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6.
Ann Hematol ; 99(6): 1241-1249, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32307568

RESUMO

Patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) can be effectively treated with tyrosine kinase inhibitors (TKIs) and achieve a lifespan similar to the general population. The success of TKIs, however, requires long-term and sometimes lifelong treatment; thus, patient-assessed health-related quality of life (HRQoL) has become an increasingly important parameter for treatment selection. Bosutinib is a TKI approved for CP CML in newly diagnosed adults and in those resistant or intolerant to prior therapy. In the Bosutinib Trial in First-Line Chronic Myelogenous Leukemia Treatment (BFORE), bosutinib demonstrated a significantly higher major molecular response rate compared with imatinib, with maintenance of HRQoL (measured by the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire), after 12 months of first-line treatment. We examined relationships between molecular response (MR) and HRQoL. MR values were represented by a log-reduction scale (MRLR; a continuous variable). A repeated-measures longitudinal model was used to estimate the relationships between MRLR as a predictor and each FACT-Leu domain as an outcome. Effect sizes were calculated to determine strength of effects and allow comparisons across domains. The majority of FACT-Leu domains (with the exception of social well-being and physical well-being) demonstrated a significant relationship with MRLR (p < 0.05). Our results showed variable impact of clinical improvement on different dimensions of HRQoL. For patients who achieved MR5, emotional well-being and leukemia-specific domains showed the greatest improvement, with medium differences in effect sizes, whereas social well-being and physical well-being had the weakest relationship with MR.


Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/psicologia , Nitrilos/uso terapêutico , Qualidade de Vida/psicologia , Quinolinas/uso terapêutico , Humanos , Leucemia Mieloide de Fase Crônica/sangue , Resultado do Tratamento
7.
Bioresour Technol ; 307: 123241, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32244078

RESUMO

Nitroaniline (NA) wastewater is known to be highly toxic and biodegradation-resistant. Based on the principles of molecular oxygen supply and biofilm formation, a novel membrane-aerated biofilter (MABF) combining membrane aeration with a biofilter was established for the first time to treat NA wastewater containing the same concentrations of p-nitroaniline (PNA) and o-nitroaniline (ONA). The NA wastewater treatment performance of the MABF was investigated, and the NA biodegradation characteristics were evaluated. When the influent NA concentration was 120 mg/L, the PNA and ONA removal rates reached 100% and 86.56%, respectively. The NA removal loading reached 111.62 g/m3·d, and the total nitrogen (TN) removal rate reached 82.97%. The synergistic effects of the diverse microorganisms in the membrane-aerated and nonaerated zones of the MABF enhanced the removal of NA and nitrogen. This MABF is an economically efficient and environmentally friendly technology for treating wastewater containing toxic and hazardous organic compounds.


Assuntos
Eliminação de Resíduos Líquidos , Águas Residuárias , Compostos de Anilina , Biodegradação Ambiental , Análise da Demanda Biológica de Oxigênio , Reatores Biológicos , Nitrogênio
8.
Anticancer Res ; 40(4): 2239-2246, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234920

RESUMO

AIM: The current study reports the type of salvage chemotherapy following osimertinib and its treatment efficacy in patients with non-small-cell lung carcinoma (NSCLC) who acquire resistance to osimertinib. PATIENTS AND METHODS: In this retrospective cohort study, data from the medical charts of 40 patients with NSCLC treated with osimertinib were obtained, primarily focusing on 14 undergoing salvage chemotherapy including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) or cytotoxic agents immediately following osimertinib. The treatment efficacy of salvage chemotherapy was evaluated. RESULTS: Five and nine patients received EGFR-TKI and cytotoxic agents following osimertinib, respectively. The overall response rate to EGFR-TKI treatment following osimertinib tended to be lower than that for cytotoxic agents (0% vs. 44.4%). The median progression-free-survival was significantly poorer in patients receiving EGFR-TKI treatment than in those receiving cytotoxic agents. CONCLUSION: Cytotoxic agent administration should be considered more frequently than EGFR-TKIs for patients with NSCLC resistant to osimertinib.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Salvação/métodos , Acrilamidas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
9.
Mutat Res ; 850-851: 503148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32247557

RESUMO

Norharman exists in cigarette smoke and cooked foods and is non-mutagenic among Salmonella strains but mutagenic to S. typhimurium TA98 and YG1024 in the presence of S9 mix and aniline and o-toluidine. Co-mutagenesis of ß-carbolines and aniline and o-toluidine occurs through the formation of novel mutagenic aminophenyl-ß-carboline derivatives including 9-(4'-aminophenyl)-9H-pyrido[3,4-b]indole [aminophenylnorharman] (APNH)] and 9-(4'- amino-3'-methylphenyl)-9H-pyrido[3,4-b]indole [aminomethylphenylnorharman] (AMPNH)]. Since humans are often simultaneously exposed to ß-carbolines and aniline and o-toluidine, their effects on humans should be clarified. The most potent of these, APNH, induced both point mutations and small deletions in the liver and colon of gpt delta transgenic mice. Major APNH-induced mutations in the liver occurred at a G:C base pair, suggesting that APNH-DNA adducts (dG-C8-APNH) are potentially involved in these mutations. Furthermore, APNH induced hepatic and colon tumors harboring K-ras, ß-catenin, and Apc mutations in F344 rats, with high incidence. Mutations at G:C base pairs were predominant, similar to those in the in vivo mutation assay using gpt delta mice. Moreover, APNH detected in human urine samples obtained from both healthy volunteers on a normal diet and inpatients receiving parenteral alimentation; therefore, APNH can be considered an endogenous carcinogen contributing to tumorigenesis. Exposure levels of these aminophenyl-ß-carboline derivatives may be lower than those of carcinogenic heterocyclic amines (HCAs) including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); however, their health risks in terms of tumorigenesis may be comparable owing to stronger genotoxic effects of APNH rather than HCAs. This review summarized APNH mutagenicity/carcinogenicity, and its in vivo formation. Moreover, the effect on tumorigenesis in humans also discussed.


Assuntos
Carbolinas/química , Indóis/toxicidade , Mutagênese/efeitos dos fármacos , Piridinas/toxicidade , Toluidinas/química , Compostos de Anilina/toxicidade , Animais , Carbolinas/toxicidade , Colo/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Mutação Puntual/efeitos dos fármacos , Toluidinas/toxicidade
10.
Zhonghua Zhong Liu Za Zhi ; 42(3): 210-215, 2020 Mar 23.
Artigo em Chinês | MEDLINE | ID: mdl-32252199

RESUMO

Objective: To investigate the effects of osimertinib on proliferation, migration and invasion of procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2) overexpressing HCC827 cells and explore the potential mechanism of PLOD2 induced osimertinib resistance. Methods: We transfected HCC827 cells with LV-vector and LV-over/PLOD2. The expression of PLOD2 was detected by quantitative real time polymerase chain reaction (qRT-PCR) and western blotting. The effects of osimertinib on the proliferation of HCC827-vector and HCC827-PLOD2 cells were evaluated by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H tetrazolium bromide (MTT) assay. The effects of osimertinib on the migration and invasion of HCC827-vector and HCC827-PLOD2 cells were determined by Transwell assays. The expressions of E-cadherin and vimentin in cells were detected by immunofluorescence (IF). The expressions of epithelial-mesenchymal transition (EMT), FAK-PI3K/AKT and MAPK signal pathway related proteins were detected by western blotting. Results: The MTT assay showed that HCC827-PLOD2 cells were hyposensitive to osimertinib. The 50% inhibitory concentration (IC(50)) and resistance index of osimertinib for HCC827-PLOD2 cells was over 1 000 nmol/L and over 100, respectively. The result of wound healing assay showed that the migration distance of HCC827-PLOD2 was about (2.13±0.21) fold changes as that of HCC827-vector cells. The result of Transwell assay showed that the numbers of HCC827-PLOD2 passing through the matrix membrane were (212.78±10.43), significantly higher than (101.32±12.52) of HCC827-vector cells (P<0.01). The result of IF showed that compared with HCC827-vector cells, the expression of E-cadherin was down-regulated while vimentin was up-regulated in HCC827-PLOD2 cells. Osimertinb downregulated E-cadherin and upregulated vimentin expression in HCC827-vector cells but had limited effect in HCC827-PLOD2 cells. The result of western blotting showed that PLOD2 significantly increased vimentin expression level while decreased E-cadherin expression level. Osimertinib inhibited the expression of p-EGFR, but did not affect the expressions of PLOD2, p-FAK, p-AKT, p-ERK, vimentin and E-cadherin in HCC827-PLOD2 cells. Conclusion: PLOD2 confers resistance to osimertinib in HCC827 cells by regulating EMT, FAK-PI3K/AKT and MAPK signal pathways.


Assuntos
Acrilamidas/farmacologia , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Pró-Colágeno-Lisina 2-Oxoglutarato 5-Dioxigenase/metabolismo , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Transição Epitelial-Mesenquimal , Humanos , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases
11.
Medicine (Baltimore) ; 99(16): e19620, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311931

RESUMO

For the diagnosis of mild cognitive impairment (MCI) and Alzheimer disease (AD), variable neuroimaging and neuropsychological tests have been used. We aimed to evaluate the correlation of neuropsychological domain with new amyloid positron emission tomography (PET) study and to validate the availability of new PET tracer.We enrolled 20 patients who underwent C-PiB-PET/CT, new PET tracer F-FC119S PET/CT from November, 2014 to July, 2015. Among them, 10 patients were diagnosed with AD and 10 patients with MCI. The current version of Seoul Neuropsychological Screening Battery (SNSB) II was performed for cognitive evaluation. Each parameter of SNSB was compared between 2 patient groups. Spearman correlation analysis between value of SNSB domain and standardized uptake value ratio (SUVR) of PET was also performed.The AD group presented significant poor z-score in Korean-Boston Naming Test(K-BNT) (P = .01),copy score of Rey Complex Figure Test (RCFT) (P = .049), immediate (P = .028)and delayed memory of Seoul Verbal Learning Test (SVLT) (P = .028), recognition of RCFT (P = .004), "animal" of Controlled Oral Word Association Test (COWAT) (P = .041), color reading of Korean-Color Word Stroop test (K-CWST) (P = .014), and Digit Symbol Coding (DSC) (P = .007) compared with MCI group. That means, except attention domain, all other cognitive domains were relatively impaired in AD compared with MCI. In correlation analysis, we found that poor performances on copy score of RCFT in MCI groups were associated with great beta amyloid burden in frontal area in both C-PiB-PET/CT and F-FC119S PET/CT. In AD group, F-FC119S PET presented more extensive correlation in each cognitive domain with multiple cortical areas compared with C-PiB-PET.The degree of amyloid burden assessed on F-FC119S PET was significantly correlated with neuropsychological test in AD, and also MCI patients. The combination of neuropsychological evaluation with novel F-FC119S PET/CT can be used for valid biomarker for MCI and AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Amiloide/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Compostos de Anilina , Radioisótopos de Carbono , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Feminino , Radioisótopos de Flúor , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Testes Neuropsicológicos , Traçadores Radioativos , Tiazóis
12.
Bull Environ Contam Toxicol ; 104(4): 511-519, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32193570

RESUMO

Through batch adsorption and column leaching experiments, this study aimed to investigate the adsorption and transport behavior of aniline in loess and related mechanism under different hydrochemical conditions. Batch experiments results indicated that aniline adsorption reached equilibrium after about 120 min, and the adsorption fitted the pseudo-second-order kinetic and Freundlich models well. The adsorption was spontaneous and exothermic process, indicating the aniline adsorbed by inherent colloidal particles (ICPs) tended to transport. Low pH value, ionic strength and temperature benefitted the adsorption. Column experiments results under different ionic strengths (100, 10 and 1 mM) confirmed the potential transport of aniline. The FT-IR spectra have further suggested that aniline was adsorbed by the ICPs through hydrogen-bond, hydrophobic effect and cation exchange interactions. Low ionic strength was advantageous for the adsorption of aniline in loess and the stabilities of ICPs in solution, but enhanced the co-transport probability of ICPs with aniline in loess.


Assuntos
Compostos de Anilina/análise , Poluentes Ambientais/análise , Sedimentos Geológicos/química , Modelos Teóricos , Solo/química , Adsorção , Concentração de Íons de Hidrogênio , Cinética , Concentração Osmolar , Temperatura
15.
Science ; 367(6484): 1372-1376, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193327

RESUMO

The structural and functional complexity of multicellular biological systems, such as the brain, are beyond the reach of human design or assembly capabilities. Cells in living organisms may be recruited to construct synthetic materials or structures if treated as anatomically defined compartments for specific chemistry, harnessing biology for the assembly of complex functional structures. By integrating engineered-enzyme targeting and polymer chemistry, we genetically instructed specific living neurons to guide chemical synthesis of electrically functional (conductive or insulating) polymers at the plasma membrane. Electrophysiological and behavioral analyses confirmed that rationally designed, genetically targeted assembly of functional polymers not only preserved neuronal viability but also achieved remodeling of membrane properties and modulated cell type-specific behaviors in freely moving animals. This approach may enable the creation of diverse, complex, and functional structures and materials within living systems.


Assuntos
Compostos de Anilina/química , Ascorbato Peroxidases/genética , Engenharia Genética , Neurônios/fisiologia , Nitrocompostos/química , Fenilenodiaminas/química , Polímeros/química , Potenciais de Ação , Animais , Ascorbato Peroxidases/metabolismo , Caenorhabditis elegans , Membrana Celular/metabolismo , Sobrevivência Celular , Células Cultivadas , Condutividade Elétrica , Células HEK293 , Hipocampo , Humanos , Potenciais da Membrana , Camundongos , Neurônios Motores/fisiologia , Células Musculares/fisiologia , Neurônios/enzimologia , Técnicas de Patch-Clamp , Polímeros/metabolismo , Ratos , Transdução Genética
16.
Chemosphere ; 250: 126300, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32113094

RESUMO

Developing novel catalyst with both high efficiency and stability presents an enticing prospect for peroxymonosulfate (PMS) activation. In this paper, nitrogen-doped porous carbon encapsulating iron nanoparticles (CN-Fe) was fabricated by a facile carbothermal reduction process using polyaniline (PANI) and α-Fe2O3 as the precursors. The stubborn antibiotics, sulfathiazole (STZ), was employed as a target pollutant, demonstrating that CN-Fe coupled with PMS could achieve 96% removal efficiency and even 57% mineralization rate of STZ within 40 min. More importantly, the rate constant of CN-Fe was calculated to be 0.07665 min-1, which was 6 times higher than that of the commercial α-Fe2O3 catalyst. Furthermore, CN-Fe also presented a favorable catalytic performance for removing other organic pollutants including phenolic compounds and organic dyes. Interestingly, the catalytic activity of the used CN-Fe catalyst could be regenerated after thermal treatment (600 °C) and the as-synthesized CN-Fe catalyst exhibited excellent long-term stability with almost no loss of activity after storage for three months. The catalytic mechanism in the CN-Fe/PMS system was elucidated by electron paramagnetic resonance (EPR), linear sweep voltammetry (LSV), radical and electron trapping tests, which confirmed that sulfate radicals (SO4-), hydroxyl radicals (OH), superoxide radicals (O2-) and singlet oxygen (1O2) were generated in the oxidation process with the assistance of electron transfer between PMS and catalyst. To our knowledge, this was the first attempt for the application of PANI-derived CN-Fe hybrid materials as PMS activators and the findings would provide a simple and promising strategy to fabricate highly efficient and environment-benign catalysts for wastewater remediation.


Assuntos
Nanopartículas Metálicas/química , Peróxidos/química , Sulfatiazol/química , Poluentes Químicos da Água/química , Compostos de Anilina , Catálise , Poluentes Ambientais , Ferro , Nitrogênio , Oxirredução , Porosidade , Oxigênio Singlete , Sulfatos , Superóxidos , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias
17.
Chemosphere ; 252: 126468, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32197178

RESUMO

An ordered g-C3N4- and polyaniline-modified titanium oxide nanotube array (g-C3N4- and PANI-co-modified TiO2 NTAs) was successfully synthesized and used as a photocatalyst. Polyaniline (PANI) was coated onto TiO2 NTAs by electrochemical polycondensation, and g-C3N4 was deposited via the soaking adsorption method. The photocatalysts were examined by several technologies. The experiments demonstrated that the amount of g-C3N4 and PANI, as well as the initial pH value, had significant effects on the photocatalytic efficiency. The resulting photocatalysts exhibited high visible light photocatalytic ability for tetrabromobisphenol A (TBBPA) for two reasons. First, PANI expanded the light absorption into the visible region. Second, rapid and efficient separation of photoinduced charges from the photogenerated potential difference were produced at the contact interface of g-C3N4 and PANI-co-modified TiO2 NTAs. The •OH, [Formula: see text] and h+ were dominant components for the photocatalytic degradation of TBBPA. In addition, the g-C3N4 and PANI-co-modified TiO2 NTAs have excellent long-term stability.


Assuntos
Nanotubos/química , Bifenil Polibromatos/química , Titânio/química , Adsorção , Compostos de Anilina , Catálise , Luz , Processos Fotoquímicos
18.
Anal Bioanal Chem ; 412(8): 1769-1784, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32043201

RESUMO

Simultaneous speciation of benzenediol isomers (BDIs), 1,2-benzenediol (catechol, CC), 1,3-benzenediol (resorcinol, RS), and 1,4-benzenediol (hydroquinone, HQ), was investigated by differential pulse voltammetry (DPV) using a graphite paste electrode (GPE) modified with Prussian blue-polyaniline nanocomposite. The modified GPE showed good stability, sensitivity, and selectivity properties for all the three BDIs. Prussian blue-doped nanosized polyaniline (PBNS-PANI) was synthesized first by using mechanochemical reactions between aniline and ferric chloride hexahydrate as the oxidants and then followed by the addition of potassium hexacyanoferrate(II) in a solid-state and template-free technique. The material was characterized by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy (XPS). The DPV measurements are performed in phosphate electrolyte solution with pH 4.0 at a potential range of - 0.1 to 1.0 V. The proposed modified electrode displayed a strong, stable, and continuous three well-separated oxidation peaks towards electrooxidation at potentials 0.20, 0.31, and 0.76 V for HQ, CC, and RS, respectively. The calibration curves were linear from 1 to 350.5 µM for both HQ and CC, while for RS, it was from 2 to 350.5 µM. The limit of detection was determined to be 0.18, 0.01, and 0.02 µM for HQ, CC, and RS, respectively. The analytical performance of the PBNS-PANI/GPE has been evaluated for simultaneous determination of HQ, CC, and RS in creek water, commercial hair dye, and skin whitening cream samples with satisfactory recoveries between 90 and 106%. Overall, we demonstrated that the presence of NS-PANI and PB resulted in a large redox-active surface area that enabled a promising analytical platform for simultaneous detection of BDIs. Graphical abstract.


Assuntos
Compostos de Anilina/química , Derivados de Benzeno/análise , Ferrocianetos/química , Nanoestruturas/química , Derivados de Benzeno/química , Calibragem , Eletrodos , Humanos , Concentração de Íons de Hidrogênio , Isomerismo , Cinética , Limite de Detecção , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Zhonghua Yu Fang Yi Xue Za Zhi ; 54(2): 213-218, 2020 Feb 06.
Artigo em Chinês | MEDLINE | ID: mdl-32074713

RESUMO

Aniline is one of the important chemical raw materials in daily life and the chemical industry. Aniline exposure might occur through intact skin, respiratory tract and digestive tract. It could pose negative impacts on many organs and systems of the human body, including toxicity or carcinogenicity to blood, liver, and spleen. This paper summarized the direct effects of aniline on human health and the indirect hazards of aniline on human health through environmental pollution and discussed the future research directions of aniline-induced health hazards.


Assuntos
Compostos de Anilina/efeitos adversos , Pesquisa Biomédica/tendências , Poluição Ambiental/efeitos adversos , Humanos
20.
J Cancer Res Clin Oncol ; 146(4): 843-858, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32056006

RESUMO

PURPOSE: Increased ATP-binding-cassette (ABC) transporter activity is a major cause of chemotherapy resistance in cancer. The ABC transporter family member ABCB1 is often overexpressed in colorectal cancer (CRC). Phosphatidylinositol-4,5-bisphosphat (PI(4,5)P2)-dependent pathways are involved in the regulation of ABCB1 function. The protein Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) is a pivotal regulator of PI(4,5)P2 and inactivated in many CRC cancers via genetic deletion or hyperphosphorylation. Therefore, MARCKS may critically impact ABCB1. METHODS: CRC samples as well as CRC cell lines were tested for a connection between MARCKS and ABCB1 via immunofluorescence and Western-blot analysis. ABCB1 function was studied via calcein influx assay under treatment with known ABCB1 inhibitors (verapamil, tariquidar) as well as the kinase inhibitor bosutinib. ABCB1 internalization and MARCKS translocation was analyzed via confocal microscopy exploiting the endocytosis inhibitors chlorpromazine and dynasore. Abundance of PI(4,5)P2 was monitored by intramolecular fluorescence resonance energy transfer (FRET). Reproductive cell survival was studied via colorimetric WST-1 and clonogenic assays in combination with exposure to the chemotherapeutics doxorubicin and 5-fuorouracil (5-FU). RESULTS: We found increased ABCB1 expression in MARCKS negative CRC patient tumor samples and established CRC cell lines. Mechanistically, the reconstitution of MARCKS function via recombinant expression or the pharmacological inhibition of MARCKS phosphorylation led to a substantial decrease in ABCB1 activity. In CRC cells, bosutinib treatment resulted in a MARCKS translocation from the cytosol to the plasma membrane, while simultaneously, ABCB1 was relocated to intracellular compartments. Inhibition of MARCKS phosphorylation via bosutinib rendered cells more sensitive to the chemotherapeutics doxorubicin and 5-FU. CONCLUSIONS: Cells devoid of MARCKS function showed incomplete ABCB1 internalization, leading to higher ABCB1 activity enhancing chemoresistance. Vice versa our data suggest the prevention of MARCKS inhibition by reversing hyperphosphorylation or genomic restoration after deletion as two promising approaches to overcome tumor cell resistance towards chemotherapeutic ABCB1 substrates.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Substrato Quinase C Rico em Alanina Miristoilada/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Compostos de Anilina , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Fluoresceínas/metabolismo , Transferência Ressonante de Energia de Fluorescência , Células HT29 , Humanos , Microscopia Confocal , Substrato Quinase C Rico em Alanina Miristoilada/deficiência , Nitrilos , Fosforilação , Quinolinas
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