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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.
Adv Exp Med Biol ; 1141: 13-100, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571164

RESUMO

The transport of specific molecules across lipid membranes is an essential function of all living organisms. The processes are usually mediated by specific transporters. One of the largest transporter families is the ATP-binding cassette (ABC) family. More than 40 ABC transporters have been identified in human, which are divided into 7 subfamilies (ABCA to ABCG) based on their gene structure, amino acid sequence, domain organization, and phylogenetic analysis. Of them, at least 11 ABC transporters including P-glycoprotein (P-GP/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2) are involved in multidrug resistance (MDR) development. These ABC transporters are expressed in various tissues such as the liver, intestine, kidney, and brain, playing important roles in absorption, distribution, and excretion of drugs. Some ABC transporters are also involved in diverse cellular processes such as maintenance of osmotic homeostasis, antigen processing, cell division, immunity, cholesterol, and lipid trafficking. Several human diseases such as cystic fibrosis, sitosterolemia, Tangier disease, intrahepatic cholestasis, and retinal degeneration are associated with mutations in corresponding transporters. This chapter will describe function and expression of several ABC transporters (such as P-GP, BCRP, and MRPs), their substrates and inhibitors, as well as their clinical significance.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Fenômenos Fisiológicos Celulares , Resistência a Múltiplos Medicamentos/genética , Regulação da Expressão Gênica , Humanos , Filogenia
3.
Adv Exp Med Biol ; 1141: 549-580, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571174

RESUMO

ATP-binding cassette (ABC) transporters are involved in active pumping of many diverse substrates through the cellular membrane. The transport mediated by these proteins modulates the pharmacokinetics of many drugs and xenobiotics. These transporters are involved in the pathogenesis of several human diseases. The overexpression of certain transporters by cancer cells has been identified as a key factor in the development of resistance to chemotherapeutic agents. In this chapter, the localization of ABC transporters in the human body, their physiological roles, and their roles in the development of multidrug resistance (MDR) are reviewed. Specifically, P-glycoprotein (P-GP), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP/ABCG2) are described in more detail. The potential of ABC transporters as therapeutic targets to overcome MDR and strategies for this purpose are discussed as well as various explanations for the lack of efficacy of ABC drug transporter inhibitors to increase the efficiency of chemotherapy.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias , Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Humanos , Neoplasias/fisiopatologia , Distribuição Tecidual
4.
Vet Parasitol ; 272: 79-82, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31395209

RESUMO

The astigmatid mite Psoroptes ovis (Acari: Proroptidae) causes the highly contagious and debilitating ovine disease, sheep scab. This ectoparasitic infection has a high economic and animal welfare impact on British sheep farming. Following recent work demonstrating resistance of Psoroptes mites to moxidectin, a widely used macrocyclic lactone (ML) treatment for scab, the current study compared the toxicity of three of the commonly administered macrocylic lactone therapeutic treatments (moxidectin, ivermectin and doramectin) to P. ovis from outbreak populations that had appeared unresponsive to treatment. These outbreak populations were from Wales and south west England. The data presented demonstrate that there is resistance to all three available ML compounds in populations of Psoroptes mites. However, considerable variation in response suggested that resistance alone was not responsible for the reported lack of efficacy in all of the submitted cases; lack of response in others may be associated with inappropriate treatment application or management. These data highlight the importance of the appropriate use of these compounds to manage national scab incidence at levels that are consistent with acceptable animal welfare standards, while attempting to reduce the development and spread of resistance.


Assuntos
Resistência a Múltiplos Medicamentos , Lactonas/administração & dosagem , Lactonas/farmacologia , Infestações por Ácaros/veterinária , Psoroptidae/efeitos dos fármacos , Criação de Animais Domésticos/normas , Animais , Antiparasitários/administração & dosagem , Antiparasitários/farmacologia , Inglaterra , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/epidemiologia , Infestações por Ácaros/prevenção & controle , Ovinos , Doenças dos Ovinos/tratamento farmacológico , Doenças dos Ovinos/epidemiologia , Doenças dos Ovinos/prevenção & controle , País de Gales
5.
Anticancer Res ; 39(8): 4101-4110, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366494

RESUMO

BACKGROUND/AIM: Despite improvements in cancer therapy, life expectancy after tumor recurrence remains low. Relapsed cancer is characterized by drug resistance, often mediated through overexpression of multidrug resistance (MDR) genes. Camellia sinensis non fermentatum extract is known for its anticancer properties in several cancer cell lines and might improve cancer therapy outcome after tumor recurrence. MATERIALS AND METHODS: Embryonal rhabdomyosarcoma cell lines, alveolar rhabdomyosarcoma cell lines and primary rhabdomyosarcoma MAST139 cells were used to test NPE® effects on cell viability in combination with chemotherapeutic agents. Cell viability was measured by the WST-1 assay and CV staining. Gene expression levels of chemotherapy-induced efflux pumps and their activity was assessed upon NPE® treatment by measuring doxorubicin retention through evaluation of the autofluorescence signal. RESULTS: Administration of increasing doxorubicin concentrations triggered immediate adaptation to the drug, which was surprisingly overcome by the addition of NPE®. Investigating the mechanism of immediate adaptation, MDR1 gene overexpression was observed upon doxorubicin treatment. Although NPE® did not alter pump gene expression, it was able to reduce pump activity, thus allowing the chemotherapeutic agent to stay inside the cells to exert its full anticancer activity. CONCLUSION: NPE® might improve chemotherapeutic treatment by re-sensitizing relapsed tumors to anticancer drugs. Fighting MDR represents the key to overcome tumor relapse and improve the overall survival of cancer patients.


Assuntos
Antineoplásicos/farmacologia , Camellia sinensis/química , Recidiva Local de Neoplasia/tratamento farmacológico , Rabdomiossarcoma Alveolar/tratamento farmacológico , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Rabdomiossarcoma Alveolar/patologia
6.
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
7.
Neoplasma ; 66(5): 847-857, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288527

RESUMO

The aim of this work was to determine the expression of the ERß (estrogen receptor ß) and multidrug resistance, namely MDR1 (P-glycoprotein, P-gp), in 152 samples of non-small cell lung cancer. The expression pattern of ERß and MDR1 were assessed by the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunohistochemistry. We also analyzed the correlation between ERß and MDR1 with clinical and pathological data. The co-expression pattern of ERß and individual MDR1 proteins was assessed by correspondence analysis and chi-squared tests. In the present study, we found that patients with tumor stage I-II showed higher ERß mRNA expression levels and decreased expression of ERß protein with increasing tumor grade, which is opposite to MDR1 expression. In addition, an opposite co-expression pattern of ERß and individual MDR1 proteins was also observed. In conclusion, the results can be used to better understand the expression control of MDR1 and may allow for the establishment of new cancer chemistry strategies that will control P-gp expression in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Receptor beta de Estrogênio/metabolismo , Neoplasias Pulmonares/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Gene ; 714: 143972, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31301483

RESUMO

Among cancers, lung cancer is the most morbidity and mortality disease that is remaining the fatalist. Generally, there are multiple treatment procedures for lung cancer, such as surgery, immunotherapy, radiotherapy and chemotherapy. There is, therefore, an urgent need for more specified and efficient methods for treatment of lung cancer such as RNAi, which in combination with traditional therapies could silence genes that are involved in the drug resistance. These genes may either be motivators of apoptosis inhibition, EMT and DNA repair system promoters or a member of intracellular signaling pathways, such as JAK/STAT, RAS/RAF/MEK, PI3K/AKT, NICD, B-catenin/TCF/LEF and their stimulator receptors including IGFR, EGFR, FGFR, VEGFR, CXCR4, MET, INTEGRINS, NOTCH1 and FRIZZLED, so could be considered as appropriate targets. In current review, the results of multiple studies which have employed drug application after one specific gene silencing or more than one gene from distinct pathways also simultaneous drug and RNAi usage in vitro and in vivo in lung cancer were summarized.


Assuntos
Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , RNA Interferente Pequeno/genética , Animais , Apoptose/genética , Humanos , Transdução de Sinais/genética
9.
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
10.
BMC Vet Res ; 15(1): 235, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286947

RESUMO

BACKGROUND: Enterococcus is an important component of normal flora in human and animals, but in recent years, the pathogenicity of Enterococcus has been confirmed in clinical medicine. More and more animal infections have been reported in veterinary clinics. For the last decades, outbreaks of encephalitis in lambs have become much more common in Northern Xinjiang, China. Consequent studies have confirmed that these affected lambs had been commonly infected with E. faecalis. More than 60 E. faecalis were isolated from the brain of infected lambs, A highly virulent strain entitled E. faecalis 2A (XJ05) were selected, sequenced and analyzed. RESULT: Using whole genome sequence and de novo assembly, 18 contigs with NGS and annotation were obtained. It is confirmed that the genome has a size of 2.9 Mb containing 2783 protein-coding genes, as well as 54 tRNA genes and 4 rRNA genes. Some key features of this strain were identified, which included 7 predicted antibiotic resistance genes and 18 candidate virulence factor genes. CONCLUSION: The E. faecalis 2A (XJ05) genome is conspicuous smaller than E.faecalis V583, but not significantly different from other non-pathogenic E. faecalis. It carried 7 resistance genes including 4 kind of antibiotics which were consistent with the results of extensive drug resistance phenotypic, including aminoglycoside, macrolide, phenicol, and tetracycline. 2A (XJ05) also carried 18 new virulence factor genes related to virulence, hemolysin genes (cylA, cylB, cylM, cylL) may play an important role in lamb encephalitis by E. faecalis 2A (XJ05).


Assuntos
Farmacorresistência Bacteriana/genética , Encefalite/veterinária , Enterococcus faecalis/genética , Enterococcus faecalis/patogenicidade , Genoma Bacteriano/genética , Doenças dos Ovinos/microbiologia , Virulência/genética , Animais , Resistência a Múltiplos Medicamentos/genética , Encefalite/microbiologia , Ovinos
11.
Malar J ; 18(1): 203, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221145

RESUMO

BACKGROUND: As malaria elimination becomes a goal in malaria-endemic nations, questions of feasibility become critical. This article explores the potential challenges associated with this goal and future strategies for malaria elimination in the Greater Mekong Sub-region. METHODS: Thirty-two semi-structured interviews were conducted with policy makers (n = 17) and principal investigators (n = 15) selected based on their involvement in malaria prevention, control and elimination in the GMS. Interviews were audio-recorded and transcribed for qualitative content (thematic) analysis using QSR NVivo. RESULTS: All respondents described current malaria control and elimination strategies, such as case detection and management, prevention and strengthening of surveillance systems as critical and of equal priority. Aware of the emergence of multi-drug resistance in the GMS, researchers and policy makers outlined the need for additional elimination tools. As opposed to a centralized strategy, more targeted and tailored approaches to elimination were recommended. These included targeting endemic areas, consideration for local epidemiology and malaria species, and strengthening the peripheral health system. A decline in malaria transmission could lead to complacency amongst funders and policy makers resulting in a reduction or discontinuation of support for malaria elimination. Strong commitment of policymakers combined with strict monitoring and supervision by funders were considered pivotal to successful elimination programmes. CONCLUSION: Against a backdrop of increasing anti-malarial resistance and decreasing choices of anti-malarial regimens, policy makers and researchers stressed the urgency of finding new malaria elimination strategies. There was consensus that multi-pronged strategies and approaches are needed, that no single potential tool/strategy can be appropriate to all settings. Hence there is a need to customize malaria control and elimination strategies based on the better surveillance data.


Assuntos
Antimaláricos/farmacologia , Erradicação de Doenças/métodos , Resistência a Múltiplos Medicamentos , Malária/prevenção & controle , Pessoal Administrativo/psicologia , Ásia Sudeste , Humanos , Pesquisa Qualitativa , Inquéritos e Questionários
12.
Br J Nurs ; 28(12): S6-S9, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31242104

RESUMO

Non-healing diabetic foot ulcers are a common and costly complication of type 2 diabetes and can result in lower extremity amputation. This case study concerns a 51-year-old man with a 17-year history of uncontrolled type 2 diabetes. He had developed a deep ulcer to the calcaneus of his left foot, which was 12x7 cm in size and infected with multi-drug-resistant Staphylococcus aureus. He was admitted to hospital for the non-healing diabetic foot ulcer and uncontrollable fever and was a candidate for amputation. He was treated with wound irrigation and debridement as well as negative-pressure wound therapy and antibiotic treatment. This strategy was effective and the wound size reduced progressively. The patient recovered well. Medical and wound care teams who deal with non-healing diabetic foot ulcers can benefit from a strategy of combination therapy.


Assuntos
Antibacterianos/uso terapêutico , Desbridamento , Pé Diabético/terapia , Tratamento de Ferimentos com Pressão Negativa , Irrigação Terapêutica , Amputação , Terapia Combinada , Diabetes Mellitus Tipo 2/complicações , Resistência a Múltiplos Medicamentos , Humanos , Masculino , Pessoa de Meia-Idade , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Resultado do Tratamento
13.
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
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 785-789, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204932

RESUMO

OBJECTIVE: To explore the reversal effect of pioglitazone (PIO) on multidrug resistance in K562/ADR cells and its mechanism. METHODS: The proliferation inhibition rate, half inhibition concentration (IC50) and drug-resistance reversal multipe were detected and the curve of proliferation inhibition rate was drawn by MTT assay, the transcription of PPARγ, CYP2C8 and CYP2J2 genes was detected by RT-PCR; the expression of PPARγ, CYP2C8 and CYP2J2 proteins was detected by Western blot. RESULTS: The IC50 of PIO on K562 and K562/ADR cells for 60 h was 326.7 µmol/L and 349.1 µmol/L respectively. The reversal multiple of 30 µmol/L PIO on ADR-resistance of K562/ADR cells was 6.4. After treatment of K562/ADR cells with PIO, the transcription of CYP2C8 and CYP2J2 and the protein expression of CYP2C8 and CYP2J2 significantly decreased, the transcription of PPARγ gene and the expression of PPARγ protein were not changed. CONCLUSIONS: Pioglitazone can reverse the adriamycin-resistance in K562/ADR cells that is closely related to the decrease of protein expression of CYP2C8 and CYP2J2. Pioglitazone is an effective multidrug resistance reversal agent for tumors.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Doxorrubicina , Resistência a Múltiplos Medicamentos , Humanos , Células K562 , Pioglitazona
15.
Life Sci ; 231: 116530, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31170419

RESUMO

AIMS: The aim of the study was to evaluate the potential of naturally occurring isothiocyanates and doxorubicin in combined treatment of doxorubicin-resistant colon cancer. Doxorubicin is a cytostatic commonly used to treat many different types of cancer but its usage is often abrogated by severe side-effects and drug-induced resistance. MAIN METHODS: The antiproliferative potential of the combined treatment was analyzed in vitro by the SRB method (sulforhodamine B) and further evaluated for the mechanisms that determine the treatment outcome using a series of assays which included oxidative stress, apoptosis and compounds accumulation assessment. Ultimately, a combined treatment potential was assessed in vivo utilizing doxorubicin-resistant colon cancer model. KEY FINDING: The results indicate that naturally occurring isothiocyanates, represented by 3,4-dimethoxybenzyl isothiocyanate (dMBITC) increase doxorubicin the efficacy in doxorubicin-resistant human colon adenocarcinoma model by attenuated drug efflux, an increased reactive oxygen species production and an increased rate of apoptosis. In in vitro studies, over a 3-fold decrease in doxorubicin IC50 value was observed on the LoVoDX cell line when used in combination with suboptimal concentrations of dMBITC. The combined therapy exhibited a significantly higher efficacy than doxorubicin-alone treatment (c.a. 50% tumor growth inhibition in comparison to c.a. 25% for doxorubicin-alone treatment) in vivo. At the same time, the combined treatment attenuates doxorubicin toxicity as evidenced by improved animals body mass, main organs weight and biochemical markers of toxicity. SIGNIFICANCE: The adopted approach provides evidence that isothiocyanates can be successfully applied in the treatment of doxorubicin-resistant colon cancer, which warrants further studies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/farmacologia , Isotiocianatos/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Colo/efeitos dos fármacos , Neoplasias do Colo/patologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Isotiocianatos/química , Camundongos , Camundongos Endogâmicos NOD , Estresse Oxidativo/efeitos dos fármacos
16.
Genes Dev ; 33(13-14): 871-885, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171704

RESUMO

Aberrant translation initiation at non-AUG start codons is associated with multiple cancers and neurodegenerative diseases. Nevertheless, how non-AUG translation may be regulated differently from canonical translation is poorly understood. Here, we used start codon-specific reporters and ribosome profiling to characterize how translation from non-AUG start codons responds to protein synthesis inhibitors in human cells. These analyses surprisingly revealed that translation of multiple non-AUG-encoded reporters and the endogenous GUG-encoded DAP5 (eIF4G2/p97) mRNA is resistant to cycloheximide (CHX), a translation inhibitor that severely slows but does not completely abrogate elongation. Our data suggest that slowly elongating ribosomes can lead to queuing/stacking of scanning preinitiation complexes (PICs), preferentially enhancing recognition of weak non-AUG start codons. Consistent with this model, limiting PIC formation or scanning sensitizes non-AUG translation to CHX. We further found that non-AUG translation is resistant to other inhibitors that target ribosomes within the coding sequence but not those targeting newly initiated ribosomes. Together, these data indicate that ribosome queuing enables mRNAs with poor initiation context-namely, those with non-AUG start codons-to be resistant to pharmacological translation inhibitors at concentrations that robustly inhibit global translation.


Assuntos
Códon de Iniciação/genética , Resistência a Múltiplos Medicamentos/genética , Ribossomos/genética , Elongação da Transcrição Genética/efeitos dos fármacos , Cicloeximida/farmacologia , Fator de Iniciação 4G em Eucariotos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter/genética , Células HEK293 , Células HeLa , Humanos , Inibidores da Síntese de Proteínas/farmacologia
17.
Life Sci ; 231: 116548, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31181228

RESUMO

AIMS: Multidrug resistance is a major obstacle in chemotherapy, which is mainly caused by the overexpression of ATP-binding cassette (ABC) transporters. Breast cancer resistance protein (BCRP) is one of the ABC transporters and is strongly associated with multidrug resistance. Results of studies on BCRP and multidrug resistance are always uncomparable and contradictory, which may be stem from the disadvantages of qualitative and semi-quantitative techniques. In addition, there are few literatures studying at low resistance level which is more similar to the clinical situation. Thus, it is imperative to develop a quantitative method to quantitate the expression of BCRP accurately and reveal its relationship with multidrug resistance. METHODS: SMMC-7721, MCF-7 and HepG-2 were induced by different concentrations of mitoxantrone, doxorubicin and methotrexate respectively to establish resistance cells. An advanced liquid chromatography linked to tandem mass spectrometry (LC-MS/MS) based method with surrogate peptide was developed and validated for determining BCRP at low resistant cells. The amount of BCRP was also evaluated by real-time-polymerase chain reaction (RT-PCR) and Western Blot (WB). KEY FINDINGS: The LC-MS/MS-based method we developed is more sensitive and stable than the similar methods and can monitor the slight variation of BCRP expression accurately and sensitively, while RT-PCR and WB cannot. SIGNIFICANCE: This study provides a solid foundation for understanding the development of drug resistance in cells and can be used to explain the conflicting results of published studies. Moreover, clinical multidrug resistances are mostly at low levels, which have not been discussed in current quantitative studies of BCRP.


Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/metabolismo , Cromatografia Líquida/métodos , Proteínas de Membrana/análise , Proteínas de Membrana/biossíntese , Proteômica/métodos , Espectrometria de Massas em Tandem/métodos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Células Hep G2 , Humanos , Células MCF-7 , Proteínas de Neoplasias/metabolismo
18.
Rozhl Chir ; 98(4): 145-151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31159547

RESUMO

Complicated intra-abdominal infections (cIAI) are a substantial cause of morbidity at intensive care units. cIAI are frequently caused by multidrug-resistant strains of Enterobacteriaceae and Pseudomonas aeruginosa. In 592 cIAI patients from the First Department of Surgery, General University Hospital in Prague, we found an alarming increase in resistance of Escherichia coli to amoxicillin/clavulanic acid, piperacillin/tazobactam and third-generation cephalosporins in 2014-2017 (from 28.7% in 2014 to 37.5% in 2017, from 25% to 32% and from 2.3% to 5.6%, respectively). Ceftolozane/tazobactam and ceftazidime/avibactam are novel cephalosporins available for the treatment of cIAI. Ceftolozane/tazobactam is highly active against multidrug-resistant strains of P. aeruginosa, including carbapenem-resistant isolates. The new non-b-lactam b-lactamase inhibitor avibactam plus ceftazidime is active against carbapenemases-producing strains of Enterobacteriaceae. Both antibiotics are included in the new WSES guidelines for the management of cIAI.


Assuntos
Antibacterianos , Infecções Intra-Abdominais , Antibacterianos/uso terapêutico , Resistência a Múltiplos Medicamentos , Humanos , Infecções Intra-Abdominais/tratamento farmacológico , Ácido Penicilânico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa
19.
Life Sci ; 231: 116557, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31194994

RESUMO

AIMS: Vinegar-baked Radix Bupleuri (VBRB) potentiates the activity of anticancer drugs in the liver by increasing their hepatic distribution. However, this phenomenon may be associated with drug transporters. We investigated the effect of saikosaponin b2 (SSb2; the main component of VBRB) on the activity and expression of different drug transporters in both normal cells and those that overexpress the transporter. MAIN METHODS: The activities of transporters were analyzed by concentration of their cellular substrates. Concentrations of colchicine (substrate of Pgp and MRP1) and cisplatin (substrate of OCT2 and MRP2) were determined by high-performance liquid chromatography (HPLC). The concentration of rhodamine B was determined by flow cytometry. The expression of transporter gene and protein were determined by qRT-PCR and Western blotting analysis. KEY FINDINGS: SSb2 increased colchicine efflux in HEK293 cells by primarily increasing Mrp1 activity, independent of gene and protein expression. SSb2 enhanced Mrp2 function and increased cisplatin efflux in BRL3A cells by upregulating Mrp2 gene expression, with a marginal effect on Pgp in normal cells. SSb2 increased OCT2 activity in OCT2-HEK293 cells by increasing the expression of OCT2 protein and mRNA; however, SSb2 inhibited MRP2 activity in MRP2-HEK293 cells by decreasing MRP2 protein expression, and decreased Pgp and MRP1 activity in Pgp- and MRP1-HEK293 cells. SIGNIFICANCE: SSb2 might potentially be the key active component of VBRB that enhances the hepatotargeting of anticancer drugs through the inhibition of multidrug resistance-associated drug transporters (Pgp, MRP1, and MRP2) in an environment-dependent manner.


Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/metabolismo , Saponinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Antineoplásicos/farmacologia , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Cisplatino/análise , Cisplatino/metabolismo , Cisplatino/farmacologia , Colchicina/análise , Colchicina/metabolismo , Colchicina/farmacologia , Resistência a Múltiplos Medicamentos/fisiologia , Células HEK293 , Humanos , Medicina Tradicional Chinesa , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia , RNA Mensageiro/metabolismo , Rodaminas/análise , Rodaminas/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
J Biomed Nanotechnol ; 15(3): 531-543, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31165698

RESUMO

MDR (multi-drug resistance) is a major obstacle to the successful treatment of cancers. The combination therapeutic based on RNAi has been investigated as a potential strategy for reversing the MDR. However, the effective delivery of siRNA in vivo remains the challenge for the reality of these candidate RNAi drugs. Cationic peptides for gene delivery have attracted considerable attention due to their biocompatibility and high safety. Herein, self-assembled polypeptide nanoparticles LAH4-L1-siRNA (PNLS) were prepared and loaded with a siRNA (siMDR1) for overcoming MDR in human breast cancer MCF-7/ADR cells in vitro and in vivo. Owing to its cationic charges and α-helical conformation, the histidinerich peptide enhanced cellular uptake of siRNA and represented high gene silencing efficiency. The cellular uptake pathways and internalization process of PNLS into cells were further investigated. In vivo biodistribution indicated that the PNLS exhibited higher tumor-targeted delivery. More importantly, PNLS combined with PTX (Paclitaxel) showed antitumor effects and high MDR1 gene silencing efficiency in the tumor-bearing nude mice. Overall, the PNLS achieved the genetargeted knockdown in vivo and hold immense promise for a new therapeutic drug for breast cancer treatment.


Assuntos
Neoplasias da Mama , Nanopartículas , Animais , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Inativação Gênica , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Paclitaxel , Peptídeos , RNA Interferente Pequeno , Distribuição Tecidual
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