demonstrate that the chemosensitizing effect of CCT is profoundly affected by Rac1-dependent macropinocytosis. Furthermore, CCT binds to NAMPT directly, resulting in elevated NAD levels within MDR cancer cells. This effect promotes the assembly of adherents junction (AJ) components with cytoskeleton, which is required for continuous induction of macropinocytosis and consequent drug internalization. Overall, our results illustrate the potential use of CCT as a combination partner for the commonly used chemotherapeutic drugs in the management of MDR cancers.


Assuntos
Antineoplásicos , Neoplasias , Animais , Humanos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias/patologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/farmacologia
17.
Anal Chem ; 95(2): 560-564, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36563048

RESUMO

Identifying effective reversal agents overcoming multidrug resistance with causal mechanisms from an efflux pump protein is of vital importance for enhanced tumor chemotherapy in clinic. To achieve this end, we construct a metal cluster-based probe, named clusterbody, to develop flow sorting-assisted single-cell mass spectrometry analysis. This clusterbody synthesized by biomimetic mineralization possesses an antibody-like property to selectively recognize an efflux pump protein. The intrinsic red fluorescence emission of the clusterbody facilitates fluorescence-activated high-throughput cell sorting of subpopulations with different multidrug resistance levels. Furthermore, based on the accurate formula of the clusterbody, the corresponding protein abundance at the single-cell level is determined through detecting gold content via precise signal amplification by laser ablation inductively coupled plasma mass spectrometry. Therefore, the effect of reversal agent treatment overcoming multidrug resistance is evaluated in a quantitative manner. This work opens a new avenue to identify reversal agents, shedding light on developing combined or synergetic tumor therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias , Humanos , Resistência a Múltiplos Medicamentos , Neoplasias/tratamento farmacológico , Transporte Biológico , Espectrometria de Massas
18.
Int J Pharm ; 631: 122488, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36521638

RESUMO

Reduced drug uptake and elevated drug efflux are two major mechanisms in cancer multidrug resistance (MDR). In the present study, a new multistage O2-producing liposome with NAG/R8-dual-ligand and stimuli-responsive dePEGylation was developed to address the abovementioned issues simultaneously. The designed C-NAG-R8-PTXL/MnO2-lip could also achieve magnetic resonance imaging (MRI)-guided synergistic chemodynamic/chemotherapy (CDT/CT). In vitro and in vivo studies showed that C-NAG-R8-PTXL/MnO2-lip enhanced circulation time by PEG and targeted the tumor site. After tumor accumulation, endogenous l-cysteine was administered, and the PEG-attached disulfide bond was broken, resulting in the dissociation of PEG shells. The previously hidden positively charged R8 by different lengths of PEG chains was exposed and mediated efficient internalization. In addition, the oxygen (O2) generated by C-NAG-R8-PTXL/MnO2-lip relieved the hypoxic environment within the tumor, thus reducing the efflux of chemotherapeutic drug. O2 was able to burst liposomes and triggered the release of PTXL. The toxic hydroxyl radical (·OH), which was produced by H2O2 and Mn2+, strengthened CDT/CT. C-NAG-R8-PTXL/MnO2-lip was also used as MRI contrast agent, which blazed the trail to rationally design theranostic agents for tumor imaging.


Assuntos
Lipossomos , Neoplasias , Humanos , Lipossomos/química , Compostos de Manganês/química , Linhagem Celular Tumoral , Peróxido de Hidrogênio , Óxidos/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resistência a Múltiplos Medicamentos , Oxigênio , Imageamento por Ressonância Magnética , Microambiente Tumoral , Nanomedicina Teranóstica
19.
Eur J Pharmacol ; 940: 175323, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36535492

RESUMO

Glutamine, as the most abundant amino acid in the body, participates in the biological synthesis of nucleotides and other non-essential amino acids in the process of cell metabolism. Recent studies showed that glutamine metabolic reprogramming is an important signal during cancer development and progression. This metabolic signature in cancer cells can promote the development of cancer by activating multiple signaling pathways and oncogenes. It can also be involved in tumor immune regulation and promote the development of drug resistance to tumors. In this review, we mainly summarize the role of glutamine metabolic reprogramming in tumors, including the regulation of multiple signaling pathways. We further discussed the promising tumor treatment strategy by targeting glutamine metabolism alone or in combination with chemotherapeutics.


Assuntos
Glutamina , Neoplasias , Humanos , Glutamina/metabolismo , Neoplasias/patologia , Transformação Celular Neoplásica/metabolismo , Aminoácidos , Resistência a Múltiplos Medicamentos
20.
Reproduction ; 165(1): 79-91, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36215093

RESUMO

In brief: Oocyte quality remains the most important and unsolved issue in reproduction. Our data show that multidrug resistance transporters and oocyte mitochondria are involved in determining oocyte quality in a mouse model. Abstract: Multidrug resistance transporter-1 (MDR-1) is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and by-products. Previous findings by our group demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Considering the importance of these organelles in the female gamete, we assessed the impact of MDR-1 dysfunction on mouse oocyte quality, with a particular focus on the meiotic spindle organization, aneuploidies, Ca2+ homeostasis, ATP production and mtDNA mutations. Our results demonstrate that young Mdr1a mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle to germinal vesicle breakdown transition, an increased percentage of symmetric divisions, chromosome misalignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more SNPs in the exomic DNA and twice the amount of mitochondrial DNA (mtDNA) SNPs compared to the wild-type ones. Ca2+ analysis revealed the inability of MDR-1 mutant oocytes to manage Ca2+ storage content and oscillations in response to several stimuli, and ATP quantification shows that mutant oocytes trend toward lower ATP levels compared to wild types. Finally, 1-year-old mutant ovaries express a lower amount of SIRT1, SIRT3, SIRT5, SIRT6 and SIRT7 compared to wild-type levels. These results together emphasize the importance of MDR-1 in mitochondrial physiology and highlight the influence of MDR-1 on oocyte quality and ovarian aging.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Cálcio , Meiose , Oócitos , Sirtuínas , Animais , Feminino , Camundongos , Trifosfato de Adenosina/metabolismo , Cálcio/metabolismo , DNA Mitocondrial/genética , Resistência a Múltiplos Medicamentos , Homeostase , Oócitos/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo , Fuso Acromático/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
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