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1.
Anticancer Res ; 39(10): 5461-5471, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570440

RESUMO

BACKGROUND/AIM: Multidrug resistance (MDR) is often associated with overexpression of P-glycoprotein (ABCB1) in cancer cells. Apatinib is a novel Vascular endothelial growth factor receptor-TKI (VEGFR-TKI) which inhibits the function of ABCB1 in certain cancers. This study aimed to investigate the effect of apatinib on the reversal of paclitaxel (PTX) resistance in A549 lung cancer cells (A549/PTX) and related mechanisms. MATERIALS AND METHODS: A549/PTX cells were treated with apatinib alone, PTX alone, or PTX and apatinib. Cell viability was measured by the CCK8 assay. Apoptosis rate, cell-cycle arrest, Rhodamine efflux and reactive oxygen species (ROS) generation were determined by flow cytometry. The intracellular paclitaxel concentration was measured by ultra performance liquid chromatography (UPLC). Protein levels were analyzed by western blotting. RESULTS: A549/PTX cells had significant resistance to PTX and higher expression of ABCB1 compared to A549 cells. Apatinib increased the cytotoxicity of PTX, enhanced PTX-induced apoptosis and cycle arrest, and triggered intracellular ROS generation in A549/PTX cells. In addition, apatinib treatment increased the concentration of intracellular PTX in A549/PTX cells. Apatinib-PTX combination inhibited AKT and ERK pathways. CONCLUSION: Apatinib reverses the drug resistance to PTX in A549 PTX-resistant cells through inhibiting the function of ABCB1 and resumes anti-cancer effects.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/farmacologia , Piridinas/farmacologia , Células A549 , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Espécies Reativas de Oxigênio/metabolismo
2.
J Cancer Res Clin Oncol ; 145(8): 1949-1976, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292714

RESUMO

PURPOSE: Efflux transporters of the adenosine triphosphate-binding cassette (ABC)-superfamily play an important role in the development of multidrug resistance (multidrug resistant; MDR) in cancer. The overexpression of these transporters can directly contribute to the failure of chemotherapeutic drugs. Several in vitro and in vivo models exist to screen for the efficacy of chemotherapeutic drugs against MDR cancer, specifically facilitated by efflux transporters. RESULTS: This article reviews a range of efflux transporter-based MDR models used to test the efficacy of compounds to overcome MDR in cancer. These models are classified as either in vitro or in vivo and are further categorised as the most basic, conventional models or more complex and advanced systems. Each model's origin, advantages and limitations, as well as specific efflux transporter-based MDR applications are discussed. Accordingly, future modifications to existing models or new research approaches are suggested to develop prototypes that closely resemble the true nature of multidrug resistant cancer in the human body. CONCLUSIONS: It is evident from this review that a combination of both in vitro and in vivo preclinical models can provide a better understanding of cancer itself, than using a single model only. However, there is still a clear lack of progression of these models from basic research to high-throughput clinical practice.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos/isolamento & purificação , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Modelos Biológicos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/genética , Técnicas de Cultura/métodos , Técnicas de Apoio para a Decisão , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Especificidade de Órgãos , Seleção de Pacientes
3.
Anticancer Res ; 39(7): 3711-3718, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262897

RESUMO

BACKGROUND/AIM: Small cell lung cancer (SCLC) originates from neuroendocrine branchial cells (15-20%). It is regarded as distinct from other lung cancers due to its biological and clinical features. In most cases of SCLC, surgery or radiotherapy alone is not an effective cure. The aim of our study was to examine the cytotoxic effects of chemotherapy supported by electroporation (EP) on a resistant SCLC model, in vitro. MATERIAL AND METHODS: The multidrug resistant small lung cell line H69AR was used to evaluate the cytotoxic effects of cisplatin (CPPD) and vinorelbine (Navirel®; NAV) at lower doses when used with EP. Cells were treated with different concentrations of CPPD and NAV, alone or in combination with the following EP parameters: 400-1200 V/cm, 8 pulses of 100 µs duration, at 1Hz. The cell viability was estimated by MTT assay after 24 and 48 h. Apoptotic cells were detected by neutral comet assay and immunofluorescence assay with PARP-6. RESULTS: CPPD and NAV alone showed a dose-dependent effect on cell viability. Cytostatic drugs combined with EP revealed increased anticancer activity. Lower doses of CPPD or NAV delivered by EP were as effective as higher doses of these drugs without EP. The electrochemotherapeutic protocols increased the number of apoptotic cells and increased immunoreactivity of PARP-6. Our results indicated higher sensitivity of H69AR cells to NAV supported by EP. CONCLUSION: In SCLC cells, an increased anticancer activity was potentiated by exposure of cells to high intensity electric pulses and low drug doses. It is suggested that this method could be effectively applied in the treatment of lung cancer.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Eletroquimioterapia , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Vinorelbina/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos
4.
SAR QSAR Environ Res ; 30(7): 457-475, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31157558

RESUMO

ABCG2 is the principal ABC transporter involved in the multidrug resistance of breast cancer. Looking at the current demand in the development of ABCG2 inhibitors for the treatment of multidrug-resistant cancer, we have explored structural requirements of phenyltetrazole derivatives for ABCG2 inhibition by combining classical QSAR, Bayesian classification modelling and molecular docking studies. For classical QSAR, structural descriptors were calculated from the free software tool PaDEL-descriptor. Stepwise multiple linear regression (SMLR) was used for model generation. A statistically significant model was generated and validated with different parameters (For training set: r = 0.825; Q2 = 0.570 and for test set: r = 0.894, r2pred = 0.783). The predicted model was found to satisfy the Golbraikh and Trospha criteria for model acceptability. Bayesian classification modelling was also performed (ROC scores were 0.722 and 0.767 for the training and test sets, respectively). Finally, the binding interactions of phenyltetrazole type inhibitor with the ABCG2 receptor were mapped with the help of molecular docking study. The result of the docking analysis is aligned with the classical QSAR and Bayesian classification studies. The combined modelling study will guide the medicinal chemists to act faster in the drug discovery of ABCG2 inhibitors for the management of resistant breast cancer.


Assuntos
Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Tetrazóis/química , Animais , Teorema de Bayes , Neoplasias da Mama/tratamento farmacológico , Cães , Desenho de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Modelos Lineares , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Tetrazóis/farmacologia
5.
Eur J Med Chem ; 176: 268-291, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31103904

RESUMO

Cancer is a prominent cause of death globally. Currently, many drugs that are in clinical practice are having a high prevalence of side effect and multidrug resistance. Risk of tumors acquiring resistance to chemotherapy (multidrug resistance) remains a significant hurdle to the successful treatment of various types of cancer. Membrane-embedded drug transporters, generally overexpressed in cancer, are the leading cause among multiple mechanisms of multidrug resistance (MDR). P-glycoprotein (P-gp) also MDR1/ABCB1, multidrug resistance associated protein 1 (MRP1/ABCC1), MRP2 and breast cancer resistance protein (BCRP/ABCG2) are considered to be a prime factor for induction of MDR. To date, several chemical substances have been tested in a number of clinical trials for their MDR modulatory activity which are not having devoid of any side effects that necessitates to find newer and safer way to tackle the current problem of multidrug resistance in cancer. The present study systematically discusses the various classes of natural products i.e flavonoids, alkaloids, terpenoids, coumarins (from plants, marine, and microorganisms) as potential MDR modulators and/or as a source of promising lead compounds. Recently a bisbenzyl isoquinoline alkaloid namely tetrandrine, isolated from Chinese herb Stephania tetrandra (Han-Fang-Chi) is in clinical trials for its MDR reversal activity.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Alcaloides/farmacologia , Animais , Benzilisoquinolinas/farmacologia , Linhagem Celular Tumoral , Flavonoides/farmacologia , Humanos , Terpenos/farmacologia
6.
Phytomedicine ; 59: 152771, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31055230

RESUMO

BACKGROUND: The multidrug resistance (MDR) phenotype encounters a major challenge to the success of established chemotherapy in cancer patients. We hypothesized that cytotoxic medicinal plants with novel phytochemicals can overcome MDR and kill MDR-cells with similar efficacy as drug sensitive cells. PURPOSE: We evaluated plant extracts from an unexplored ecosystem in Egypt with unusual climate and nutrient conditions for their activity against sensitive and multidrug-resistant cancer cell lines. MATERIAL AND METHODS/STUDY DESIGN: Methylene chloride: methanol (1:1) and methanol: H2O (7:3) extracts of 40 plants were prepared resulting in a sum of 76 fraction containing compounds with varying polarity. The resazurin reduction assay was employed to evaluate the cytotoxicity of these extracts on five matched pairs of drug-sensitive and their drug-resistant cell lines. Flow cytometry and Western blotting was used to determine cell cycle analyses, apoptosis, and autophagy. Reactive oxygen species (ROS) were measured spectrophotometrically. RESULTS: Extracts derived from Withania obtusifolia (WO), Jasonia candicans (JC), Centaurea lippii (CL), and Pulicaria undulata (PU) were the most active ones among 76 extracts from 40 Egyptian medicinal plants. They showed a significant reduction of cell viability on drug-sensitive CCRF-CEM leukemia cell line with IC50 values less than 7 µg/ml. Low cross-resistance degrees were observed in multidrug-resistant CEM/ADR5000 cells towards CL (1.82-fold) and JC (6.09-fold). All other drug-resistant cell lines did not reveal cross-resistance to the four extracts. Further mechanistic assessment have been studied for these four extracts. CONCLUSION: The methylene chloride: methanol (1:1) fractions of WO, JC, CL, and PU are promising cytotoxic extracts that could be used to combat MDR cancer cells through different cell death pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Magnoliopsida/química , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Fitoterapia , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Antineoplásicos Fitogênicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Centaurea/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Egito , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Compostos Fitoquímicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Pulicaria/química , Espécies Reativas de Oxigênio/metabolismo , Withania/química
7.
J Microbiol ; 57(6): 423-430, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31054136

RESUMO

Antibiotics have long been used for anti-infective control of bacterial infections, growth promotion in husbandry, and prophylactic protection against plant pathogens. However, their inappropriate use results in the emergence and spread of multiple drug resistance (MDR) especially among various bacterial populations, which limits further administration of conventional antibiotics. Therefore, the demand for novel anti-infective approaches against MDR diseases becomes increasing in recent years. The peptide nucleic acid (PNA)-based technology has been proposed as one of novel anti-infective and/or therapeutic strategies. By definition, PNA is an artificially synthesized nucleic acid mimic structurally similar to DNA or RNA in nature and linked one another via an unnatural pseudo-peptide backbone, rendering to its stability in diverse host conditions. It can bind DNA or RNA strands complimentarily with high affinity and sequence specificity, which induces the target-specific gene silencing by inhibiting transcription and/or translation. Based on these unique properties, PNA has been widely applied for molecular diagnosis as well as considered as a potential anti-infective agent. In this review, we discuss the general features of PNAs and their application to various bacterial pathogens as new anti-infective or antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Ácidos Nucleicos Peptídicos/farmacologia , Anti-Infecciosos/química , Bactérias/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Ácidos Nucleicos Peptídicos/química
8.
Top Curr Chem (Cham) ; 377(3): 15, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073777

RESUMO

As the emergence of resistance to clinical cancer treatments poses a significant problem in cancer management, there is a constant need to explore novel anticancer agents which have the ability to overcome multidrug resistance (MDR) mechanisms. The search for the development of novel isatin-based antitumor agents accelerated after the approval by the Food and Drug Administration (FDA) of sunitinib malate, a C-3 isatin derivative, as a multitargeted receptor tyrosine kinase inhibitor. However, it is interesting to note that, over the last decade, various N-substituted analogs of isatin with intact carbonyl functionalities have been found to show more promising anticancer potential than its C-3 derivatives. Microtubule-targeting agents are a class of anticancer drugs which affect mitosis by targeting microtubules and suppressing their dynamic behavior. This review presents a systematic compilation of the in vitro cytotoxic and anticancer properties of various N-substituted isatins and illustrates their mechanism of action to overcome MDR by acting as microtubule-destabilizing agents. Predictions of the biological activities and cytotoxic effects of potential N-substituted isatins against various cancer cell lines have also been performed using the PASS computer-aided drug discovery program. Findings from such in vitro and in silico studies will act as a guide for the development of structure-activity relationship and will facilitate the design and exploration of more potent analogs of isatin with high potency and lower side effects for treatment of drug-resistant cancer. Mechanism of action of N-substituted isatin as microtubule-destabilizing agent on tumor cells. N-Substituted isatins bind to colchicine binding site on ß-tubulin, which inhibits microtubule polymerization and thereby destabilizes microtubule dynamics, resulting in mitotic arrest leading to tumor cell growth suppression.


Assuntos
Antineoplásicos/farmacologia , Simulação por Computador , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Isatina/farmacologia , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Isatina/química , Microtúbulos/efeitos dos fármacos
9.
Int J Nanomedicine ; 14: 2619-2636, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043778

RESUMO

Background: Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems has opened a new window to overcome these problems. There has been a strong interest development of new platform and system for delivof chemotherapeutic agents. Purpose: In the present study, a green synthesis method was chosen and performed for preparation of a novel amphoteric calix[4]arene (Calix) macrocycle with low toxicity to the human body. Materials and methods: The amphoteric Calix was coated on the surface of Fe3O4 magnetic nanoparticles and used as a magnetic nanocarrier for simultaneous delivery of two anticancer agents, doxorubicin and methotrexate, against MCF7 cancer cells. Several chemical characterizations were done for validation of prepared nanocarrier, and in vitro loading and release studies of drugs were performed with good encapsulation efficiency. Results: In vitro biological studies including hemolysis assay, erythrocytes sedimentation rate, red blood cells aggregation, cyto cellular internalization, and apoptosis evaluations were performed. Based on results, the developed nanocarrier has many advantages and capability for an efficient codelivery of DOX and MTX, which has a highly potent ability to kill cancer cells. Conclusion: All these results persuade us, this nanocarrier could be effectively used for cancer therapy of MCF7 breast cancer cells and is suitable for use in further animal studies in future investigations.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Calixarenos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas de Magnetita/química , Fenóis/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Calixarenos/síntese química , Varredura Diferencial de Calorimetria , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Difusão Dinâmica da Luz , Endocitose , Feminino , Humanos , Células MCF-7 , Nanopartículas de Magnetita/ultraestrutura , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Tamanho da Partícula , Fenóis/síntese química , Espectroscopia de Infravermelho com Transformada de Fourier
10.
BMC Vet Res ; 15(1): 162, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118023

RESUMO

BACKGROUND: Diarrhoea, a global economically important disease burden affecting swine and, especially piglets, is commonly caused by infection with entero-toxigenic E. coli (ETEC). Adherence of ETEC to porcine intestinal epithelial cells following infection, is necessary for its pathogenesis. While antimicrobials are commonly given as therapy or as feed additives for prophylaxis against microbial infections, the concern over increased levels of antimicrobial resistance necessitate the search for safe and effective alternatives in livestock feed. Attention is shifting to natural products including plants as suitable alternatives to antimicrobials. The activity of acetone crude leaf extracts of nine under-explored South African endemic plants from the Myrtaceae family with good antimicrobial activity were tested against pathogenic E. coli of porcine origin using a microplate serial dilution method. Bioautography, also with p-iodonitrotetrazolium violet as growth indicator was used to view the number of bioactive compounds in each extract. In vitro toxicity of extracts was determined against Caco-2 cells using the 3-(4,5-dimethythiazolyl-2)-2,5-diphenyltetrazolium bromide reduction assay. The antimicrobial susceptibility of E. coli isolates was tested on a panel of antimicrobials using the Kirby-Bauer agar diffusion method while the anti-adherence mechanism was evaluated using a Caco-2 cell enterocyte anti-adhesion model. RESULTS: The MIC of the extracts ranged from 0.07-0.14 mg/mL with S. legatii having the best mean MIC (0.05 mg/mL). Bioautography revealed at least two active bands in each plant extract. The 50% lethal concentration (LC50) values ranged between 0.03-0.66 mg/mL. Eugenia zeyheri least cytotoxic (LC50 = 0.66 mg/ml) while E. natalitia had the highest cytotoxicity (LC50 = 0.03 mg/mL). All the bacteria were completely resistant to doxycycline and colistin sulphate and many of the plant extracts significantly reduced adhesion of E. coli to Caco-2 cells. CONCLUSIONS: The extracts of the plants had good antibacterial activity as well as a protective role on intestinal epithelial cells against enterotoxigenic E. coli bacterial adhesion. This supports the potential use of these species in limiting infection causes by E. coli. Some of these plants or extracts may be useful as phytogenic feed additives but it has to be investigated by animal feed trials.


Assuntos
Antibacterianos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Escherichia coli Enterotoxigênica/efeitos dos fármacos , Eugenia/química , Extratos Vegetais/farmacologia , Syzygium/química , Acetona/química , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Dose Letal Mediana , Testes de Sensibilidade Microbiana , Extratos Vegetais/toxicidade , Folhas de Planta/química
11.
Talanta ; 201: 309-316, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31122428

RESUMO

Two different colors of water-soluble core-shell quantum dots CdTe/CdS (green and orange red) have been synthesized and characterized in this paper. The formation of core-shell quantum dots not only improves the fluorescence quantum yield, but also reduces the biological toxicity of quantum dots, and improves the fluorescence lifetime. Two novel fluorescent bioprobes, CdTe/CdS (λem = 545 nm)-5-Fu and Bio-CdTe/CdS (λem = 600 nm)-TAM, have been synthesized via the interaction of these two core-shell quantum dots with anticancer drugs (5-Fu) and P-gp inhibitors (TAM), respectively. These two fluorescent probes have been simultaneously used in fluorescence imaging of human breast cancer cells MDA-MB-231/MDR. It can be observed that under the action of P-gp inhibitors distributed on the cell membrane, anticancer drugs can be retained in cancer cells. According to the color of quantum dots on the probe, the visualization results of the action of anticancer drugs and P-gp inhibitors can be obtained. This study shows that to prepare functional bioprobes using core-shell quantum dots CdTe/CdS has great potential in the field of biomedical research such as anticancer drugs.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Corantes Fluorescentes/química , Pontos Quânticos/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Cádmio/química , Cádmio/toxicidade , Compostos de Cádmio/química , Compostos de Cádmio/toxicidade , Linhagem Celular Tumoral , Fluorescência , Corantes Fluorescentes/toxicidade , Fluoruracila/farmacologia , Humanos , Pontos Quânticos/toxicidade , Solubilidade , Espectrometria de Fluorescência/métodos , Sulfetos/química , Sulfetos/toxicidade , Tamoxifeno/farmacologia , Telúrio/química , Telúrio/toxicidade , Água/química
12.
Med Sci Monit ; 25: 2542-2552, 2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30955024

RESUMO

BACKGROUND In clinical practice, many patients become multidrug resistant during chemotherapy, resulting in reduced or no healing effect. Therefore, the present study focused on bufalin, which is extracted from a traditional Chinese medicine named Chan Su (Venenum bufonis). We assessed the effect of bufalin in reversing K562/A02 cell drug resistance and inducing apoptosis, and explored the possible mechanism by which bufalin induces K562/A02 cell apoptosis. MATERIAL AND METHODS We used flow cytometry to evaluate intracellular ADM concentration, and RT-PCR and Western blot analysis were used to assess the effect of nuclear factor erythroid-2-related factor 2 (Nrf2) bufalin-related resistance gene expression. We used MTT and flow cytometry to detect apoptosis, and RT-PCR and Western blot were used to detect endoplasmic reticulum stress and apoptosis gene action. RESULTS We found that bufalin can increase the concentration of Adriamycin (ADM) in K562/A02 cells by inhibiting the expression of Nrf2 and related drug resistance factors. The results showed that bufalin induced apoptosis of K562/A02 cells by the IRE1alpha/TRAF2/JNK/caspase-12 pathway. CONCLUSIONS These results suggest bufalin can reverse drug resistance in K562/A02 cells and that it induces apoptosis of K562/A02 cells by the IRE1alpha/TRAF2/JNK/caspase-12 pathway.


Assuntos
Apoptose/efeitos dos fármacos , Bufanolídeos/metabolismo , Células K562/efeitos dos fármacos , Bufanolídeos/farmacologia , China , Doxorrubicina/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa/métodos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , RNA Mensageiro/genética
13.
Chemosphere ; 228: 159-165, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029961

RESUMO

The presence of the transmembrane proteins of the ATP-binding cassette (ABC) family, which perform the efflux of several substances, contributes to the survival of aquatic organisms in a contaminated environmental. Those proteins provide a phenotype named the multixenobiotic resistance mechanism (MXR) by performing the efflux of a wide range of endogenous and exogenous compounds (ABCB) and biotransformation products and anionic compounds (ABCC). The aim of the present study was to evaluate the cellular defense pathway of an established culture from zebrafish hepatocytes (ZF-L) after 24 and 48 h of exposure to glyphosate and Original Roundup®, an herbicide used globally. Through abcb4, abcc1, abcc2 and abcc4 gene expression, ABCB and ABCC2 protein expression and ABC pump activity in ZF-L cells exposed to glyphosate and Roundup®. The results showed an increase in ABCB gene and protein expression; however, although ABCC2 showed an increase in gene expression, its protein expression was lower than in the control group. Regarding ABC activity, only exposure to Roundup® at the lowest concentration showed an increase at 48 h, but in the presence of inhibitors, both glyphosate and Roundup® appeared to modulate ABC activity, reducing its inhibition and returning activity to levels without inhibitor.


Assuntos
Transportadores de Cassetes de Ligação de ATP/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Glicina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Células Cultivadas , Glicina/farmacologia , Hepatócitos/metabolismo , Herbicidas/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/efeitos dos fármacos , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
14.
Eur J Pharmacol ; 852: 231-243, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30959046

RESUMO

Multidrug resistance (MDR) remains an obstacle to chemotherapy related with the overexpression of several efflux membrane proteins, and p-glycoprotein (P-gp) is the most studied among them. Thus, continuous investigational efforts are necessary to find valuable MDR reversal agents, and the flavonoid compound glabridin (GBD) seems to be a promising candidate. This study aimed to investigate the potential of GBD against MDR and explore the possible mechanisms. First, we found that GBD could decrease the half maximal inhibitory concentration of paclitaxel and doxorubicin (DOX) in breast cancer cells like MDA-MB-231/MDR1 cells and MCF-7/ADR cells. It was further explained that GBD enhanced the apoptosis of MDA-MB-231/MDR1 cells induced by DOX, due to the increased accumulation of DOX. Then, tests were performed to explore the possible MDR reversal mechanisms. On one hand, GBD can suppress the expression of P-gp. On the other hand, GBD can downregulate the activity of P-gp ATPase when cotreated with DOX or verapamil, revealing that GBD was a substrate of P-gp. Moreover, the obtained kinetic inhibition parameters proved that GBD was a competitive inhibitor of P-gp, and in molecular docking simulation modeling, GBD exhibited stronger binding affinity with P-gp than DOX. In conclusion, GBD can increase the accumulation of DOX in MDA-MB-231/MDR1 cells by suppressing the expression of P-gp and competitively inhibiting the P-gp efflux pump and enhance the apoptosis of MDA-MB-231/MDR1 cells induced by DOX, and thus realize reversal effects on MDR. Therefore, the combination therapy of anticancer drugs and flavonoid-like GBD is a promising strategy to overcome P-gp-mediated MDR.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isoflavonas/farmacologia , Fenóis/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Isoflavonas/metabolismo , Cinética , Simulação de Acoplamento Molecular , Fenóis/metabolismo , Conformação Proteica
15.
Eur J Pharmacol ; 852: 244-253, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30965056

RESUMO

Multiple drug resistance (MDR) often occurs after prolonged chemotherapy, leading to refractory tumor and cancer recurrence. Autophagy as a primarily process during starvation or stress has a bipolar nature in cancer. It can cause MDR to become more difficult or make resistant cancer cells more susceptible to chemotherapeutic agents. A number of natural products have been introduced to drug discovery for many years. Some of these compounds have been shown to reverse drug resistance by different regulatory mechanisms. In this review, the focus is on the role of medicinal plants in the MDR phenomenon, primarily through the autophagy process.


Assuntos
Autofagia/efeitos dos fármacos , Produtos Biológicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Plantas Medicinais/química , Animais , Humanos
16.
Int J Nanomedicine ; 14: 2207-2218, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988617

RESUMO

Background: Psoralen (PSO), a major active component of Psoralea corylifolia, has been shown to overcome multidrug resistance in cancer. A drug carrier comprising a lipid-monolayer shell and a biodegradable polymer core for sustained delivery and improved efficacy of drug have exhibited great potential in efficient treatment of cancers. Methods: The PSO-loaded lipid polymer hybrid nanoparticles were prepared and characterized. In vitro cytotoxicity assay, cellular uptake, cell cycle analysis, detection of ROS level and mitochondrial membrane potential (ΔΨm) and western blot were performed. Results: The P-LPNs enhanced the cytotoxicity of doxorubicin (DOX) 17-fold compared to free DOX in multidrug resistant HepG2/ADR cells. Moreover, P-LPNs displayed pro-apoptotic activity, increased levels of ROS and depolarization of ΔΨm. In addition, there were no signifi-cant effects on cellular uptake of DOX, cell cycle arrest, or the expression of P-glycoprotein. Mechanistic studies suggested that P-LPNs enhanced DOX cytotoxicity by increased release of cytochrome c and enhanced caspase3 cleavage, causing apoptosis in HepG2/ADR cells. Conclusion: The lipid-polymer hybrid nanoparticles can be considered a powerful and promising drug delivery system for effective cancer chemotherapy.


Assuntos
Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ficusina/farmacologia , Lipídeos/química , Nanopartículas/química , Polímeros/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Células Hep G2 , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Espécies Reativas de Oxigênio/metabolismo
17.
J Photochem Photobiol B ; 194: 119-127, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30953913

RESUMO

'Go green' has also been implied to nanotechnology by harbouring eco-benign principle for a cleaner production of silver nanoparticles (AgNPs). This was achieved using a nitrate reducing Bacillus subtilis L1 (KT266579.1) inhabiting rhizosphere soil under optimized laboratory conditions, highlighting on its antibacterial modus operandi. Nano-characteristics and antimicrobial mechanism were investigated using spectroscopic and electron microscopic studies. Spectroscopic and microscopic characterization revealed typical surface plasmon resonance (SPR) with λmax 420 nm showing mean particle size of ~28.30 nm and spherical shaped nanoparticles. Antimicrobial susceptibility pattern of clinically important pathogens (n = 15) exposed to AgNPs at 10 µg, 15 µg and 20 µg/mL for 18 h was found significant in a dose dependent fashion. Electron and atomic force microscopic (AFM) studies have demonstrated the typical bactericidal effect of AgNPs (<25 µg/mL) associated with 'pitting effect', cell shrinkage and increase in surface roughness. The EDX spectrum of the control and treated bacteria showed the intrusion of AgNPs inside the bacterial cells endorsing the event of bacterial paralysis. DNA fragmentation assay demonstrated significant DNA damage in the form of smear, indicative of genotoxicity at ≤32 µg and ≤16 µg/mL of AgNPs respectively for Gram positive and negative strains in <12 h. These results suggest that AgNPs possess excellent antimicrobial activity, providing a potential lead for developing a broad spectrum antibacterial agent and extending its therapeutic modalities targeting antibiotic resistant strains at gene level.


Assuntos
Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Bioengenharia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Nanopartículas Metálicas , Prata/metabolismo , Prata/farmacologia , Antibacterianos/biossíntese , Antibacterianos/química , Antibacterianos/farmacologia , Análise Custo-Benefício , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Concentração de Íons de Hidrogênio , Imagem Molecular , Prata/química , Temperatura Ambiente
18.
Eur J Med Chem ; 172: 71-94, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30947123

RESUMO

In this study, a new series of N,N-bis(alkanol)amine aryl ester heterodimers was synthesized and studied. The new compounds were designed based on the structures of our previous arylamine ester derivatives endowed with high P-gp-dependent multidrug resistance reversing activity on a multidrug-resistant leukemia cell line. All new compounds were active in the pirarubicin uptake assay on the doxorubicin-resistant erythroleukemia K562 cells (K562/DOX). Compounds bearing a linker made up of 10 methylenes showed unprecedented high reversal activities regardless of the combination of aromatic moieties. Docking results obtained by an in silico study supported the data obtained by the biological tests and a study devoted to establish the chemical stability in phosphate buffer solution (PBS) and human plasma showed that only a few compounds exhibited a significant degradation in the human plasma matrix. Ten selected non-hydrolysable derivatives were able to inhibit the P-gp-mediated rhodamine-123 efflux on K562/DOX cells, and the evaluation of their apparent permeability and ATP consumption on other cell lines suggested that the compounds can behave as unambiguous or not transported substrates. The activity of these the compounds on the transport proteins breast cancer resistance protein (BCRP) and multidrug resistance associated protein 1 (MRP1) was also analyzed. All tested derivatives displayed a moderate potency on the BCRP overexpressing cells; while only four molecules showed to be effective on MRP1 overexpressing cells, highlighting a clear structural requirement for selectivity. In conclusion, we have identified a new very powerful series of compounds which represent interesting leads for the development of new potent and efficacious P-gp-dependent MDR modulators.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Aminas/farmacologia , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Células CACO-2 , Dimerização , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
20.
Phytother Res ; 33(4): 1208-1221, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30838722

RESUMO

The aim of this study was to examine the antitumour effects of plant phenolic acids, gallic acid (GA) and ellagic acid (EA), on human promyelocytic leukaemia sensitive HL60 cell line and its resistant sublines exhibiting two MDR phenotypes: HL60/VINC (overexpressing P-glycoprotein) and HL60/MX2 (characterized by the presence of mutated α isoform of topoisomerase II). Both studied compounds exerted comparable cytotoxic activities towards sensitive HL60 cells and their MDR counterparts. It was also found that GA and EA modulated the cellular level of reactive oxygen species in a dose-dependent and time-dependent manner. Furthermore, it was demonstrated that GA (IC90 ) and EA (IC50 and IC90 ) significantly increased the percentage of sub-G1 subpopulation of all studied leukaemia cells causing oligonucleosomal DNA fragmentation. Both compounds used at IC90 triggered mainly the apoptotic death of these cells. However, GA had no effect on the activity of caspase-3 as well as caspase-8 in sensitive HL60 cells and their MDR counterparts. In contrast, EA provoked a significant activation of these caspases in all studied leukaemia cells. It was also found that lysosomes were not involved in triggering programmed death of sensitive HL60 and MDR cells by GA and EA.


Assuntos
Antineoplásicos/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ácido Elágico/uso terapêutico , Ácido Gálico/uso terapêutico , Células HL-60/efeitos dos fármacos , Leucemia Promielocítica Aguda/tratamento farmacológico , Polifenóis/uso terapêutico , Antineoplásicos/farmacologia , Ácido Elágico/farmacologia , Ácido Gálico/farmacologia , Humanos , Leucemia Promielocítica Aguda/patologia , Polifenóis/farmacologia
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