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1.
Gene ; 715: 144005, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31376410

RESUMO

Members of the highly conserved pleiotropic CK1 family of serine/threonine-specific kinases are tightly regulated in the cell and play crucial regulatory roles in multiple cellular processes from protozoa to human. Since their dysregulation as well as mutations within their coding regions contribute to the development of various different pathologies, including cancer and neurodegenerative diseases, they have become interesting new drug targets within the last decade. However, to develop optimized CK1 isoform-specific therapeutics in personalized therapy concepts, a detailed knowledge of the regulation and functions of the different CK1 isoforms, their various splice variants and orthologs is mandatory. In this review we will focus on the stress-induced CK1 isoform delta (CK1δ), thereby addressing its regulation, physiological functions, the consequences of its deregulation for the development and progression of diseases, and its potential as therapeutic drug target.


Assuntos
Caseína Quinase Idelta/química , Caseína Quinase Idelta/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/enzimologia , Transdução de Sinais , Animais , Caseína Quinase Idelta/antagonistas & inibidores , Caseína Quinase Idelta/genética , Sistemas de Liberação de Medicamentos/métodos , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 179: 849-862, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302589

RESUMO

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Dicetopiperazinas/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Dicetopiperazinas/química , Dicetopiperazinas/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Estrutura Molecular , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
3.
Anticancer Res ; 39(7): 3433-3442, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262867

RESUMO

BACKGROUND/AIM: DOG1 is a calcium-activated chloride channel that has gained attention as a promising drug target due to its involvement in several processes essential for tumor development and progression. DOG1 is overexpressed in >95% of gastrointestinal stromal tumors (GIST). The aim was to determine DOG1 inhibition antitumoral effects on GIST. MATERIALS AND METHODS: Human GIST (GIST-T1 and GIST882) cell lines were used to study the effect of DOG1 inhibitors on chloride currents, viability, colony formation, and cell cycle. RESULTS: CaCCinh-A01 decreased chloride currents. CaCCinh-A01 and T16inh-A01 reduced GIST cell viability and CaCCinh-A01 affected cell cycle distribution leading to G1 cell-cycle arrest. CaCCinh-A01 also increased the sub-G1 phase population, indicative of apoptosis, in GIST882. CaCCinh-A01 strongly reduced the colony forming ability of the cells, whereas T16inh-A01 did not. CONCLUSION: DOG1 inhibition has antitumoral effects in GIST cells in vitro, and could potentially serve as a target for GIST therapy.


Assuntos
Anoctamina-1/antagonistas & inibidores , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Anoctamina-1/fisiologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Gastrointestinais/fisiopatologia , Tumores do Estroma Gastrointestinal/fisiopatologia , Humanos , Proteínas de Neoplasias/fisiologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Tiofenos/farmacologia
5.
Cancer Radiother ; 23(5): 432-438, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331844

RESUMO

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Neoplasias Pulmonares , Neoplasias Meníngeas/secundário , Proteínas de Neoplasias/antagonistas & inibidores , Quinase do Linfoma Anaplásico/análise , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/enzimologia , Neoplasias Encefálicas/radioterapia , Carbazóis/farmacocinética , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Cisplatino/administração & dosagem , Ensaios Clínicos como Assunto , Terapia Combinada , Irradiação Craniana/efeitos adversos , Irradiação Craniana/métodos , Crizotinibe/farmacocinética , Crizotinibe/uso terapêutico , Gerenciamento Clínico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Meníngeas/enzimologia , Neoplasias Meníngeas/radioterapia , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/análise , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/prevenção & controle , Estudos Observacionais como Assunto , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Pemetrexede/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos
6.
SAR QSAR Environ Res ; 30(7): 457-475, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31157558

RESUMO

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


Assuntos
Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Tetrazóis/química , Animais , Teorema de Bayes , Neoplasias da Mama/tratamento farmacológico , Cães , Desenho de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Modelos Lineares , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Tetrazóis/farmacologia
8.
Nat Commun ; 10(1): 2484, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171773

RESUMO

Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an 'inside-out' externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Antineoplásicos Imunológicos/farmacologia , Carcinoma Hepatocelular/metabolismo , Citofagocitose/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Neoplasias Hepáticas/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Animais , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais Murinos , Antígenos de Neoplasias/metabolismo , Linfócitos B , Linhagem Celular Tumoral , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Imunoterapia , Células Matadoras Naturais , Macrófagos , Camundongos , Terapia de Alvo Molecular , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Neoplasias/metabolismo , Proteínas Oncogênicas/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Receptores de IgG , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Crit Rev Oncol Hematol ; 139: 41-52, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31112881

RESUMO

Recurrent or metastatic head and neck squamous-cell carcinomas (R/M HNSCC) are a group of cancers with a very poor prognosis. Many clinical trials testing novel target therapies in this setting are currently ongoing. We performed a systematic review focusing our attention on all clinical trials, ongoing or already published, concerning the use of novel drugs for treatment of R/M HNSCC. We found that the research of novel molecules effective in treatment of R/M HNSCC has been intense during last decade, and nowadays it is still very active. Unfortunately, the results in this setting have been, overall, disappointing: until now, only cetuximab and, recently, nivolumab and pembrolizumab received authorization for treatment of R/M HNSCC. Nevertheless, the promising results showed by some novel drugs may lead to continue the research in this field, with the aim of producing more evidence and finding new therapeutic indication.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundário , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Proteínas de Neoplasias/metabolismo , Prognóstico , Recidiva
10.
Int J Clin Oncol ; 24(8): 893-898, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111287

RESUMO

The development of allogeneic hematopoietic-stem-cell transplantation has improved the prognosis of younger acute myeloid leukemia (AML) patients. However, the outcome of older AML patients remains poor. The majority of AML patients are elderly. For elderly AML patients unfit for intensive chemotherapy, less toxic single agent that targets a specific gene mutation or combination therapy with a single agent is needed. The role of chromosomal abnormalities and genetic mutations in leukemia has become more apparent, and detailed prognostic stratification based on the type of genetic mutation has been established. Next-generation sequencing (NGS) has been used for gene analysis of AML. In the future, the evaluation of biologically homogeneous population on the basis of chromosomal abnormalities and gene mutations will lead to a paradigm shift that will help in the development of optimized therapy. As rapid diagnosis of gene mutations is required by the clinical physicians to decide on induction therapy, it is important to have a swift turnaround time for comprehensive DNA sequencing to provide actionable data to clinical physicians. It is required to conduct a feasibility study to evaluate the turnaround time from sending the specimens to receiving the results while maintaining the quality of the specimens contributing to gene analysis. To detect infrequent gene mutations, investigators need to perform multicenter studies and/or cooperative-group trials with a certain sample size to examine the frequency of the gene mutations in elderly AML patients, enabling sufficient statistical power for meaningful comparisons.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Hematológicas/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Medicina de Precisão , Neoplasias Hematológicas/genética , Humanos , Japão , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Prognóstico
11.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013622

RESUMO

G-quadruplex (G4) DNA secondary structures formed in human telomeres have been shown to inhibit cancer-specific telomerase and alternative lengthening of telomere (ALT) pathways. Thus, human telomeric G-quadruplexes are considered attractive targets for anticancer drugs. Human telomeric G-quadruplexes are structurally polymorphic and predominantly form two hybrid-type G-quadruplexes, namely hybrid-1 and hybrid-2, under physiologically relevant solution conditions. To date, only a handful solution structures are available for drug complexes of human telomeric G-quadruplexes. In this review, we will describe two recent solution structural studies from our labs. We use NMR spectroscopy to elucidate the solution structure of a 1:1 complex between a small molecule epiberberine and the hybrid-2 telomeric G-quadruplex, and the structures of 1:1 and 4:2 complexes between a small molecule Pt-tripod and the hybrid-1 telomeric G-quadruplex. Structural information of small molecule complexes can provide important information for understanding small molecule recognition of human telomeric G-quadruplexes and for structure-based rational drug design targeting human telomeric G-quadruplexes.


Assuntos
Quadruplex G , Proteínas de Neoplasias/química , Telomerase/química , Homeostase do Telômero , Telômero/química , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Ressonância Magnética Nuclear Biomolecular , Telomerase/antagonistas & inibidores , Telomerase/metabolismo , Telômero/metabolismo
12.
Molecules ; 24(7)2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30974737

RESUMO

Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1⁻G13 were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhibited improved antitumor efficacy compared with INH. Moreover, conjugates G10 and G11 showed potent anticancer activity with IC50 values (0.85 and 0.4 µM respectively) comparable to that of doxorubicin (DOX). This may be attributable to the preferential accumulation of these conjugates in tumor cells. G10, G11, and G12 also demonstrated moderate MAOA inhibitory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a combination of the MAOA inhibitor INH with tumor-targeting heptamethine cyanine dyes may prove to be a highly promising tool for the treatment of advanced prostate cancer.


Assuntos
Carbocianinas , Corantes Fluorescentes , Isoniazida , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase , Monoaminoxidase , Proteínas de Neoplasias , Neoplasias da Próstata , Carbocianinas/síntese química , Carbocianinas/química , Carbocianinas/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Isoniazida/química , Isoniazida/farmacologia , Masculino , Monoaminoxidase/química , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia
13.
Molecules ; 24(8)2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31018549

RESUMO

Carcinogenesis is the process whereby a normal cell is transformed into a neoplastic cell. This action involves several steps starting with initiation and followed by promotion and progression. Driving these stages are oxidative stress and inflammation, which in turn encompasses a myriad of aberrant gene expressions, both within the transforming cell population and the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review, we discuss whereby the chemoprevention activities of the red beetroot itself may disrupt carcinogenesis and the activities of the water-soluble betalains extracted from the plant.


Assuntos
Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Beta vulgaris/química , Betalaínas/farmacologia , Carcinogênese/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias/prevenção & controle , Animais , Anticarcinógenos/química , Anticarcinógenos/isolamento & purificação , Antioxidantes/química , Antioxidantes/isolamento & purificação , Betalaínas/química , Betalaínas/isolamento & purificação , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Flavonóis/química , Flavonóis/isolamento & purificação , Flavonóis/farmacologia , Humanos , Camundongos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/farmacologia , Extratos Vegetais/química , Raízes de Plantas/química , Triterpenos/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Future Oncol ; 15(13): 1505-1524, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30977669

RESUMO

Bladder cancer (BC) is the most frequent cancer affecting the urinary tract. With the growing era of targeted therapies around the 2000s, many trials evaluated the efficacy of targeted therapy in advanced BC. However, no approval was given yet to any form of targeted therapy when it comes to BC. The aim of this paper was to report the most pivotal trials that evaluated different families of targeted therapy in the treatment of BC, according to their biomarkers (FGFR3, EGFR, HER2, VEGF and PI3K/AKT/mTOR). The ongoing trials testing targeted therapies in advanced BC were then summarized. Finally, the different immunotherapies approved for this disease and their potential combination with targeted therapy were addressed.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Humanos , Proteínas de Neoplasias/metabolismo , Prognóstico , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia
15.
Mar Drugs ; 17(4)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934819

RESUMO

Sulfated polysaccharides from sea cucumbers possess distinct chemical structure and various biological activities. Herein, three types of polysaccharides were isolated and purified from Pattalus mollis, and their structures and bioactivities were analyzed. The fucosylated glycosaminoglycan (PmFG) had a CS-like backbone composed of the repeating units of {-4-d-GlcA-ß-1,3-d-GalNAc4S6S-ß-1-}, and branches of a sulfated α-l-Fuc (including Fuc2S4S, Fuc3S4S and Fuc4S with a molar ratio of 2:2.5:1) linked to O-3 of each d-GlcA. The fucan sulfate (PmFS) had a backbone consisting of a repetitively linked unit {-4-l-Fuc2S-α-1-}, and interestingly, every trisaccharide unit in its backbone was branched with a sulfated α-l-Fuc (Fuc4S or Fuc3S with a molar ratio of 4:1). Apart from the sulfated polysaccharides, two neutral glycans (PmNG-1 & -2) differing in molecular weight were also obtained and their structures were similar to animal glycogen. Anticoagulant assays indicated that PmFG and PmFS possessed strong APTT prolonging and intrinsic factor Xase inhibition activities, and the sulfated α-l-Fuc branches might contribute to the anticoagulant and anti-FXase activities of both PmFG and PmFS.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Pepinos-do-Mar/química , Animais , Anticoagulantes/isolamento & purificação , Coagulação Sanguínea/efeitos dos fármacos , Sequência de Carboidratos , Química Física , Cromatografia Líquida de Alta Pressão , Cisteína Endopeptidases , Humanos , Estrutura Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Ressonância Magnética Nuclear Biomolecular , Polissacarídeos/isolamento & purificação , Relação Estrutura-Atividade , Sulfatos/química , Sulfatos/isolamento & purificação , Sulfatos/farmacologia
16.
Eur J Med Chem ; 172: 71-94, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30947123

RESUMO

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


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Aminas/farmacologia , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ésteres/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminas/síntese química , Aminas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Células CACO-2 , Dimerização , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
17.
Artif Cells Nanomed Biotechnol ; 47(1): 725-736, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30861353

RESUMO

Oxaliplatin resistance limits the efficiency of treatment for colorectal cancer (CRC). Studies have shown that abnormal expression of microRNAs (miRNAs) were associated with tumorigenesis, cancer development and chemoresistance. The purpose of this study was to identify potential miRNAs related to oxaliplatin resistance in CRC cells. In this work, using small RNA sequencing (small RNA-Seq) and transcriptome sequencing (RNA-Seq), we found that down-regulated miR-483-3p was concurrent with up-regulated FAM171B in oxaliplatin-resistant colorectal cancer cell line HCT116/L as compared with its parental cell line HCT116. Transient transfection of miR-483-3p mimics markedly decreased the levels of FAM171B and restored oxaliplatin responsiveness of HCT116/L cells, and this alteration enhanced cell apoptosis and weakened cell migration. Whereas miR-483-3p inhibitor dramatically promoted the expression of FAM171B and enhanced oxaliplatin resistance of HCT116 cells by repressing cell apoptosis. Furthermore, knockdown of FAM171B in HCT116/L cells could also sensitize its reaction of the treatment with oxaliplatin, which was verified by the reduced cell migration. These findings demonstrate that FAM171B is a functional target of miR-483-3p in the regulation of oxaliplatin resistance in human CRC cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Membrana/antagonistas & inibidores , MicroRNAs/genética , Proteínas de Neoplasias/genética , Oxaliplatina/farmacologia , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Expressão Gênica , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Proteínas de Membrana/genética , MicroRNAs/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores
18.
ACS Appl Mater Interfaces ; 11(13): 12327-12334, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30864434

RESUMO

Self-assembled nanostructures of amphiphilic peptides have a wide range of applications in bioimaging and delivery systems. In this study, we design and synthesize a biocompatible amphiphilic peptide (C-3) consisting of an RVRRFFF sequence and a nitrobenzoxadiazole fluorophore that can self-assemble into stable micelles for specifically detecting furin, a kind of proprotein convertase with promoting tumor progression. The self-assembly of C-3 with a ß-sheet nanostructure is capable of a rapid and specific response to furin in only 5 min in aqueous solution because of the existence of the RVRR motif in the C-3 molecule. The C-3 nanostructures thus can selectively distinguish high furin-expressing cancer cells, like MDA-MB-231 cells, a kind of human breast cancer cells, from normal cells. Furthermore, the C-3 self-assembly can stay in living cells for a long time and are capable of durable detection of intracellular furin, being good for tracer analysis. To our knowledge, this is the first example of self-assembly of a soluble amphiphilic peptide that can selectively detect furin in high furin-expressing live cells.


Assuntos
Neoplasias da Mama , Sistemas de Liberação de Medicamentos/métodos , Furina/antagonistas & inibidores , Nanoestruturas/química , Proteínas de Neoplasias/antagonistas & inibidores , Peptídeos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Furina/metabolismo , Humanos , Camundongos , Proteínas de Neoplasias/metabolismo , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Estrutura Secundária de Proteína , Células RAW 264.7
19.
BMC Cancer ; 19(1): 237, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30876464

RESUMO

BACKGROUND: Patients with ovarian cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Studies have found TM4SF1 participates in regulating tumor cell invasion and migration. Therefore, it is expected to become a target for anti-invasion and metastasis in ovarian cancer. METHODS: The expression of TM4SF1 in normal ovarian epithelial tissues, benign ovarian tumor tissues, primary foci of epithelial ovarian cancer and the matched lymph mode metastatic foci was detected using immunohistochemistry to analyze its association with prognosis. The expression of TM4SF1 in HO8910PM, SKOV3 was inhibited using RNAi, and the growth, proliferation, migration, invasion abilities of HO8910PM and SKOV3 cells and the growth of xenograft tumors in nude mice were examined. RESULTS: (1) The positive expression rate of TM4SF1 protein in epithelial ovarian cancer tissues (90.90%) was higher than that in benign ovarian tumor tissues (65.22%) and normal ovarian epithelial tissues (31.25%), and both differences were significant (P < 0.05). The expression of TM4SF1 protein was positive in all metastatic lymph node foci and matched primary foci (100%). (2) The level of TM4SF1 protein expression was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade. However, The positive TM4SF1 protein expression was not an independent factor of prognosis (P > 0.05). (3) Silencing TM4SF1 expression did not affect growth, proliferation, or cell cycle distribution but inhibited the migration and invasion abilities of HO8910PM and SKOV3 cells. Silencing TM4SF1 expression inhibited the growth of xenograft tumors in nude mice. CONCLUSION: TM4SF1 is a potential target for anti-invasion and metastasis in ovarian cancer.


Assuntos
Antígenos de Superfície/metabolismo , Carcinoma Epitelial do Ovário/patologia , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/patologia , Regulação para Cima , Animais , Carcinoma Epitelial do Ovário/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Nus , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Estadiamento de Neoplasias , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Prognóstico , Interferência de RNA/fisiologia
20.
Chem Commun (Camb) ; 55(26): 3833-3836, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30869688
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