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1.
J Mater Chem B ; 12(10): 2587-2593, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38363549

RESUMO

Due to increasing bacterial resistance to disinfectants, there is an urgent need for new therapeutic agents and strategies to effectively inhibit bacteria. Accordingly, we have designed and synthesized a novel crown ether known as C7Te, and its oxidized form C7TeO. These compounds have demonstrated antibacterial effectiveness against Gram-negative E. coli (BL21). Notably, C7Te has the capability to enhance the inhibition of E. coli and the prevention of biofilm formation by H2O2 through a redox response. It can also effectively disrupt preformed E. coli biofilms by penetrating biofilm barriers effectively. Additionally, computer modeling of the bacterial cell membrane using nanodiscs composed of phospholipids and encircled amphipathic proteins with helical belts has revealed that C7Te can insert into and interact with phospholipids and proteins. This interaction results in the disruption of the bacterial cell membrane leading to bacterial cell death. The utilization of redox-responsive crown ethers to augment the antibacterial capabilities of H2O2-based disinfectants represents a novel approach to supramolecular bacterial inhibition.


Assuntos
Éteres de Coroa , Desinfetantes , Escherichia coli , Éteres de Coroa/farmacologia , Peróxido de Hidrogênio/farmacologia , Antibacterianos/farmacologia , Bactérias , Oxirredução , Desinfetantes/farmacologia
2.
Biomater Adv ; 159: 213814, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38417206

RESUMO

Controllable preparation of materials with new structure has always been the top priority of polymer materials science research. Here, the supramolecular binding strategy is adopted to develop covalent organic frameworks (COFs) with novel structures and functions. Based on this, a two-dimensional crown-ether ring threaded covalent organic framework (COF), denoted as Crown-COPF with intrinsic photothermal (PTT) and photodynamic (PDT) therapeutic capacity, was facilely developed using crown-ether threaded rotaxane and porphyrin as building blocks. Crown-COPF with discrete mechanically interlocked blocks in the open pore could be used as a molecular machine, in which crown-ether served as the wheel sliding along the axle under the laser stimulation. As a result, Crown-COPF combining with the bactericidal power of crown ether displayed a significant photothermal and photodynamic antibacterial activity towards both the Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus), far exceeding the traditional Crown-free COF. Noteworthily, the bactericidal performance could be further enhanced via impregnation of Zn2+ ions (Crown-COPF-Zn) flexible coordinated with the multiple coordination sites (crown-ether, bipyridine, and porphyrin), which not only endow the positive charge with the skeleton, enhancing its ability to bind to the bacterial membrane, but also introduce the bactericidal ability of zinc ions. Notably, in vivo experiments on mice with back infections indicates Crown-COPF-Zn with self-adaptive multinuclear zinc center, could effectively promote the repairing of wounds. This study paves a new avenue for the effectively preparation of porous polymers with brand new structure, which provides opportunities for COF and mechanically interlocked polymers (MIPs) research and applications.


Assuntos
Éteres de Coroa , Ciclodextrinas , Estruturas Metalorgânicas , Poloxâmero , Porfirinas , Rotaxanos , Animais , Camundongos , Estruturas Metalorgânicas/farmacologia , Rotaxanos/farmacologia , Éteres de Coroa/farmacologia , Polímeros/farmacologia , Antibacterianos/farmacologia , Escherichia coli , Íons , Zinco/farmacologia , Cicatrização
3.
Histochem Cell Biol ; 158(3): 261-277, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35648291

RESUMO

Overexpression of ABC transporters, such as ABCB1 and ABCG2, plays an important role in mediating multidrug resistance (MDR) in cancer. This feature is also attributed to a subpopulation of cancer stem cells (CSCs), having enhanced tumourigenic potential. ABCG2 is specifically associated with the CSC phenotype, making it a valuable target for eliminating aggressive and resistant cells. Several natural and synthetic ionophores have been discovered as CSC-selective drugs that may also have MDR-reversing ability, whereas their interaction with ABCG2 has not yet been explored. We previously reported the biological activities, including ABCB1 inhibition, of a group of adamantane-substituted diaza-18-crown-6 (DAC) compounds that possess ionophore capabilities. In this study, we investigated the mechanism of ABCG2-inhibitory activity of DAC compounds and the natural ionophores salinomycin, monensin and nigericin. We used a series of functional assays, including real-time microscopic analysis of ABCG2-mediated fluorescent substrate transport in cells, and docking studies to provide comparative aspects for the transporter-compound interactions and their role in restoring chemosensitivity. We found that natural ionophores did not inhibit ABCG2, suggesting that their CSC selectivity is likely mediated by other mechanisms. In contrast, DACs with amide linkage in the side arms demonstrated noteworthy ABCG2-inhibitory activity, with DAC-3Amide proving to be the most potent. This compound induced conformational changes of the transporter and likely binds to both Cavity 1 and the NBD-TMD interface. DAC-3Amide reversed ABCG2-mediated MDR in model cells, without affecting ABCG2 expression or localization. These results pave the way for the development of new crown ether compounds with improved ABCG2-inhibitory properties.


Assuntos
Antineoplásicos , Éteres de Coroa , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Éteres de Coroa/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ionóforos/farmacologia
4.
Thorac Cancer ; 13(2): 257-264, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34855286

RESUMO

BACKGROUND: This study aimed to evaluate the inhibitory effects and potential mechanisms of icotinib combined with antiangiogenic drugs on lung adenocarcinoma in vivo. METHODS: A total of 72 mouse xenograft models established with human lung adenocarcinoma cells (HCC827) were randomly divided into six groups, including control, icotinib (Ic), bevacizumab (Bev), recombinant human endostatin (En), Ic + Bev and Ic + En groups. Mouse weights and tumor volumes were measured regularly. Half of the nude mice in each group were sacrificed after 16 days of drug treatment. The remaining animals were observed for another 16 days without drug supply. Immunohistochemical staining was performed to detect microvessel density in tumor heart, liver, brain specimens from the nude mice and Ki67 expression. Differential expression of vascular endothelial growth factor (VEGFA) in tumor tissue specimens was determined by ELISA and Western blot. RESULTS: The results showed that the combined drugs inhibited tumor growth more substantially compared with single drugs, without increasing the toxic effects. The antiangiogenesis effect of the combination was better than that of single drug treatment. In addition, both types of targeted drugs and combination medication not only significantly reduced microvessel density in the tumor tissue itself, but also had a certain impact on decreasing microvessel density in the liver. The combination decreased VEGFA and Ki-67 amounts significantly more than icotinib or endostatin as a monotherapy. CONCLUSIONS: Icotinib combined with bevacizumab or rh-endostatin has a stronger inhibitory effect on tumor growth than single-target drug in vivo, with no additional side effects.


Assuntos
Bevacizumab/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Éteres de Coroa/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Quimioterapia Combinada , Endostatinas/farmacologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
5.
J Asian Nat Prod Res ; 24(3): 268-277, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34009076

RESUMO

Natural products based novel crown ethers have been prepared by employing biologically active natural structures including tetrahydroisoquinoline, chrysin and biochanin-A as the side arms. The resulting crown scaffolds were evaluated for their anticancer potential against two cancer cell lines i.e. NCI-H460 (non-small lung carcinoma), MCF-7 (breast adenocarcinoma). The comparative study showed that the addition of crown scaffold put marked effects on antiproliferative profile of parent natural precursors and is significant for lung carcinoma in particular. Biochanin-A derived crown ether showed three (03) folds higher antiproliferative activity (IC50 = 6.08 ± 0.07 µM) against lung carcinoma as compared to standard drug cisplatin (IC50 = 19.00 ± 1.24 µM). Cytotoxic trends for NIH-3T3 cell lines were also examined and found reduced as compared to parent natural structures. Hence, these findings could open a new pathway towards developing effective carcinostatic drugs.HIGHLIGHTSFour natural products based novel crown ethers have been developed.Comparative antiproliferative screening of crown ethers and natural precursors.Addition of crown showed marked effects on anticancer profile of natural products.Crown formation is significant for lung carcinoma potential in particular.Biochanin-A derived crown ether found three folds more active than standard drug.


Assuntos
Antineoplásicos , Produtos Biológicos , Éteres de Coroa , Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Éteres de Coroa/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular
6.
Pak J Pharm Sci ; 34(5(Special)): 2003-2008, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34862866

RESUMO

Natural products embedded crown ethers were prepared by utilizing bioactive natural products including chrysin, tetrahydroisoquinoline (THIQ), and biochanin-A. The prepared crown ether scaffolds were evaluated and compared with their natural product precursors for insulin secretory activity on isolated mice islets and for their fluorescent properties. All the crown adducts were found more active as compared to their natural product precursors. Bischrysin 32-crown-10 (6d), THIQ 15-Crown-5 (6a) and chrysin 16-crown-5 (6c) showed mild, moderate and strong insulin secretory activity, respectively when compared with the standard drug tolbutamide (TB). Particularly crown derivative 6c showed strong activity (31.10 ng/islet/h) that is almost two (02) fold higher than that of standard drug TB (16.82 ng/islet/h). To the best of our knowledge crown ethers based antidiabetic study is being reported for the first time in literature through this work. Furthermore, fluorescence study showed the significant increase in absorption and emission maximum (hypsochromic effect) in crown structures when compared with their natural product precursors. Present optimistic results obtained from this study may be a guided template for developing new effective insulin secretory agents.


Assuntos
Produtos Biológicos/farmacologia , Éteres de Coroa/farmacologia , Hipoglicemiantes/farmacologia , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Animais , Produtos Biológicos/isolamento & purificação , Éteres de Coroa/isolamento & purificação , Hipoglicemiantes/isolamento & purificação , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Tolbutamida/farmacologia
7.
Molecules ; 26(21)2021 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-34770832

RESUMO

In the current study, a 2D similarity/docking-based study was used to predict the potential binding modes of icotinib, almonertinib, and olmutinib into EGFR. The similarity search of icotinib, almonertinib, and olmutinib against a database of 154 EGFR ligands revealed the highest similarity scores with erlotinib (0.9333), osimertinib (0.9487), and WZ4003 (0.8421), respectively. In addition, the results of the docking study of the three drugs into EGFR revealed high binding free energies (ΔGb = -6.32 to -8.42 kcal/mol) compared to the co-crystallized ligands (ΔGb = -7.03 to -8.07 kcal/mol). Analysis of the top-scoring poses of the three drugs was done to identify their potential binding modes. The distances between Cys797 in EGFR and the Michael acceptor sites in almonertinib and olmutinib were determined. In conclusion, the results could provide insights into the potential binding characteristics of the three drugs into EGFR which could help in the design of new more potent analogs.


Assuntos
Acrilamidas/farmacologia , Éteres de Coroa/farmacologia , Indóis/farmacologia , Simulação de Acoplamento Molecular , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Acrilamidas/química , Sítios de Ligação/efeitos dos fármacos , Éteres de Coroa/química , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Indóis/química , Ligantes , Estrutura Molecular , Piperazinas/química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Quinazolinas/química
8.
Future Med Chem ; 13(23): 2083-2105, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34633220

RESUMO

Transthyretin (TTR) is associated with several human amyloid diseases. Various kinetic stabilizers have been developed to inhibit the dissociation of TTR tetramer and the formation of amyloid fibrils. Most of them are bisaryl derivatives, natural flavonoids, crown ethers and carborans. In this review article, we focus on TTR tetramer stabilizers, genetic therapeutic approaches and fibril remodelers. The binding modes of typical bisaryl derivatives, natural flavonoids, crown ethers and carborans are discussed. Based on knowledge of the binding of thyroxine to TTR tetramer, many stabilizers have been screened to dock into the thyroxine binding sites, leading to TTR tetramer stabilization. Particularly, those stabilizers with unique binding profiles have shown great potential in developing the therapeutic management of TTR amyloidogenesis.


Assuntos
Amiloide/antagonistas & inibidores , Compostos de Boro/farmacologia , Éteres de Coroa/farmacologia , Desenvolvimento de Medicamentos , Flavonoides/farmacologia , Pré-Albumina/antagonistas & inibidores , Amiloide/metabolismo , Compostos de Boro/química , Éteres de Coroa/química , Flavonoides/química , Humanos , Pré-Albumina/metabolismo
9.
Molecules ; 26(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921479

RESUMO

Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. Ten of the compounds (8, 10-17, and 21) increased intracellular calcium ([Ca2+]i) in human neutrophils, with the most potent being compound 15 (N,N'-bis[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca2+]i flux. Indeed, a number of these compounds (i.e., 8, 10-17, and 21) inhibited [Ca2+]i flux in human neutrophils activated by N-formyl peptide (fMLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca2+]i flux in HL60 cells transfected with N-formyl peptide receptor 1 or 2 (FPR1 or FPR2). In addition, several of the active compounds inhibited neutrophil reactive oxygen species production induced by phorbol 12-myristate 13-acetate (PMA) and neutrophil chemotaxis toward fMLF, as both of these processes are highly dependent on regulated [Ca2+]i flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca2+, Na+, and K+ to obtain a set of molecular electronic properties and to correlate these properties with biological activity. According to density-functional theory (DFT) modeling, Ca2+ ions were more effectively bound by these compounds versus Na+ and K+. The DFT-optimized structures of the ligand-Ca2+ complexes and quantitative structure-activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the N,N'-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca2+ transfer. Thus, our modeling experiments provide a molecular basis to explain at least part of the ionophore mechanism of biological action of aza-crown ethers.


Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Éteres de Coroa/síntese química , Éteres de Coroa/farmacologia , Modelos Moleculares , Cálcio/metabolismo , Quimiotaxia/efeitos dos fármacos , Teoria da Densidade Funcional , Células HL-60 , Humanos , Ligantes , Neutrófilos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Formil Peptídeo/metabolismo , Análise de Regressão , Eletricidade Estática , Termodinâmica
10.
Sci Rep ; 10(1): 20924, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262410

RESUMO

Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.


Assuntos
Autofagia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Autofagossomos/efeitos dos fármacos , Autofagossomos/metabolismo , Autofagossomos/ultraestrutura , Autofagia/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Éteres de Coroa/farmacologia , Éteres de Coroa/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Ftalazinas/farmacologia , Ftalazinas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais/efeitos dos fármacos
11.
Bioorg Chem ; 105: 104421, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33181408

RESUMO

EGFR-TK pathway is of high importance for the treatment of non-small-cell lung cancers (NSCLC), and it will be challenging to develop anti-tumor drugs that could inhibit both EGFR wild-type and mutant tumor cells. Here, a series of icotinib derivatives containing 1,2,3-triazole moiety were designed and synthesized through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. Preliminary CCK-8 assay showed that the prepared icotinib-1,2,3-triazole compounds such as a7 or a12 demonstrated potent in vitro antitumor activity against the NSCLC cells expressing both wild type EGFR and mutational EGFR. Further, the mechanism of action for compounds a7 and a12 induced NSCLC cells death was also detailed, and the results suggested a possible induced NSCLC cells death via inducing mitochondrial apoptosis and arresting cell cycle. Remarkably, the inhibition of EGFR by these icotinib derivatives was also studied. The results showed that compound a12 was a potent inhibitor for EGFR with IC50 value of 1.49 µM. Combining these results, an EGFR inhibitor a12 represents a promising new anti-NSCLC candidate that could induce apoptosis and arrest cell cycle.


Assuntos
Antineoplásicos/farmacologia , Éteres de Coroa/farmacologia , Desenho de Fármacos , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Éteres de Coroa/síntese química , Éteres de Coroa/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
12.
Inorg Chem ; 59(20): 15120-15134, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33000942

RESUMO

The dianionic aza crown ether-dtc N,N'-bis(dithiocarbamate)-1,10-diaza-18-crown-6 (L2-) is a versatile ligand capable of yielding binuclear complexes with group 10 elements, also known as Ni-triade, [µ-(κ2-S,-S'-L)M2(PPh3)4]Cl2 (M = Pd (1), Pt (2)), [µ-(κ2-S,-S'-L)M2(PPh3)4](BPh4)2 (M = Pd (3), Pt (4)), and µ-(κ-S,-S'-L)Ni2(PPh3)2Cl2 (5), and has proven to be an excellent option to the design of metal-based drugs able to provide multiple response to cell resistance. Palladium and platinum complexes, 1 and 2, were tested for cytotoxicity in the human cervix carcinoma cell line HeLa-229, the human ovarian carcinoma cell line A2780, and the cisplatin-resistant mutant A2780cis, finding significant activity toward all three cancer cell lines, with low micromolar IC50 values, comparable to cisplatin. Markedly, against the cisplatin resistant cell line A2780cis, compound 2 exhibits better cytotoxic activity than the clinical drug (IC50 = 2.3 ± 0.2 µM for 2 versus 3.6 ± 0.5 µM for cisplatin). Moreover, an enhancement of the antitumor response is achieved when adding an equimolar amount of alkali metal chloride (NaCl or KCl) to the medium, for instance, testing compound 1 against the cisplatin-resistant A2780cis cells, the IC50 decreases from 9.3 ± 0.4 to 7.4 ± 0.3 and 5.4 ± 0.1 µM, respectively, after addition of the salt solution. For the platinum derivative 2, the IC50 improves by ca. 40% reaching 1.3 ± 0.1 µM when potassium chloride is added. Likewise, the resistant factor found for 2 (RF = 1) confirms that this complex circumvents cisplatin-resistance in A2780cis and is improved with the addition of potassium chloride (RF = 0.65). The presence of the aza crown ether moiety as linker in the systems studied herein is a key point since, in addition to allowing and facilitating interaction with alkali metal ions, this unit is flexible enough to adapt to a variety of environments, as confirmed by the X-ray crystal structures described, where different conformations and ways to fold in are found. In order to gain insight into the electronic and structural facts involved in the interaction of complex 2 with the alkali metal ions, a DFT study was performed, and the description of the molecular electrostatic potentials (MEPs) is also presented.


Assuntos
Antineoplásicos/farmacologia , Compostos Aza/farmacologia , Complexos de Coordenação/farmacologia , Éteres de Coroa/farmacologia , Tiocarbamatos/farmacologia , Antineoplásicos/síntese química , Compostos Aza/síntese química , Complexos de Coordenação/síntese química , Éteres de Coroa/síntese química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Paládio/química , Platina/química , Tiocarbamatos/síntese química
13.
Pharmacol Res ; 159: 105007, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32561477

RESUMO

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were first-line treatments for NSCLC patients with EGFR-mutations. However, about 30 % of responders relapsed within six months because of acquired resistance. In this study, we used Connectivity Map (CMap) to discover a drug capable of reversing acquired EGFR-TKIs resistance. To investigate Lymecycline's ability to reverse acquired EGFR-TKIs resistance, two Icotinib resistant cell lines were constructed. Lymecycline's ability to suppress the proliferation of Icotinib resistant cells in vitro and in vivo was then evaluated. Molecular targets were predicted using network pharmacology and used to identify the molecular mechanism. Growth factor receptor-bound protein 2 (GRB2) is an EGFR-binding adaptor protein essential for EGFR phosphorylation and regulation of AKT/ERK/STAT3 signaling pathways. Lymecycline targeted GRB2 and inhibited the resistance of the cell cycle to EGFR-TKI, arresting disease progression and inducing apoptosis in cancer cells. Combined Lymecycline and Icotinib treatment produced a synergistic effect and induced apoptosis in HCC827R5 and PC9R10 cells. Cell proliferation in resistant cancer cells was significantly inhibited by the combined Lymecycline and Icotinib treatment in mouse models. Lymecycline inhibited the resistance of the cell cycle to EGFR-TKI and induced apoptosis in NSCLC by inhibiting EGFR phosphorylation and GRB2-mediated AKT/ERK/STAT3 signaling pathways. This provided strong support that Lymecycline when combined with EGFR targeting drugs, enhanced the efficacy of treatments for drug-resistant NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Éteres de Coroa/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Adaptadora GRB2/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Limeciclina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína Adaptadora GRB2/genética , Proteína Adaptadora GRB2/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Am J Hypertens ; 33(8): 775-783, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32301965

RESUMO

BACKGROUND: Aberrant activation of epidermal growth factor receptor (EGFR) signaling pathway is associated with the pathogenesis of pulmonary hypertension (PH). However, the effect of icotinib, a first generation of EGFR tyrosine kinase inhibitor (EGFR-TKI), on PH remains to be elucidated. METHODS: PH rat model was established by a single intraperitoneal injection of monocrotaline (MCT, 60 mg/kg). Icotinib (15, 30, and 60 mg/kg/day) was administered by oral gavage from the day of MCT injection. After 4 weeks, hemodynamic parameters and histological changes of the pulmonary arterial vessels were assessed, and the phenotypic switching of pulmonary arterial smooth muscle cells (PASMCs) was determined in vivo. Moreover, the effects of icotinib (10 µM) on epidermal growth factor (EGF, 50 ng/ml)-stimulated proliferation, migration, and phenotypic switching of human PASMCs were explored in vitro. RESULTS: Icotinib significantly reduced the right ventricular systolic pressure and right ventricle hypertrophy index in rats with MCT-induced PH. Moreover, icotinib improved MCT-induced pulmonary vascular remodeling. The expression of contractile marker (smooth muscle 22 alpha (SM22α)) and synthetic markers (osteopontin (OPN) and vimentin) in pulmonary artery was restored by icotinib treatment. In vitro, icotinib suppressed EGF-induced PASMCs proliferation and migration. Meanwhile, icotinib inhibited EGF-induced downregulation of α-smooth muscle actin and SM22α and upregulation of OPN and Collagen I in PASMCs, suggesting that icotinib could inhibit EGF-induced phenotypic switching of PASMCs. Mechanistically, these effects of icotinib were associated with the inhibition of EGFR-Akt/ERK signaling pathway. CONCLUSIONS: Icotinib can attenuate MCT-induced pulmonary vascular remodeling and improve PH. This effect of icotinib might be attributed to preventing PASMC dysfunction by inhibiting EGFR-Akt/ERK signaling pathway.


Assuntos
Éteres de Coroa/farmacologia , Receptores ErbB/antagonistas & inibidores , Hipertensão Pulmonar/fisiopatologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Quinazolinas/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/farmacologia , Hipertensão Pulmonar/induzido quimicamente , Técnicas In Vitro , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas dos Microfilamentos/efeitos dos fármacos , Proteínas dos Microfilamentos/metabolismo , Monocrotalina/toxicidade , Proteínas Musculares/efeitos dos fármacos , Proteínas Musculares/metabolismo , Músculo Liso Vascular/fisiopatologia , Osteopontina/efeitos dos fármacos , Osteopontina/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/fisiopatologia , Ratos , Transdução de Sinais , Remodelação Vascular/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos , Vimentina/efeitos dos fármacos , Vimentina/metabolismo
15.
Biochim Biophys Acta Biomembr ; 1862(7): 183261, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32151610

RESUMO

Antimicrobial peptides are widely studied as an alternative to traditional antibiotics. However, they are difficult to develop, as multiple factors influence their potency and selectivity toward bacterial cells. In this paper, we investigate three simplified model peptides that bear crown ethers, and the effects of simple structural modifications (peptide length and crown ether ring size) on their secondary structures and their permeabilizing activity on living cells and model membranes made with egg yolk phosphatidylcholine or 1-palmitoyl-2-oleoylphosphatidylglycerol. Circular dichroism studies show that the peptide length and the crown ether ring size do influence the conformation, but no trend could be determined from the results. Permeabilization studies with model membranes and with red blood cells demonstrated that from 13 residues to 16 residues, there is a gradual increase in activity as the peptides get longer. However, the shortest tested analogs, with 12 residues, also exhibited an increase in activity caused by the removal of one amino acid that was bearing a crown ether. Permeabilization assays showed that larger ring size analogs showed higher hemolytic activities. Altogether, the results reported help design new and more selective antimicrobial peptides.


Assuntos
Peptídeos Catiônicos Antimicrobianos/química , Membrana Celular/química , Éteres de Coroa/química , Fosfatidilcolinas/química , Sequência de Aminoácidos/genética , Antibacterianos/efeitos adversos , Antibacterianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Membrana Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Dicroísmo Circular , Éteres de Coroa/farmacologia , Gema de Ovo/química , Humanos , Bicamadas Lipídicas/química , Fosfatidilcolinas/farmacologia , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
16.
Cancer Med ; 9(1): 12-18, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31692291

RESUMO

The response to icotinib in advanced non-small cell lung cancers (NSCLC) with EGFR uncommon mutation (EGFRum) is unclear. Here we reported the efficacy and potential resistance mechanism of icotinib in Chinese EGFRum NSCLC patients. Between July 2013 and November 2016, 3117 NSCLC patients were screened for EGFRum in a multi-center study in China. Circulating tumor DNA (ctDNA) was detected and analyzed using next-generation sequencing (NGS) after progression from icotinib. The efficacy, safety and the potential resistance mechanism of icotinib were explored. After a median follow-up of 6.2 months, 69 patients (70.41%) developed disease progression, the objective rate (ORR) and disease control rate (DCR) were 13.27% and 29.59% respectively, and the median progression-free survival (PFS) was 5.5 months (95% CI: 1.2-13.0 months). Both complex-pattern with EGFR classical mutations (EGFRcm) and single-pattern have better PFS than complex-pattern without EGFRcm (median PFS was 7.2 (95% CI: 4.65-9.75), 5.2 (95% CI: 3.24-7.16) and 3.2 (95% CI: 2.97-3.44) months, respectively, P < .05); patients harboring S768I mutation had the worst PFS than others (2.0 months, P < .05). Diarrhea was the most frequent side effect (42.9%). Forty-eight (69.6%) patients developed drug resistance after 3.0 months and 81.2% of them acquired T790M mutation. Better response was observed in complex-pattern with the EGFRcm group. S768I mutation carriers may not benefit from icotinib. Acquired T790M mutation was common in icotinib-resistant EGFRum NSCLC patients.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Éteres de Coroa/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Idoso , Povo Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , China/epidemiologia , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Éteres de Coroa/uso terapêutico , Análise Mutacional de DNA , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Estudos Retrospectivos
17.
Ir J Med Sci ; 189(3): 791-797, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31797203

RESUMO

BACKGROUND: Lung cancer is a disease that severely endangers human health. Non-small cell lung cancer (NSCLC) accounts for approximately 4/5 of lung cancers. AIMS: To investigate the efficacy of early combination of local radiotherapy and granulocyte macrophage colony-stimulating factor (GM-CSF) for advanced NSCLC treated with icotinib. METHODS: Forty-two patients with stage IV NSCLC complicated with EGFR gene mutation were selected and randomly divided into two groups, with 21 patients in each group. Patients in control group were treated with icotinib, and patients in experimental group were treated with icotinib combined with local radiotherapy and subcutaneous injection of GM-CSF. One-year progression free survival between two groups was compared. RESULTS: Three months after treatment, the efficacy in experimental group was significantly better than that in control group, and objective response rate was 95.24% in experimental group, which was higher than the 71.43% in control group. Patients in experimental group had no differences in white blood cell and neutrophil, but had significantly lower carcino-embryonic antigen and neuron-specific enolase levels and higher CD3+, CD4+, and CD4+/CD8+ than those in control group and before treatment. There were no differences in the proportion of patients with adverse reactions between two groups. One-year progression free survival was significantly better in experimental group than in control group. CONCLUSIONS: Early combination of local radiotherapy and GM-CSF has a significant efficacy for advanced NSCLC accounts for approximately 4/5 of lung cancers treated with icotinib, and it can improve patients' autoimmunity and lengthen progression free survival.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Éteres de Coroa/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Quinazolinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Éteres de Coroa/farmacologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Quinazolinas/farmacologia , Adulto Jovem
18.
Math Biosci Eng ; 16(6): 7707-7718, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31698635

RESUMO

Objective: To investigate the inhibitory effect of Icotinib on proliferation and epithelial-mesenchymal transition of A549 cells. Methods: A549 cells were treated with Icotinib of different concentrations. The morphology of the cells was observed by inverted phase contrast microscope. The effect of different concentrations of Icotinib on the proliferation inhibition rate of A549 cells was detected by MTT assay. Flow cytometry was used to detect effect of Icotinib on the apoptosis rate of A549 cells. ELISA assay was used to detect the expression of EMT-related proteins, E-cadherin, N-cadherin, Vimentin and fibronectin, in A549 cells cultured supernatant. Transwell assay was used to examine the effects of different concentrations of Icotinib on the migration and invasion abilities of A549 cells. Results: Morphological changes were observed after A549 cells exposed to different concentrations of Icotinib for 48 hours. The inhibition rate of proliferation for each treatment group increased from MTT assay results. Flow cytometry results showed that cell apoptosis rate was significantly increased. Expression of E-cadherin was up-regulated and expression of N-cadherin, Vimentin and fibronectin were down-regulated from ELISA results. A549 cell migration and invasion abilities were significantly suppressed by Icotinib at different concentrations. Conclusion: Icotinib inhibits A549 cell proliferation, migration and invasion in both concentration and time-dependent manners, in turn it promotes A549 cell apoptosis in the same way. Icotinib also inhibits epithelial-mesenchymal transition by regulating EMT-related proteins expression in A549 cells.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Éteres de Coroa/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Quinazolinas/farmacologia , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Invasividade Neoplásica
19.
Respir Res ; 20(1): 217, 2019 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-31606039

RESUMO

BACKGROUND: Icotinib has been widely used in patients with non-small cell lung cancer (NSCLC), and have significantly enhanced the overall survival rate of NSCLC patients. However, acquired drug resistance limits its clinical efficacy. Tumor cell-derived exosomes have been reported to participate in various biological processes, including tumor invasion, metastasis and drug resistance. MATERIALS AND METHODS: In the present study, drug resistance was measured by MTT assay. Exosomes were extracted from the cell supernatant using ultracentrifugation and identified by exosomal marker. HCC827 cells were treated with exosomes derived from icotinib-resistant (IR) HCC827 to observe the invasion and migration of parent cells. The expression of exo-mRNA was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-PCR). In addition, 10 exo-mRNAs detecting from the plasma and bronchoalveolar lavage fluid (BALF) of NSCLC patients with icotinib treatment were used to establish a new drug resistant-warning formula. RESULTS: The oncogene MET into exosomes was identified from icotinib-resistant lung cancer cells, and this was also presented in exosomes in NSCLC patients diagnosed with cancer metastasis after icotinib treatment. The knockdown of MET in exosomes significantly decreased the ability of invasion and migration in HCC827 cells. CONCLUSION: It was suggested that MET might be specifically package and transferred by exosomes to modify the invasion and migration ability of the surrounding icotinib-sensitive cells.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Movimento Celular/genética , Éteres de Coroa/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/metabolismo , Invasividade Neoplásica/genética , Oncogenes/genética , Proteínas Proto-Oncogênicas c-met/biossíntese , Proteínas Proto-Oncogênicas c-met/genética , Quinazolinas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Líquido da Lavagem Broncoalveolar/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia
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