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1.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445533

RESUMO

Aeromonas spp. cause many diseases in aquaculture habitats. Hermetia illucens (Hi) larvae were used as feed-in aquacultures and in eradicating pathogenic fish bacteria. In the present study, we applied consecutive extractions of the same biomass of BSFL fat using the acidic water-methanol solution. The major constituents of the sequential extracts (SEs) were free fatty acids (FFAs), and fatty acids derivatives as identified by gas chromatography spectrometry (GC-MS). Our improved procedure enabled gradual enrichment in the unsaturated fatty acids (USFAs) content in our SEs. The present study aimed to compare the composition and antimicrobial properties of SEs. Among actual fish pathogens, A. hydrophila and A. salmonicida demonstrated multiple drug resistance (MDR) against different recommended standard antibiotics: A. salmonicida was resistant to six, while A. hydrophila was resistant to four antibiotics from ten used in the present study. For the first time, we demonstrated the high dose-dependent antibacterial activity of each SE against Aeromonas spp., especially MDR A. salmonicida. The bacteriostatic and bactericidal (MIC/MBC) activity of SEs was significantly enhanced through the sequential extractions. The third sequential extract (AWME3) possessed the highest activity against Aeromonas spp.: inhibition zone diameters were in the range (21.47 ± 0.14-20.83 ± 0.22 mm) at a concentration of 40 mg/mL, MIC values ranged between 0.09 and 0.38 mg/mL for A. hydrophila and A. salmonicida, respectively. AWME3 MBC values recorded 0.19 and 0.38 mg/mL, while MIC50 values were 0.065 ± 0.004 and 0.22 ± 0.005 mg/mL against A. hydrophila and A. salmonicida, respectively. Thus, the larvae fat from Hermitia illucens may serve as an excellent reservoir of bioactive molecules with good capacity to eradicate the multidrug-resistant bacteria, having promising potential for practical application in the aquaculture field.


Assuntos
Aeromonas/patogenicidade , Antibacterianos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Ácidos Graxos/farmacologia , Doenças dos Peixes/prevenção & controle , Larva/química , Extratos de Tecidos/farmacologia , Animais , Dípteros , Doenças dos Peixes/microbiologia , Peixes
2.
Malawi Med J ; 33(1): 59-64, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-34422235

RESUMO

Background: Non-susceptibility of bacteria to antiseptic agents used for preoperative skin preparations threaten the effectiveness of prevention of surgical site infections. Data concerning susceptibility of multidrug resistant bacteria strains to antiseptic agents was limited at our setting. This study presents the susceptibility of extended spectrum ß-lactamases producing Klebsiella pneumoniae and Escherichia coli (with and without biofilm formation) to antiseptic agents used for preoperative skin preparations at zonal referral hospital in Mwanza, Tanzania. Methods: This cross-sectional descriptive study was conducted through July 2020. Presumptive extended spectrum beta-lactamase producing Klebsiella pneumoniae and Escherichia coli were recovered for this study. Disc combination method was used to confirm production of ESBL while tube method was used to detect biofilms formation. Then, isolates were tested for susceptibility towards 10% povidone iodine, 70% methylated spirit, 50% hydrogen peroxide (6% of industrial H2O2 diluted in equal volume with sterile distilled water) and 2% chlorhexidine. STATA software version 13.0 was used for data analysis. Results: A total of 31 presumptive ESBL producers were recovered and phenotypically confirmed, whereas 54.8% (n=17) were K. pneumoniae and 45.2% (n=14) were E. coli. Five (35.7%) E. coli and seven (41.2%) K. pneumoniae had positive biofilms test results. Four (12.9%) bacteria were non-susceptible to antiseptic agents used for preoperative skin preparations. However, none exhibited resistance towards 10% PVP-I. Conclusion: In this study we highlight the existence of multidrug resistant Gram-negative bacteria with resistance to antiseptic agents used for preoperative skin preparation at a zonal referral hospital in Mwanza, Tanzania.


Assuntos
Anti-Infecciosos Locais/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos Locais/uso terapêutico , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Biofilmes , Estudos Transversais , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/microbiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/isolamento & purificação , Humanos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/isolamento & purificação , Testes de Sensibilidade Microbiana , Tanzânia
3.
ACS Appl Mater Interfaces ; 13(33): 38959-38968, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34379404

RESUMO

Chemotherapy continues to be the most commonly applied strategy for cancer. Despite the impressive clinical success obtained with several drugs, increasing numbers of (multi)drug-resistant tumors are reported. To overcome this shortcoming, novel drug candidates and delivery systems are urgently needed. Herein, a therapeutic copper polypyridine complex encapsulated in natural nanocarrier apoferritin is reported. The generated nanoparticles showed higher cytotoxicity toward various (drug-resistant) cancer cell lines than noncancerous cells. The study of the mechanism revealed that the compound triggers cell autophagy-dependent apoptosis. Promisingly, upon injection of the nanodrug conjugate into the bloodstream of a mouse model bearing a multidrug-resistant colon tumor, a strong tumor growth inhibition effect was observed. To date, this is the first study describing the encapsulation of a copper complex in apoferritin that acts by autophagy-dependent apoptosis.


Assuntos
Antineoplásicos/química , Apoferritinas/química , Neoplasias do Colo/tratamento farmacológico , Complexos de Coordenação/química , Cobre/química , Nanocápsulas/química , Animais , Antineoplásicos/farmacologia , Apoferritinas/metabolismo , Morte Celular Autofágica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Complexos de Coordenação/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais
4.
J Cancer Res Clin Oncol ; 147(9): 2591-2607, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34213662

RESUMO

PURPOSE: Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044. METHODS: DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions. RESULTS: A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells. CONCLUSION: The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Leucemia/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Apoptose , Proliferação de Células , Cisplatino/farmacologia , Humanos , Leucemia/metabolismo , Leucemia/patologia , Ligantes , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Células Tumorais Cultivadas
5.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201296

RESUMO

Osteosarcoma (OSA) is the most common malignant bone neoplasia in humans and dogs. In dogs, treatment consists of surgery in combination with chemotherapy (mostly carboplatin and/or doxorubicin (Dox)). Chemotherapy is often rendered ineffective by multidrug resistance. Previous studies have revealed that Dox conjugated with 4 nm glutathione-stabilized gold nanoparticles (Au-GSH-Dox) enhanced the anti-tumor activity and cytotoxicity of Dox in Dox-resistant feline fibrosarcoma cell lines exhibiting high P-glycoprotein (P-gp) activity. The present study investigated the influence of Au-GSH-Dox on the canine OSA cell line D17 and its relationship with P-gp activity. A human Dox-sensitive OSA cell line, U2OS, served as the negative control. Au-GSH-Dox, compared to free Dox, presented a greater cytotoxic effect on D17 (IC50 values for Au-GSH-Dox and Dox were 7.9 µg/mL and 15.2 µg/mL, respectively) but not on the U2OS cell line. All concentrations of Au-GSH (ranging from 10 to 1000 µg/mL) were non-toxic in both cell lines. Inhibition of the D17 cell line with 100 µM verapamil resulted in an increase in free Dox but not in intracellular Au-GSH-Dox. The results indicate that Au-GSH-Dox may act as an effective drug in canine OSA by bypassing P-gp.


Assuntos
Doxorrubicina/química , Doxorrubicina/farmacologia , Glutationa/química , Ouro/química , Nanopartículas Metálicas/química , Osteossarcoma/tratamento farmacológico , Adolescente , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Criança , Cães , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos
6.
Biomed Pharmacother ; 139: 111632, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243600

RESUMO

P-glycoprotein, encoded by ATP-binding cassette transporters B1 gene (ABCB1), renders multidrug resistance (MDR) during cancer chemotherapy. Several synthetic small molecule inhibitors affect P-glycoprotein (P-gp) transport function in MDR tumor cells. However, inhibition of P-gp transport function adversely accumulates chemotherapeutic drugs in non-target normal tissues. Moreover, most small-molecule P-gp inhibitors failed in the clinical trials due to the low therapeutic window at the maximum tolerated dose. Therefore, downregulation of ABCB1-gene expression (P-gp) in tumor tissues seems to be a novel approach rather than inhibiting its transport function for the reversal of multidrug resistance (MDR). Several plant-derived phytochemicals modulate various signal transduction pathways and inhibit translocation of transcription factors, thereby reverses P-gp mediated MDR in tumor cells. Therefore, phytochemicals may be considered an alternative to synthetic small molecule P-gp inhibitors for the reversal of MDR in cancer cells. This review discussed the role of natural phytochemicals that modulate ABCB1 expression through various signal transduction pathways in MDR cancer cells. Therefore, modulating the cell signaling pathways by phytochemicals might play crucial roles in modulating ABCB1 gene expression and the reversal of MDR.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Humanos
7.
Chem Commun (Camb) ; 57(55): 6776-6779, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34137399

RESUMO

We report the straightforward synthesis of ATP-responsive nanoscale metal azolate framework-7 (MAF-7) for gene/drug codelivery. The MAF-7 functions as (i) the armour to preserve DNAzymes, (ii) an ATP scavenger to lower the intracellular ATP level, and (iii) a built-in Zn2+ arsenal to initiate the biocatalysis of DNAzymes, ultimately inhibiting P-gp expression to enhance chemotherapy.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Azóis/química , Portadores de Fármacos/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Estruturas Metalorgânicas/química , Nanoestruturas/química , Trifosfato de Adenosina/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo
8.
Nutrients ; 13(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069490

RESUMO

The multidrug resistance phenotype is a global phenomenon and causes chemotherapy failure in various cancers, such as in uterine sarcomas that have a high mortality rate. To overcome this phenotype, there is growing research interest in developing new treatment strategies. In this study, we highlight the potential of two essential oils from the Apiaceae family, Pituranthos chloranthus (PC) and Teucrium ramosissimum Desf. (TR), to act as chemopreventive and chemosensitizing agents against two uterine sarcoma cell lines, MES-SA and P-gp-overexpressing MES-SA/Dx5 cells. We found that PC and TR were able to inhibit the cell viability of sensitive MES-SA and resistant MES-SA/Dx5 cells by a slight modulation of the cell cycle and its regulators, but also through a significant induction of apoptosis. The molecular mechanism involved both caspase pathways associated with an overproduction of reactive oxygen species (ROS) and mitochondrial membrane depolarization. Very interestingly, the combination of doxorubicin with PC or TR induced a synergism to increase cell death in resistant MES-SA/Dx5 cells and, subsequently, had the benefit of decreasing the resistance index to doxorubicin. These synergistic effects were reinforced by a decrease in P-gp expression and its P-gp adenosine triphosphatase (ATPase) activity, which subsequently led to intracellular doxorubicin accumulation in resistant sarcoma cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Doxorrubicina/farmacologia , Magnoliopsida/química , Óleos Voláteis/farmacologia , Sarcoma/tratamento farmacológico , Teucrium/química , Neoplasias Uterinas/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Extratos Vegetais/farmacologia , Óleos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Tecidos Moles
9.
J Med Microbiol ; 70(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34170219

RESUMO

Introduction. Members of the genus Citrobacter are facultative anaerobic Gram-negative bacilli belonging to the Enterobacterales [Janda J Clin Microbiol 1994; 32(8):1850-1854; Arens Clin Microbiol Infect 1997;3(1):53-57]. Formerly, Citrobacter species were occasionally reported as nosocomial pathogens with low virulence [Pepperell Antimicrob Agents Chemother 2002;46(11):3555-60]. Now, they are consistently reported to cause nosocomial infections of the urinary tract, respiratory tract, bone, peritoneum, endocardium, meninges, intestines, bloodstream and central nervous system. Among Citrobacter species, the most common isolates are C. koseri and C. freundii, while C. amalonaticus has seldom been isolated [Janda J Clin Microbiol 1994; 32(8):1850-1854; Marak Infect Dis (Lond) 2017;49(7):532-9]. Further, Citrobacter spp. are usually susceptible to carbapenems, aminoglycosides, tetracyclines and colistin [Marak Infect Dis (Lond) 2017;49(7):532-9].Hypothesis/Gap Statement. As C. amalonaticus is rare, only one clinical isolate, coharbouring carbapenem resistance gene bla IMP-4 and quinolone resistance gene qnrs1, has been reported.Aim. To characterize a carbapenem-resistant C. amalonaticus strain from PR China coharbouring bla IMP-4 and qnrs1.Methodology. Three hundred and forty nonrepetitive carbapenem-resistant Enterobacterales (CRE) strains were collected during 2011-2018. A carbapenem-resistant C. amalonaticus strain was detected and confirmed using a VITEK mass spectrometry-based microbial identification system and 16S rRNA sequencing. Minimum inhibitory concentrations (MICs) for clinical antimicrobials were obtained by the broth microdilution method. Whole-genome sequencing (WGS) was performed for antibiotic resistance gene analysis, and a phylogenetic tree of C. amalonaticus strains was constructed using the Bacterial Pan Genome Analysis (BPGA) tool. The transferability of the resistance plasmid was verified by conjugal transfer.Results. A rare carbapenem-resistant C. amalonaticus strain (CA71) was recovered from a patient with cerebral obstruction and the sequences of 16S rRNA gene shared more than 99 % similarity with C. amalonaticus CITRO86, FDAARGOS 165. CA71 is resistant to ß-lactam, quinolone and aminoglycoside antibiotics, and even imipenem and meropenem (MICs of 2 and 4 mg l-1 respectively), and is only sensitive to polymyxin B and tigecycline. Six antibiotic resistance genes were detected via WGS, including the ß-lactam genes bla IMP-4, bla CTX-M-18 and bla Sed1, the quinolone gene qnrs1, and the aminoglycoside genes AAC(3)-VIIIa, AadA24. Interestingly, bla IMP-4 and qnrs1 coexist on an IncN1-type plasmid (pCA71-IMP) and successfully transferred to Escherichia coli J53 via conjugal transfer. Phylogenetic analysis showed that CA71 is most similar to C. amalonaticus strain CJ25 and belongs to the same evolutionary cluster along with seven other strains.Conclusion. To the best of our knowledge, this is the first report of a carbapenem-resistant C. amalonaticus isolate coharbouring bla IMP-4 and qnrs1.


Assuntos
Proteínas de Bactérias/genética , Enterobacteriáceas Resistentes a Carbapenêmicos/genética , Citrobacter/genética , Resistência a Múltiplos Medicamentos/genética , Antibacterianos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/classificação , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Citrobacter/classificação , Citrobacter/efeitos dos fármacos , Citrobacter/isolamento & purificação , Conjugação Genética , DNA Bacteriano/genética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Infecções por Enterobacteriaceae/microbiologia , Genoma Bacteriano/genética , Humanos , Testes de Sensibilidade Microbiana , Filogenia , Plasmídeos/genética , RNA Ribossômico 16S/genética , beta-Lactamases/genética
10.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069596

RESUMO

Acinetobacter baumannii is a serious nosocomial pathogen with multiple drug resistance (MDR), the control of which has become challenging due to the currently used antibiotics. Our main objective in this study is to determine the antibacterial and antibiofilm activities of the antimicrobial peptide, Octominin, against MDR A. baumannii and derive its possible modes of actions. Octominin showed significant bactericidal effects at a low minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of 5 and 10 µg/mL, respectively. Time-kill kinetic analysis and bacterial viability tests revealed that Octominin showed a concentration-dependent antibacterial activity. Field-emission scanning electron microscopy (FE-SEM) analysis revealed that Octominin treatment altered the morphology and membrane structure of A. baumannii. Propidium iodide (PI) and reactive oxygen species (ROS) generation assays showed that Octominin increased the membrane permeability and ROS generation in A. baumannii, thereby causing bacterial cell death. Further, a lipopolysaccharides (LPS) binding assay showed an Octominin concentration-dependent LPS neutralization ability. Biofilm formation inhibition and eradication assays further revealed that Octominin inhibited biofilm formation and showed a high biofilm eradication activity against A. baumannii. Furthermore, up to a concentration of 100 µg/mL, Octominin caused no hemolysis and cell viability changes in mammalian cells. An in vivo study in zebrafish showed that the Octominin-treated group had a significantly higher relative percentage survival (54.1%) than the untreated group (16.6%). Additionally, a reduced bacterial load and fewer alterations in histological analysis confirmed the successful control of A. baumannii by Octominin in vivo. Collectively, these data suggest that Octominin exhibits significant antibacterial and antibiofilm activities against the multidrug-resistant A. baumannii, and this AMP can be developed further as a potent AMP for the control of antibiotic resistance.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Peptídeos Catiônicos Antimicrobianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/metabolismo , Animais , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Biofilmes/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Cinética , Viabilidade Microbiana/efeitos dos fármacos , Modelos Animais , Fragmentos de Peptídeos/metabolismo , Peixe-Zebra
11.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069640

RESUMO

Bacteria have evolved an array of mechanisms enabling them to resist the inhibitory effect of antibiotics, a significant proportion of which target the ribosome. Indeed, resistance mechanisms have been identified for nearly every antibiotic that is currently used in clinical practice. With the ever-increasing list of multi-drug-resistant pathogens and very few novel antibiotics in the pharmaceutical pipeline, treatable infections are likely to become life-threatening once again. Most of the prevalent resistance mechanisms are well understood and their clinical significance is recognized. In contrast, ribosome protection protein-mediated resistance has flown under the radar for a long time and has been considered a minor factor in the clinical setting. Not until the recent discovery of the ATP-binding cassette family F protein-mediated resistance in an extensive list of human pathogens has the significance of ribosome protection proteins been truly appreciated. Understanding the underlying resistance mechanism has the potential to guide the development of novel therapeutic approaches to evade or overcome the resistance. In this review, we discuss the latest developments regarding ribosome protection proteins focusing on the current antimicrobial arsenal and pharmaceutical pipeline as well as potential implications for the future of fighting bacterial infections in the time of "superbugs."


Assuntos
Resistência Microbiana a Medicamentos/fisiologia , Proteínas Ribossômicas/metabolismo , Ribossomos/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Modelos Moleculares , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Ribossômicas/efeitos dos fármacos , Ribossomos/efeitos dos fármacos
12.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065900

RESUMO

Within the last decades cancer treatment improved by the availability of more specifically acting drugs that address molecular target structures in cancer cells. However, those target-sensitive drugs suffer from ongoing resistances resulting from mutations and moreover they are affected by the cancer phenomenon of multidrug resistance. A multidrug resistant cancer can hardly be treated with the common drugs, so that there have been long efforts to develop drugs to combat that resistance. Transmembrane efflux pumps are the main cause of the multidrug resistance in cancer. Early inhibitors disappointed in cancer treatment without a proof of expression of a respective efflux pump. Recent studies in efflux pump expressing cancer show convincing effects of those inhibitors. Based on the molecular symmetry of the efflux pump multidrug resistant protein (MRP) 4 we synthesized symmetric inhibitors with varied substitution patterns. They were evaluated in a MRP4-overexpressing cancer cell line model to prove structure-dependent effects on the inhibition of the efflux pump activity in an uptake assay of a fluorescent MRP4 substrate. The most active compound was tested to resentisize the MRP4-overexpressing cell line towards a clinically relevant anticancer drug as proof-of-principle to encourage for further preclinical studies.


Assuntos
Antineoplásicos/farmacologia , Di-Hidropiridinas/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Neoplasias Pancreáticas/genética , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/química , Neoplasias Pancreáticas/tratamento farmacológico , Relação Estrutura-Atividade , Regulação para Cima/efeitos dos fármacos
13.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066940

RESUMO

Acute myeloid leukemia (AML), the most common type of leukemia in older adults, is a heterogeneous disease that originates from the clonal expansion of undifferentiated hematopoietic progenitor cells. These cells present a remarkable variety of genes and proteins with altered expression and function. Despite significant advances in understanding the molecular panorama of AML and the development of therapies that target mutations, survival has not improved significantly, and the therapy standard is still based on highly toxic chemotherapy, which includes cytarabine (Ara-C) and allogeneic hematopoietic cell transplantation. Approximately 60% of AML patients respond favorably to these treatments and go into complete remission; however, most eventually relapse, develop refractory disease or chemoresistance, and do not survive for more than five years. Therefore, drug resistance that initially occurs in leukemic cells (primary resistance) or that develops during or after treatment (acquired resistance) has become the main obstacle to AML treatment. In this work, the main molecules responsible for generating chemoresistance to Ara-C in AML are discussed, as well as some of the newer strategies to overcome it, such as the inclusion of molecules that can induce synergistic cytotoxicity with Ara-C (MNKI-8e, emodin, metformin and niclosamide), subtoxic concentrations of chemotherapy (PD0332991), and potently antineoplastic treatments that do not damage nonmalignant cells (heteronemin or hydroxyurea + azidothymidine).


Assuntos
Citarabina/uso terapêutico , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Morte Celular/efeitos dos fármacos , Citarabina/farmacologia , Humanos , Modelos Biológicos
14.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065600

RESUMO

Curcumin is a natural bioactive component derived from the turmeric plant Curcuma longa, which exhibits a range of beneficial activities on human cells. Previously, an inhibitory effect of curcumin on platelets was demonstrated. However, it is unknown whether this inhibitory effect is due to platelet apoptosis or procoagulant platelet formation. In this study, curcumin did not activate caspase 3-dependent apoptosis of human platelets, but rather induced the formation of procoagulant platelets. Interestingly, curcumin at low concentration (5 µM) potentiated, and at high concentration (50 µM) inhibited ABT-737-induced platelet apoptosis, which was accompanied by inhibition of ABT-737-mediated thrombin generation. Platelet viability was not affected by curcumin at low concentration and was reduced by 17% at high concentration. Furthermore, curcumin-induced autophagy in human platelets via increased translocation of LC3I to LC3II, which was associated with activation of adenosine monophosphate (AMP) kinase and inhibition of protein kinase B activity. Because curcumin inhibits P-glycoprotein (P-gp) in cancer cells and contributes to overcoming multidrug resistance, we showed that curcumin similarly inhibited platelet P-gp activity. Our results revealed that the platelet inhibitory effect of curcumin is mediated by complex processes, including procoagulant platelet formation. Thus, curcumin may protect against or enhance caspase-dependent apoptosis in platelets under certain conditions.


Assuntos
Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Plaquetas/efeitos dos fármacos , Curcumina/farmacologia , Nitrofenóis/farmacologia , Sulfonamidas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Monofosfato de Adenosina/metabolismo , Plaquetas/metabolismo , Curcuma/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Piperazinas/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo
15.
Int J Mol Sci ; 22(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071136

RESUMO

In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. We also observed an increase in the level of polyubiquitinated proteins (via K48-linkage) and a decrease in the gene expression of some deubiquitinases after treatment with bortezomib. Resistant cells expressed higher levels of genes encoding 26S proteasome components and the chaperone HSP90, which is involved in 26S proteasome assembly. After 4 h of preincubation, bortezomib induced a more pronounced depression of proteasome activity in S cells than in R or T cells. However, none of these changes alone or in combination sufficiently suppressed the sensitivity of R or T cells to bortezomib, which remained at a level similar to that of S cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia Linfoide/patologia , Proteínas de Neoplasias/metabolismo , Inibidores de Proteases/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Ciclo Celular/efeitos dos fármacos , Divisão Celular , Linhagem Celular Tumoral , Enzimas Desubiquitinantes , Fluoresceínas/metabolismo , Genes cdc/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucemia Linfoide/genética , Leucemia Linfoide/metabolismo , Camundongos , Proteínas de Neoplasias/genética , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Proteínas Recombinantes/metabolismo , Transcrição Genética/efeitos dos fármacos , Proteínas Ubiquitinadas/metabolismo , Vincristina/farmacologia
16.
Molecules ; 26(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071141

RESUMO

The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX-2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff's bases as: antibacterial, COX-2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Quinazolinonas/farmacologia , Quinoxalinas/farmacologia , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Células CACO-2 , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Desenho de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/antagonistas & inibidores , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
17.
Eur J Med Chem ; 220: 113487, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33933752

RESUMO

Clinically, chemotherapy is the mainstay in the treatment of multiple cancers. However, highly adaptable and activated survival signaling pathways of cancer cells readily emerge after long exposure to chemotherapeutics drugs, resulting in multi-drug resistance (MDR) and treatment failure. Recently, growing evidences indicate that the molecular action mechanisms of cancer MDR are closely associated with abnormalities in saccharides. In this review, saccharides affecting cancer MDR development are elaborated and analyzed in terms of aberrant aerobic glycolysis and its related enzymes, abnormal glycan structures and their associated enzymes, and glycoproteins. The reversal strategies including depletion of ATP, circumventing the original MDR pathway, activation by or inhibition of sugar-related enzymes, combination therapy with traditional cytotoxic agents, and direct modification on the sugar moiety, are ultimately proposed. It follows that abnormal saccharides have a significant effect on cancer MDR development, providing a new perspective for overcoming MDR and improving the outcome of chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Polissacarídeos/farmacologia , Antineoplásicos/química , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Polissacarídeos/química
18.
Eur J Med Chem ; 221: 113520, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34029775

RESUMO

Systematic toxicity and drug resistance significantly limited FDA-approved platinum drugs for further clinical applications. In order to reverse the resistance (MDR) and enhance their anticancer efficiency, four Pt(IV) complexes (12-15) conjugating with P-glycoprotein (P-gp) inhibitors were designed and synthesized. Among them, complex 14 (IC50 = 3.37 µM) efficiently reversed cisplatin resistance in SGC-7901/CDDP cell line and increased selectivity index (6.9) against normal HL-7702 cell line. Detailed mechanisms in SGC-7901/CDDP cells assays revealed that complex 14 efficiently induced apoptosis via down-regulating expression of P-gp for enhanced intracellular uptake of platinum, arrested cells at G2/M phase, induced DNA damage and initiated mitochondrial apoptosis pathway. Further in vivo studies demonstrated that the enhanced accumulation of complex 14 contributed to tumor inhibition of 75.6% in SGC-7901/CDDP xenografts, which was much higher than cisplatin (25.9%) and oxaliplatin (43%). Moreover, the low systematic toxicity made 14 a potential novel P-gp-mediated MDR modulator.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos Organoplatínicos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Int J Biol Macromol ; 183: 1270-1282, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34004196

RESUMO

Multidrug resistance (MDR) remains the primary issue leading to the failure of chemotherapy. In this study, a d-α-tocopherol polyethylene 1000 glycol succinate (TPGS) and chondroitin sulfate (CS) dual-modified lipid-albumin nanosystem was constructed for targeted delivery of paclitaxel (PTX) in treating MDR cancer. The obtained nanosystem (TLA/PTX@CS) had an average size of around 176 nm and a negative zeta potential of around -18 mV. TPGS was confirmed to improve the intracellular accumulation of PTX and facilitate the mitochondrial-targeting of lipid-albumin nanosystem. Functionalized with the outer CS shell, TLA/PTX@CS entered MDR breast cancer (MCF-7/MDR) cells via CD44 receptor-mediated endocytosis. CS shell was degraded by concentrated hyaluronidase in the lysosomes, thereby releasing PTX into cytoplasm and inhibiting cell proliferation. In vivo studies revealed that TLA/PTX@CS possessed prolonged blood circulation, resulting in elevated tumor accumulation, excellent antitumor efficacy with a tumor inhibition ratio of 75.3%, and significant survival benefit in MCF-7/MDR tumor-bearing mice. Hence, this TPGS and CS dual-modified lipid-albumin nanosystem provides a promising strategy for targeted delivery of chemotherapeutic drug and reversal of MDR in cancer treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sulfatos de Condroitina/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Paclitaxel/administração & dosagem , Vitamina E/química , Albuminas/química , Animais , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Lipídeos/química , Células MCF-7 , Camundongos , Nanopartículas , Paclitaxel/química , Paclitaxel/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Theranostics ; 11(13): 6334-6354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995661

RESUMO

Clinically, the primary cause of chemotherapy failure belongs to the occurrence of cancer multidrug resistance (MDR), which directly leads to the recurrence and metastasis of cancer along with high mortality. More and more attention has been paid to multifunctional nanoplatform-based dual-therapeutic combination to eliminate resistant cancers. In addition to helping both cargoes improve hydrophobicity and pharmacokinetic properties, increase bioavailability, release on demand and enhance therapeutic efficacy with low toxic effects, these smart co-delivery nanocarriers can even overcome drug resistance. Here, this review will not only present different types of co-delivery nanocarriers, but also summarize targeted and stimuli-responsive combination nanomedicines. Furthermore, we will focus on the recent progress in the co-delivery of dual-drug using such intelligent nanocarriers for surmounting cancer MDR. Whereas it remains to be seriously considered that there are some knotty issues in the fight against MDR of cancers via using co-delivery nanoplatforms, including limited intratumoral retention, the possible changes of combinatorial ratio under complex biological environments, drug release sequence from the nanocarriers, and subsequent free-drug resistance after detachment from the nanocarriers. It is hoped that, with the advantage of continuously developing nanomaterials, two personalized therapeutic agents in combination can be better exploited to achieve the goal of cooperatively combating cancer MDR, thus advancing the time to clinical transformation.


Assuntos
Portadores de Fármacos/administração & dosagem , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Nanomedicina Teranóstica/métodos , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Gases/administração & dosagem , Humanos , Concentração de Íons de Hidrogênio , Proteínas de Neoplasias/antagonistas & inibidores , Oxirredução , Peptídeos/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Tensoativos/administração & dosagem , Tensoativos/uso terapêutico
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