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1.
Rev Med Suisse ; 16(710): 1912-1915, 2020 Oct 14.
Artigo em Francês | MEDLINE | ID: mdl-33058576

RESUMO

The extraordinary development of medicine with the advent of solid organ and bone marrow transplants, chemotherapy and immunotherapy, as well as the explosion of invasive procedures (« foreign material ¼) has made our medicine dependant to the use of antibiotics. The overuse of « empirical ¼ antibiotics in breeding and medicine has favored the emergence and rapid dissemination of multidrug resistant pathogens (MDRs). This leaded clinicians today in a difficult situation. They should limit their empirical use of « broad-spectrum antibiotics ¼, although they face a higher risk of MDRs. To help them in this task, anti-microbial stewardship programs have been put in place, emphasizing the use of « hospital antibiograms ¼ and rapid and reliable microbiological diagnosis.


Assuntos
Antibacterianos , Gestão de Antimicrobianos/métodos , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Antibacterianos/provisão & distribução , Antibacterianos/uso terapêutico , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Hospitais , Humanos
2.
Anticancer Res ; 40(9): 4921-4928, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878780

RESUMO

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Organosselênicos/farmacologia , Fenotiazinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/patologia , Camundongos , Estrutura Molecular , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/química , Fenotiazinas/síntese química , Fenotiazinas/química
3.
Plant Dis ; 104(10): 2563-2570, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32762501

RESUMO

Rhizoctonia solani is a widely distributed soilborne plant pathogen, and can cause significant economic losses to crop production. In chemical controls, SYP-14288 is highly effective against plant pathogens, including R. solani. To examine the sensitivity to SYP-14288, 112 R. solani isolates were collected from infected rice plants. An established baseline sensitivity showed that values of effective concentration for 50% growth inhibition (EC50) ranged from 0.0003 to 0.0138 µg/ml, with an average of 0.0055 ± 0.0030 µg/ml. The frequency distribution of the EC50 was unimodal and the range of variation factor (the ratio of maximal over minimal EC50) was 46.03, indicating that all wild-type strains were sensitive to SYP-14288. To examine the risk of fungicide resistance, 20 SYP-14288-resistant mutants were generated on agar plates amended with SYP-14288. Eighteen mutants remained resistant after 10 transfers, and their fitness was significantly different from the parental strain. All of the mutants grew more slowly but showed high virulence to rice plants, though lower than the parental strain. A cross-resistance assay demonstrated that there was a positive correlation between SYP-14288 and fungicides having or not having the same mode of action with SYP-14288, including fluazinam, fentin chloride, fludioxonil, difenoconazole, cyazofamid, chlorothalonil, and 2,4-dinitrophen. This result showed a multidrug resistance induced by SYP-14288, which could be a concern in increasing the spectrum of resistance in R. solani to commonly used fungicides.


Assuntos
Fungicidas Industriais/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Doenças das Plantas , Rhizoctonia/efeitos dos fármacos
4.
Ecotoxicol Environ Saf ; 202: 110940, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800223

RESUMO

Recent evidence indicates that chronic, low-dose exposure to mixtures of pesticides can cause adverse responses in a variety of cells, tissues and organs, although interactions between pesticides circulating in the blood and cancer cells remain largely unexplored. The aim of this study was to investigate the potential of a mixture of four pesticides to induce multidrug resistance against the chemotherapeutic agents cisplatin, 5-fluorouracil and temozolomide in the human U87 glioblastoma cell line, and to explore the molecular mechanisms underlying this resistance. We found that the repeated administration of the pesticide mixture (containing the insecticides chlorpyrifos-ethyl and deltamethrin, the fungicide metiram, and the herbicide glyphosate) induced a strong drug resistance in U87 cells. The resistance was durable and transferred to subsequent cell generations. In addition, we detected a significant over-expression of the ATP-binding cassette (ABC) membrane transporters P-gp/ABCB1 and BRCP/ABCG2 as well as a glutathione-S-transferase (GST)/M1-type cellular detoxification function, known to have important roles in multidrug resistance, thus providing molecular support for the acquired multidrug resistance phenotype and shedding light on the mechanism of resistance. We further determined that there was lower mortality in the resistant brain tumor cells and that the mitochondrial apoptosis pathway was activated at a lower rate after chemotherapy compared to non-resistant control cells. In addition, multidrug-resistant cells were found to have both higher motility and wound-healing properties, suggesting a greater metastatic potential. Our results suggest that the investigation of P-gp, BRCP and GST/M1 multidrug resistance gene expression and/or protein levels in biopsy specimens of brain tumor patients who were at risk of pesticide exposure could be beneficial in determining chemotherapy dose and prolonging patient survival.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Praguicidas/toxicidade , Testes de Toxicidade Crônica , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/farmacologia
5.
PLoS One ; 15(6): e0233993, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32484843

RESUMO

Multidrug resistance (MDR) to chemotherapeutic drugs remains one of the major impediments to the treatment of cancer. Discovery and development of drugs that can prevent and reverse the acquisition of multidrug resistance constitute a foremost challenge in cancer therapeutics. In this work, we screened a library of 1,127 compounds with known targets for their ability to overcome Pgp-mediated multidrug resistance in cancer cell lines. We identified four compounds (CHIR-124, Elesclomol, Tyrphostin-9 and Brefeldin A) that inhibited the growth of two pairs of parental and Pgp-overexpressing multidrug-resistant cell lines with similar potency irrespective of their Pgp status. Mechanistically, CHIR-124 (a potent inhibitor of Chk1 kinase) inhibited Pgp activity in both multidrug-resistant cell lines (KB-V1 and A2780-Pac-Res) as determined through cell-based Pgp-efflux assays. Other three inhibitors on the contrary, were effective in Pgp-overexpressing resistant cells without increasing the cellular accumulation of a Pgp substrate, indicating that they overcome resistance by avoiding efflux through Pgp. None of these compounds modulated the expression of Pgp in resistant cell lines. PIK-75, a PI3 Kinase inhibitor, was also determined to inhibit Pgp activity, despite being equally potent in only one of the two pairs of resistant and parental cell lines. Strong binding of both CHIR-124 and PIK-75 to Pgp was predicted through docking studies and both compounds inhibited Pgp in a biochemical assay. The inhibition of Pgp causes accumulation of these compounds in the cells where they can modulate the function of their target proteins and thereby inhibit cell proliferation. In conclusion, we have identified compounds with various cellular targets that overcome multidrug resistance in Pgp-overexpressing cell lines through mechanisms that include Pgp inhibition and efflux evasion. These compounds, therefore, can avoid challenges associated with the co-administration of Pgp inhibitors with chemotherapeutic or targeted drugs such as additive toxicities and differing pharmacokinetic properties.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Neoplasias/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Brefeldina A/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrazinas/farmacologia , Hidrazonas/farmacologia , Neoplasias/genética , Neoplasias/patologia , Quinolinas/farmacologia , Quinuclidinas/farmacologia , Sulfonamidas/farmacologia , Tirfostinas/farmacologia
6.
Arch Microbiol ; 202(8): 2105-2115, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32500253

RESUMO

In this study, the antibacterial, anti-efflux, anti-biofilm, anti-slime (exopolysaccharide) production and urease inhibitory efficacies of green synthesized gold nanoparticles (AuNPs) coated Anthemis atropatana extract against multidrug- resistant (MDR) Klebsiella pneumoniae strains were evaluated. The green synthesized AuNPs were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffractometer (XRD), particle size distribution, zeta potential and Fourier-transform infrared spectroscopy (FTIR). Then, antibacterial, anti-slime (exopolysaccharide) production, anti-biofilm and anti-efflux activities of AuNPs were investigated using micro-dilation, Congored agar, microtiter plate and MIC of ethidium bromide methods, respectively. Subsequently, the expression of mrkA, wzm and acrB genes was evaluated using quantitative Real-Time PCR (qRT-PCR). The synthesized AuNPs exhibited antibacterial activity against MDR strains of K. pneumoniae (minimum inhibitory concentration (MIC) of 6.25-50 µg/ml), as well as showed significant anti-slime (exopolysaccharide) production, anti-biofilm and anti-efflux activities against MDR strains. AuNPs showed significant inhibition against jack-bean urease and down-regulated the expression of mrkA, wzm and acrB genes. Moreover, the in vitro cytotoxic activity confirmed by MTT assay on the HEK-293 normal cell line showed negligible cytotoxicity. Thus, the present study suggests the potential use of AuNPs in the development of novel therapeutics for the prevention of biofilm-associated K. pneumoniae infections.


Assuntos
Anthemis/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ouro/farmacologia , Klebsiella pneumoniae/efeitos dos fármacos , Nanopartículas Metálicas , Extratos Vegetais/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Ouro/química , Células HEK293 , Humanos , Nanopartículas Metálicas/química , Testes de Sensibilidade Microbiana , Extratos Vegetais/química , Urease/metabolismo
7.
PLoS One ; 15(5): e0232825, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407391

RESUMO

As part of a Germany-wide project that evaluates strategies for the reduction of multi-resistant bacteria along the poultry production chain, the impact of different hatching egg disinfectants on hatchability and health of the broiler chicks was evaluated. Animal trials were conducted with extended-spectrum beta-lactamase- (ESBL) producing Escherichia (E.) coli contaminated hatching eggs and six disinfection protocols that used formaldehyde, hydrogen peroxide, low-energy electron irradiation, peracetic acid and an essential oil preparation. Each protocol was tested on a group of 50 chicks. Equally sized positive and negative control groups were carried along for each trial. Hatchability, mortality and body weight were recorded as performance parameters. During necropsy of half of the animals in each group on day 7 and 14 respectively, macroscopic abnormalities, body weight, weights of liver and gut convolute were recorded and a range of tissue samples for histological examination were collected as part of the health assessment. A decrease in hatchability was recorded for spray application of essential oils. Body weight development was overall comparable, in several groups even superior, to the Ross308 performance objectives, but a reduced performance was seen in the hydrogen peroxide group. Histologically, lymphoid follicles were regularly seen in all sampled organs and no consistent differences were observed between contaminated and non-contaminated groups. Significances were infrequently and inconsistently seen. In conclusion, remarkable findings were a decrease in hatchability caused by the essential oils spray application and a reduced body weight development in the hydrogen peroxide group. Therefore, the essential oils preparation as spray application was deemed inappropriate in practice, while the application of hydrogen peroxide was considered in need of further research. The other trial results indicate that the tested hatching egg disinfectants present a possible alternative to formaldehyde.


Assuntos
Desinfetantes/farmacologia , Desinfecção/métodos , Ovos/microbiologia , Escherichia coli/efeitos dos fármacos , Animais , Galinhas/microbiologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Escherichia coli/patogenicidade , Alemanha , Humanos , Óleos Voláteis/efeitos adversos , Óleos Voláteis/farmacologia
8.
Phytomedicine ; 70: 153215, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32388040

RESUMO

BACKGROUND: Recalcitrant cancers appear as a major obstacle to chemotherapy, prompting scientists to intensify the search for novel drugs to tackle the cell lines expressing multi-drug resistant (MDR) phenotypes. PURPOSE: The purpose of this study was to evaluate the antiproliferative potential of a ferrulic acid derivative, 8,8-bis-(dihydroconiferyl)-diferulate (DHCF2) on a panel of 18 cancer cell lines, including various sensitive and drug-resistant phenotypes, belonging to human and animals. The mode of induction of cell death by this compound was further studied. METHODS: The antiproliferative activity, autophagy, ferroptotic and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the activity of caspases. Cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA) were assessed by flow cytometry. RESULTS: DHCF2 demonstrated impressive cytotoxic effects towards the 18 cancer cell lines tested, with IC50 values all below 6.5 µM. The obtained IC50 values were in the range of 1.17 µM (towards CCRF-CEM leukemia cells) to 6.34 µM (towards drug-resistant HCT116 p53-/- human colon adenocarcinoma cells) for DHCF2 and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against multidrug-resistant CEM/ADR5000 leukemia cells) for the reference drug, doxorubicin. DHCF2 had IC50 values lower than those of doxorubicin, against CEM/ADR5000 cells and on some melanoma cell lines, such as MaMel-80a cells, Mel-2a cells, MV3 cells and SKMel-505 cells. DHCF2 induced autophagy as well as apoptosis in CCRF-CEM cells though caspases activation, MMP alteration and increase of ROS production. CONCLUSION: The studied diferulic acid, DHCF2, is a promising antiproliferative compound. It deserves further indepth investigations with the ultimate aim to develop a novel drug to fight cancer drug resistance.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade
10.
Med. clín (Ed. impr.) ; 154(9): 351-357, mayo 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-193216

RESUMO

Una de las prioridades actuales de la Organización Mundial de la Salud son las bacterias multirresistentes, dado que constituyen un problema en todo el mundo por su rápida diseminación, así como por la dificultad de su tratamiento. Además, se asocian a una alta morbilidad, mortalidad y a unos costes económicos elevados. Hay bacterias multirresistentes tanto grampositivas como gramnegativas, destacando entre ellas Pseudomonas aeruginosa y Acinetobacter baumannii resistentes a las carbapenemas, enterobacterias productoras de carbapenemasas, Staphylococcus aureus resistente a la meticilina y/o con sensibilidad intermedia a la vancomicina y Enterococcus faecium (y menos frecuentemente Enterococcus faecalis) resistente a la vancomicina. En esta revisión se comentarán los nuevos antibióticos que se han incorporado en los últimos años al arsenal terapéutico, así como otros antibióticos prometedores que se encuentran en sus últimas fases de desarrollo


One of the current priorities of the World Health Organization is multidrug-resistant bacteria, because they are a global problem due to their rapid spread and the difficulty of their treatment. In addition, they are associated with high morbidity, mortality and high economic costs. There are multidrug-resistant bacteria, both Gram-positive and Gram-negative, including Pseudomonas aeruginosa and Acinetobacter baumannii resistant to carbapenems, enterobacteria producing carbapenemases, Staphylococcus aureus resistant to methicillin and/or with intermediate sensitivity to vancomycin, and Enterococcus faecium (and less frequently Enterococcus faecalis) resistant to vancomycin. This review will comment on the new antibiotics that have been incorporated into the therapeutic arsenal in recent years, as well as other promising antibiotics that are in their final stages of development


Assuntos
Humanos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Tazobactam/uso terapêutico , Bacilos Gram-Positivos/efeitos dos fármacos
11.
J Med Chem ; 63(10): 5458-5476, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32329342

RESUMO

SIS3 is a specific inhibitor of Smad3 that inhibits the TGFß1-induced phosphorylation of Smad3. In this article, a variety of SIS3 derivatives were designed and synthesized to discover potential inhibitors against P-glycoprotein-mediated multidrug resistance aided by late-stage functionalization of a 2-(4-(pyridin-2-yl)phenoxy)pyridine analogue. A novel class of potent P-gp reversal agents were investigated, and a lead compound 37 was identified as a potent P-gp reversal agent with strong bioactivity and outstanding affinity for P-gp.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Descoberta de Drogas/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Isoquinolinas/química , Isoquinolinas/farmacologia , Piridinas/química , Piridinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Resistência a Múltiplos Medicamentos/fisiologia , Humanos , Isoquinolinas/metabolismo , Células K562 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular/métodos , Piridinas/metabolismo , Pirróis/metabolismo , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Mol Pharmacol ; 97(6): 402-408, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32276963

RESUMO

The 78-kDa glucose-regulated protein (GRP78), an endoplasmic reticulum (ER) chaperone, is a master regulator of the ER stress. A number of studies revealed that high levels of GRP78 protein in cancer cells confer multidrug resistance (MDR) to therapeutic treatment. Therefore, drug candidate that reduces GRP78 may represent a novel approach to eliminate MDR cancer cells. Our earlier studies showed that a set of 4H-chromene derivatives induced selective cytotoxicity in MDR cancer cells. In the present study, we elucidated its selective mechanism in four MDR cancer cell lines with one lead candidate (CXL146). Cytotoxicity results confirmed the selective cytotoxicity of CXL146 toward the MDR cancer cell lines. We noted significant overexpression of GRP78 in all four MDR cell lines compared with the parental cell lines. Unexpectedly, CXL146 treatment rapidly and dose-dependently reduced GRP78 protein in MDR cancer cell lines. Using human leukemia (HL) 60/mitoxantrone (MX) 2 cell line as the model, we demonstrated that CXL146 treatment activated the unfolded protein response (UPR); as evidenced by the activation of inositol-requiring enzyme 1α, protein kinase R-like ER kinase, and activating transcription factor 6. CXL146-induced UPR activation led to a series of downstream events, including extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase activation, which contributed to CXL146-induced apoptosis. Targeted reduction in GRP78 resulted in reduced sensitivity of HL60/MX2 toward CXL146. Long-term sublethal CXL146 exposure also led to reduction in GRP78 in HL60/MX2. These data collectively support GRP78 as the target of CXL146 in MDR treatment. Interestingly, HL60/MX2 upon long-term sublethal CXL146 exposure regained sensitivity to mitoxantrone treatment. Therefore, further exploration of CXL146 as a novel therapy in treating MDR cancer cells is warranted. SIGNIFICANCE STATEMENT: Multidrug resistance is one major challenge to cancer treatment. This study provides evidence that cancer cells overexpress 78-kDa glucose-regulated protein (GRP78) as a mechanism to acquire resistance to standard cancer therapies. A chromene-based small molecule, CXL146, selectively eliminates cancer cells with GRP78 overexpression via activating unfolded protein response-mediated apoptosis. Further characterization indicates that CXL146 and standard therapies complementarily target different populations of cancer cells, supporting the potential of CXL146 to overcome multidrug resistance in cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Benzopiranos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Choque Térmico/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Proteínas de Choque Térmico/efeitos dos fármacos , Humanos , Mitoxantrona/farmacologia
13.
Nat Ecol Evol ; 4(6): 863-869, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32251388

RESUMO

Multidrug resistance (MDR) of pathogens is an ongoing public health crisis exacerbated by the horizontal transfer of antibiotic resistance genes via conjugative plasmids. Factors that stabilize these plasmids in bacterial communities contribute to an even higher incidence of MDR, given the increased likelihood that a host will already contain a plasmid when it acquires another through conjugation. Here, we show one such stabilizing factor is host-plasmid coevolution under antibiotic selection, which facilitated the emergence of MDR via two distinct plasmids in communities consisting of Escherichia coli and Klebsiella pneumoniae once antibiotics were removed. In our system, evolution promoted greater stability of a plasmid in its coevolved host. Further, pleiotropic effects resulted in greater plasmid persistence in both novel host-plasmid combinations and, in some cases, multi-plasmid hosts. This evolved stability favoured the generation of MDR cells and thwarted their loss within communities with multiple plasmids. By selecting for plasmid persistence, the application of antibiotics may promote MDR well after their original period of use.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Escherichia coli/genética , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Plasmídeos/efeitos dos fármacos
14.
Biochim Biophys Acta Mol Cell Res ; 1867(8): 118728, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32343987

RESUMO

Acquired multidrug resistance of cancer cells challenges the chemotherapeutic interventions. To understand the role of molecular chaperone, Hsp90 in drug adapted tumor cells, we have used in vitro drug adapted epidermoid tumor cells as a model system. We found that chemotherapeutic drug adaptation of tumor cells is mediated by induced activities of both Hsp90 and P-glycoprotein (P-gp). Although the high-affinity conformation of Hsp90 has correlated with the enhanced drug efflux activity, we did not observe a direct interaction between P-gp and Hsp90. The enrichment of P-gp and Hsp90 at the cholesterol-rich membrane microdomains is found obligatory for enhanced drug efflux activity. Since inhibition of cholesterol biosynthesis is not interfering with the drug efflux activity, it is presumed that the net cholesterol redistribution mediated by Hsp90 regulates the enhanced drug efflux activity. Our in vitro cholesterol and Hsp90 interaction studies have furthered our presumption that Hsp90 facilitates cholesterol redistribution. The drug adapted cells though exhibited anti-proliferative and anti-tumor effects in response to 17AAG treatment, drug treatment has also enhanced the drug efflux activity. Our findings suggest that drug efflux activity and metastatic potential of tumor cells are independently regulated by Hsp90 by distinct mechanisms. We expose the limitations imposed by Hsp90 inhibitors against multidrug resistant tumor cells.


Assuntos
Antineoplásicos/farmacologia , Colesterol/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Indutores da Angiogênese , Animais , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Progressão da Doença , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Proteínas de Choque Térmico HSP90/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/genética , Humanos , Lactamas Macrocíclicas/farmacologia , Masculino , Camundongos Nus , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Exp Clin Cancer Res ; 39(1): 50, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32164732

RESUMO

BACKGROUND: Inhibition of ABC transporters is considered the most effective way to circumvent multidrug resistance (MDR). In the present study, we evaluated the MDR modulatory potential of ERK5-IN-1, a potent extracelluar signal regulated kinase 5 (ERK5) inhibitor. METHODS: The cytotoxicity and MDR reversal effect of ERK5-IN-1 were assessed by MTT assay. The KBv200-inoculated nude mice xenograft model was used for the in vivo study. Doxorubicin efflux and accumulation were measured by flow cytometry. The modulation of ABCB1 activity was measured by colorimetric ATPase assay and [125I]-iodoarylazidoprazosin (IAAP) photolabeling assay. Effect of ERK5-IN-1 on expression of ABCB1 and its downstream markers was measured by PCR and/or Western blot. Cell surface expression and subcellular localization of ABCB1 were tested by flow cytometry and immunofluorescence. RESULTS: Our results showed that ERK5-IN-1 significantly increased the sensitivity of vincristine, paclitaxel and doxorubicin in KBv200, MCF7/adr and HEK293/ABCB1 cells, respectively. This effect was not found in respective drug sensitive parental cell lines. Moreover, in vivo combination studies showed that ERK5-IN-1 effectively enhanced the antitumor activity of paclitaxel in KBv200 xenografts without causing addition toxicity. Mechanistically, ERK5-IN-1 increased intracellular accumulation of doxorubicin dose dependently by directly inhibiting the efflux function of ABCB1. ERK5-IN-1 stimulated the ABCB1 ATPase activity and inhibited the incorporation of [125I]-iodoarylazidoprazosin (IAAP) into ABCB1 in a concentration-dependent manner. In addition, ERK5-IN-1 treatment neither altered the expression level of ABCB1 nor blocked the phosphorylation of downstream Akt or Erk1/2. No significant reversal effect was observed on ABCG2-, ABCC1-, MRP7- and LRP-mediated drug resistance. CONCLUSIONS: Collectively, these results indicated that ERK5-IN-1 efficiently reversed ABCB1-mediated MDR by competitively inhibiting the ABCB1 drug efflux function. The use of ERK5-IN-1 to restore sensitivity to chemotherapy or to prevent resistance could be a potential treatment strategy for cancer patients.


Assuntos
Benzodiazepinas/administração & dosagem , Doxorrubicina/administração & dosagem , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Células HEK293 , Células HL-60 , Humanos , Camundongos , Camundongos Nus , Proteína Quinase 7 Ativada por Mitógeno/antagonistas & inibidores , Neoplasias , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Nanoscale Horiz ; 5(3): 481-487, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32118218

RESUMO

The presence of drug efflux pumps and endo/lysosomal entrapment phenomena in multidrug-resistant cancer cells leads to insufficient and off-target accumulation of anticancer drugs in the cells, which severely reduces the drugs' therapeutic efficacies. Here, we prepare a novel type of photosensitizer (PS)-loaded supramolecular nanogel, which can utilize the endo/lysosomal entrapment for enhanced photodynamic therapy (PDT) of multidrug-resistant cancer. The PS-loaded nanogels can elude the drug efflux pumps, and be markedly internalized by drug-resistant cancer cells through the endocytic pathway. With their pH-sensitive properties, the internalized nanogels can aggregate in the acidic endosomes/lysosomes, thus retarding their exocytosis from the cells. Moreover, the lysosomes of the nanogel-treated cells are severely damaged after irradiation, which inhibits the protective autophagy and improves the photodynamic therapeutic performance of the nanogels. Besides, the in vivo experiments show that the nanogels significantly prolong the tumor retention of the PSs, thus enabling multiple PDT treatments after a single drug injection.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fotoquimioterapia/métodos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Endossomos/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Lisossomos/metabolismo , Nanogéis/uso terapêutico , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico
17.
Cancer Sci ; 111(5): 1619-1630, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32058643

RESUMO

Recent studies have shown that MDR could be induced by the high stemness of cancer cells. In a previous study, we found bufalin could reverse MDR and inhibit cancer cell stemness in colorectal cancer, but the relationship between them was unclear. Here we identified overexpressing CD133 increases levels of Akt/nuclear factor-κB signaling mediators and MDR1, while increasing cell chemoresistance. Furthermore, bufalin reverses colorectal cancer MDR by regulating cancer cell stemness through the CD133/nuclear factor-κB/MDR1 pathway in vitro and in vivo. Taken together, our results suggest that bufalin could be developed as a novel 2-pronged drug that targets CD133 and MDR1 to eradicate MDR cells and could ultimately be combined with conventional chemotherapeutic agents to improve treatment outcomes for patients with colorectal cancer.


Assuntos
Antígeno AC133/metabolismo , Antineoplásicos/farmacologia , Bufanolídeos/farmacologia , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Antígeno AC133/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/uso terapêutico , Bufanolídeos/uso terapêutico , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Transdução de Sinais , Fator de Transcrição RelA/genética
18.
J Colloid Interface Sci ; 565: 254-269, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31978788

RESUMO

Multidrug resistance (MDR) is one of the major obstacles to clinical cancer chemotherapy. Herein, we designed new pH-sensitive pluronic micelles with the synergistic effects of oxidative therapy and MDR reversal. Pluronic (P123) was modified with α-tocopheryl succinate (α-TOS) via an acid-labile ortho ester (OE) linkage to give a pH-sensitive copolymer (POT). Self-assembled POT micelles exhibited desirable size (~80 nm), excellent anti-dilution ability, high drug loading (~85%), acid-triggered degradation and drug release behaviours. In vitro cell experiments verified that POT micelles could significantly reverse MDR through suppressing the function of drug effluxs mediated by P123 and induce more reactive oxygen species (ROS) generation mediated by α-TOS, resulting in enhanced cytotoxicity and apoptosis in MDR cells. In vivo studies further revealed that DOX-loaded POT micelles (POT-DOX) possessed the highest drug accumulation (3.03% ID/g at 24 h) and the strongest tumour growth inhibition (TGI 83.48%). Pathological analysis also indicated that POT-DOX could induce more apoptosis or necrosis at the site of tumour without distinct damage to normal tissues. Overall, these smart POT micelles have great potential as promising nano-carriers for MDR reversal and cancer treatment.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Poloxaleno/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Micelas , Estrutura Molecular , Estresse Oxidativo , Tamanho da Partícula , Poloxaleno/síntese química , Poloxaleno/química , Propriedades de Superfície , Células Tumorais Cultivadas
19.
Int J Mol Sci ; 21(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936346

RESUMO

The aim of the manuscript is to discuss the influence of plant polyphenols in overcoming multidrug resistance in four types of solid cancers (breast, colorectal, lung and prostate cancer). Effective treatment requires the use of multiple toxic chemotherapeutic drugs with different properties and targets. However, a major cause of cancer treatment failure and metastasis is the development of multidrug resistance. Potential mechanisms of multidrug resistance include increase of drug efflux, drug inactivation, detoxification mechanisms, modification of drug target, inhibition of cell death, involvement of cancer stem cells, dysregulation of miRNAs activity, epigenetic variations, imbalance of DNA damage/repair processes, tumor heterogeneity, tumor microenvironment, epithelial to mesenchymal transition and modulation of reactive oxygen species. Taking into consideration that synthetic multidrug resistance agents have failed to demonstrate significant survival benefits in patients with different types of cancer, recent research have focused on beneficial effects of natural compounds. Several phenolic compounds (flavones, phenolcarboxylic acids, ellagitannins, stilbens, lignans, curcumin, etc.) act as chemopreventive agents due to their antioxidant capacity, inhibition of proliferation, survival, angiogenesis, and metastasis, modulation of immune and inflammatory responses or inactivation of pro-carcinogens. Moreover, preclinical and clinical studies revealed that these compounds prevent multidrug resistance in cancer by modulating different pathways. Additional research is needed regarding the role of phenolic compounds in the prevention of multidrug resistance in different types of cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Flavonoides/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Flavonoides/efeitos adversos , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
20.
Cancer Res ; 80(4): 663-674, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31888888

RESUMO

Clinical evidence shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and, eventually, most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366-iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance. SIGNIFICANCE: Modulation of the MDR phenotype has the potential to increase the efficacy of anticancer therapies. These findings show that the MDR transporter is a "double-edged sword" that can be turned against resistant cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Neoplasias/tratamento farmacológico , Oxiquinolina/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Quelantes de Ferro/uso terapêutico , Neoplasias/patologia , Oxiquinolina/análogos & derivados , Oxiquinolina/uso terapêutico
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