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1.
Int J Mol Sci ; 22(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33673002

RESUMO

Pan-Gyn cancers entail 1 in 5 cancer cases worldwide, breast cancer being the most commonly diagnosed and responsible for most cancer deaths in women. The high incidence and mortality of these malignancies, together with the handicaps of taxanes-first-line treatments-turn the development of alternative therapeutics into an urgency. Taxanes exhibit low water solubility that require formulations that involve side effects. These drugs are often associated with dose-limiting toxicities and with the appearance of multi-drug resistance (MDR). Here, we propose targeting tubulin with compounds directed to the colchicine site, as their smaller size offer pharmacokinetic advantages and make them less prone to MDR efflux. We have prepared 52 new Microtubule Destabilizing Sulfonamides (MDS) that mostly avoid MDR-mediated resistance and with improved aqueous solubility. The most potent compounds, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methylaminobenzenesulfonamide 38, N-methyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 42, and N-benzyl-N-(3,4,5-trimethoxyphenyl-4-methoxy-3-aminobenzenesulfonamide 45 show nanomolar antiproliferative potencies against ovarian, breast, and cervix carcinoma cells, similar or even better than paclitaxel. Compounds behave as tubulin-binding agents, causing an evident disruption of the microtubule network, in vitro Tubulin Polymerization Inhibition (TPI), and mitotic catastrophe followed by apoptosis. Our results suggest that these novel MDS may be promising alternatives to taxane-based chemotherapy in chemoresistant Pan-Gyn cancers.


Assuntos
Antineoplásicos/farmacologia , Sulfonamidas/farmacologia , Taxoides/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Polimerização/efeitos dos fármacos , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Taxoides/uso terapêutico , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapêutico
2.
Eur J Med Chem ; 216: 113316, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33676300

RESUMO

A series of novel N-benzylbenzamide derivatives were designed and synthesized as tubulin polymerization inhibitors. Among fifty-one target compounds, compound 20b exhibited significant antiproliferative activities with IC50 values ranging from 12 to 27 nM against several cancer cell lines, and possessed good plasma stability and satisfactory physicochemical properties. Mechanism studies demonstrated that 20b bound to the colchicine binding site and displayed potent anti-vascular activity. Notably, the corresponding disodium phosphate 20b-P exhibited an excellent safety profile with the LD50 value of 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth and decreased microvessel density in liver cancer cell H22 allograft mouse model without obvious toxicity. Collectively, 20b and 20b-P are novel promising anti-tubulin agents with more druggable properties and deserve to be further investigated for cancer therapy.


Assuntos
Antineoplásicos/química , Benzamidas/química , Desenho de Fármacos , Moduladores de Tubulina/química , Tubulina (Proteína)/química , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzamidas/metabolismo , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Sítios de Ligação , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/química , Colchicina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico
3.
Respir Med ; 178: 106322, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33550151

RESUMO

The global COVID-19 pandemic is currently underway. In December 2020, the European Agency of Medicine (EMA) licensed the first Sars-CoV-2 vaccine. Therapeutic management of the COVID-19 positive patient should primarily aim to avoid the severe complications and organ injury caused by generalized inflammation caused by a cytokine storm and occurring in the most severe stages of viral infection. Current knowledge of the pathophysiological mechanisms of SARS- CoV-2 suggests a central role for exaggerated activation of the innate immune system as an important contributor to the adverse outcomes of COVID-19. Several studies have shown that blocking the cytokine storm or acting early with prevention of it can be effective; studies are underway to evaluate agents that may be able to reduce this hyperinflammatory state. The search for effective management strategies for COVID-19 continues to evolve. The actions of colchicine, one of the oldest anti-inflammatory therapies, target multiple targets associated with excessive COVID-19 inflammation. Colchicine is easily administered, generally well tolerated, and inexpensive. This article reports the scientific and molecular rationale for the use of colchicine as monotherapy or in combination in the various stages of SARS-CoV-2 infection to modulate and control the inflammatory state. Low-dose colchicine may be considered safe and effective for the treatment and prevention of cytokine storm in patients with SARS-CoV-2 infection, particularly as an adjunctive remedy to other therapeutic agents. Well-organized clinical studies are needed in this direction.


Assuntos
/tratamento farmacológico , Colchicina/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , /complicações , Síndrome da Liberação de Citocina/etiologia , Humanos
4.
Biomed Pharmacother ; 133: 110973, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378993

RESUMO

Microtubules (composed of α- and ß-tubulin heterodimers) ubiquitous cellular polymers are important components of the cytoskeleton and play diverse roles within the cell, such as maintenance of cell structure, protein trafficking or chromosomal segregation during cell division. The polymers of tubulin play a pivotal role in mitosis and are regarded as an excellent target for chemotherapeutic agents to treat cancer. This review presents a brief overview of the synthesis and mechanism of action of new compounds targeting the dynamic of microtubule - tubulin polymerization/depolymerization. It is divided into the following parts: section I concerns targeting microtubules- tubulin-binding drugs derivatives of stilbene. In section II there are presented photoswitchable inhibitors of microtubule dynamics. Section III concerns using macrocyclic compounds as tubulin inhibitors. In this review, the authors focused primarily on reports produced inthe last five years and the latest strategies in this field.


Assuntos
Antineoplásicos/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Microtúbulos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Estilbenos/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Microtúbulos/metabolismo , Microtúbulos/patologia , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/patologia
5.
Rheumatol Int ; 40(9): 1423-1431, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32661928

RESUMO

Concerns regarding the comorbidity as a significant risk factor for Coronavirus Disease-2019 (COVID-19), gave rise to an urgent need for studies evaluating patients with chronic conditions such as autoinflammatory diseases (AIDs). We prepared a web-based survey investigating the clinical findings and contact histories among pediatric patients with AIDs. Confirmed COVID-19 cases, patients with contact history and those with symptoms which were highly suggestive of COVID-19 were called via phone or recruited to a video or face to face appointment. Data of AIDs were obtained from their medical records, retrospectively. Laboratory and screening findings were confirmed by our national health registry website. There were 404 patients (217 female) eligible for the enrollment. During pandemic, 375 (93%) were on colchicine treatment and 48 (11.8%) were receiving biologic treatment. Twenty-four out of 404 patients were admitted to hospital due to COVID-19 suspicion. Severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) was identified through rhinopharyngeal swabs in seven patients, six of whom were only on colchicine treatment. Only one patient with no finding of any severe respiratory complications was hospitalized. All of seven patients recovered completely. Among patients on biologic drugs, neither a symptom nor a positive polymerase chain reaction test for COVID 19 was detected. In conclusion, pediatric patients with AIDs, those receiving biologic treatment and/or colchicine, may not be at increased risk for neither being infected nor the severe disease course.


Assuntos
Colchicina/uso terapêutico , Infecções por Coronavirus/fisiopatologia , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Moduladores de Tubulina/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adalimumab/uso terapêutico , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Produtos Biológicos , Criança , Pré-Escolar , Estudos de Coortes , Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Síndromes Periódicas Associadas à Criopirina/complicações , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Etanercepte/uso terapêutico , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Doenças Hereditárias Autoinflamatórias/complicações , Humanos , Lactente , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Turquia , Adulto Jovem
6.
JAMA Netw Open ; 3(6): e2013136, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32579195

RESUMO

Importance: Severe acute respiratory syndrome coronavirus 2 infection has evolved into a global pandemic. Low-dose colchicine combines anti-inflammatory action with a favorable safety profile. Objective: To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19). Design, Setting, and Participants: In this prospective, open-label, randomized clinical trial (the Greek Study in the Effects of Colchicine in COVID-19 Complications Prevention), 105 patients hospitalized with COVID-19 were randomized in a 1:1 allocation from April 3 to April 27, 2020, to either standard medical treatment or colchicine with standard medical treatment. The study took place in 16 tertiary hospitals in Greece. Intervention: Colchicine administration (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg twice daily) with standard medical treatment for as long as 3 weeks. Main Outcomes and Measures: Primary end points were (1) maximum high-sensitivity cardiac troponin level; (2) time for C-reactive protein to reach more than 3 times the upper reference limit; and (3) time to deterioration by 2 points on a 7-grade clinical status scale, ranging from able to resume normal activities to death. Secondary end points were (1) the percentage of participants requiring mechanical ventilation, (2) all-cause mortality, and (3) number, type, severity, and seriousness of adverse events. The primary efficacy analysis was performed on an intention-to-treat basis. Results: A total of 105 patients were evaluated (61 [58.1%] men; median [interquartile range] age, 64 [54-76] years) with 50 (47.6%) randomized to the control group and 55 (52.4%) to the colchicine group. Median (interquartile range) peak high-sensitivity cardiac troponin values were 0.0112 (0.0043-0.0093) ng/mL in the control group and 0.008 (0.004-0.0135) ng/mL in the colchicine group (P = .34). Median (interquartile range) maximum C-reactive protein levels were 4.5 (1.4-8.9) mg/dL vs 3.1 (0.8-9.8) mg/dL (P = .73), respectively. The clinical primary end point rate was 14.0% in the control group (7 of 50 patients) and 1.8% in the colchicine group (1 of 55 patients) (odds ratio, 0.11; 95% CI, 0.01-0.96; P = .02). Mean (SD) event-free survival time was 18.6 (0.83) days the in the control group vs 20.7 (0.31) in the colchicine group (log rank P = .03). Adverse events were similar in the 2 groups, except for diarrhea, which was more frequent with colchicine group than the control group (25 patients [45.5%] vs 9 patients [18.0%]; P = .003). Conclusions and Relevance: In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution. Trial Registration: ClinicalTrials.gov Identifier: NCT04326790.


Assuntos
Proteína C-Reativa/metabolismo , Colchicina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Pneumonia Viral/tratamento farmacológico , Troponina/metabolismo , Moduladores de Tubulina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Causas de Morte , Infecções por Coronavirus/metabolismo , Diarreia/induzido quimicamente , Progressão da Doença , Feminino , Grécia , Hospitalização , Humanos , Inflamação/metabolismo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade , Pandemias , Pneumonia Viral/metabolismo , Respiração Artificial/estatística & dados numéricos , Fatores de Tempo , Resultado do Tratamento
8.
Toxicol Appl Pharmacol ; 396: 115001, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32277947

RESUMO

Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo, and the Notch1 signaling pathway was suppressed by MBZ treatment.


Assuntos
Antineoplásicos/uso terapêutico , Mebendazol/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Animais , Western Blotting , Caspase 3/metabolismo , Caspase 7/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Receptor Notch1/metabolismo , Tubulina (Proteína)/metabolismo
9.
Eur J Med Chem ; 197: 112308, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32339853

RESUMO

A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat cancer.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/tratamento farmacológico , Piridinas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologia
10.
Eur J Med Chem ; 197: 112323, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32339854

RESUMO

Inhibition of tubulin polymerisation with small molecules has been clinically validated as a promising therapy for multiple solid tumours. Herein, a series of chiral azetidin-2-ones were asymmetrically synthesised and biologically evaluated for antitumour activities. Among them, a chiral fluorinated azetidin-2-one, 18, was found to exhibit the most potent activities against five cancer cell lines, including a drug-resistant cell line, with IC50 values ranging from 1.0 to 3.6 nM. Further mechanistic studies revealed that the compound 18 worked by disrupting tubulin polymerisation, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis, and suppressing angiogenesis. Additionally, 18 exhibited higher human-microsomal metabolic stability and aqueous solubility compared to those of combretastatin A-4. Finally, 18 was also found to effectively inhibit tumour growth in a xenograft mice model with low toxicity and thus might be a promising lead for further clinical development.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Azetidinas/uso terapêutico , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Tubulina (Proteína)/metabolismo , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/toxicidade , Animais , Apoptose/efeitos dos fármacos , Azetidinas/síntese química , Azetidinas/metabolismo , Azetidinas/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Estabilidade de Medicamentos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/toxicidade , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Medicine (Baltimore) ; 99(16): e19814, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32312000

RESUMO

RATIONALE: Behçet Disease (BD) is a chronic inflammatory vasculitis with thrombogenicity and multisystem involvement. Deep vein thrombosis (DVT) in the lower extremities is the most frequent manifestation of vascular involvement in BD. The causes of thrombosis vary widely and include congenital predisposition and acquired factors, but of all the thrombosis, the cause is rarely BD. Furthermore, there are few reports of treatment for thrombosis in BD. PATIENT CONCERNS: We herein describe the case of an Asian male patient aged 40 years, admitted to our hospital for left leg pain, edema, and swelling. DIAGNOSES: We confirmed the DVT and pulmonary artery thrombosis (PAT) by contrast computed tomography angiogram. At the same time, the patient developed oral ulcerations and skin lesions consistent with BD. INTERVENTIONS: The patient was initially treated with anticoagulants. However, because the improvement of DVT was inadequate, we added colchicine in anticipation of anti-inflammatory effects. After that, anticoagulation was discontinued, and only colchicine was continuously prescribed. OUTCOMES: We observed an almost complete resolution of DVT and PAT with no recurrence of thrombosis for 6 months after discharge. LESSONS: This case shows us that we should consider BD as a differential diagnosis of DVT and that colchicine therapy is effective for inflammation-induced thrombosis in BD.


Assuntos
Síndrome de Behçet/complicações , Colchicina/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Trombose Venosa/tratamento farmacológico , Adulto , Anticoagulantes/uso terapêutico , Grupo com Ancestrais do Continente Asiático/etnologia , Síndrome de Behçet/patologia , Colchicina/administração & dosagem , Angiografia por Tomografia Computadorizada/métodos , Quimioterapia Combinada , Edema/diagnóstico , Edema/etiologia , Humanos , Perna (Membro)/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Dor/diagnóstico , Dor/etiologia , Artéria Pulmonar/patologia , Trombose/tratamento farmacológico , Resultado do Tratamento , Moduladores de Tubulina/administração & dosagem , Trombose Venosa/etiologia
13.
Am J Cardiol ; 125(11): 1694-1699, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278464

RESUMO

Data are scarce regarding sex differences among patients with acute myocarditis (AM). Our aim was to define the sex differences in clinical characteristics as well as in-hospital outcomes in a cohort of consecutive patients hospitalized due to AM. We analyzed data of 322 consecutive patients from January 2005 to December 2017 who were hospitalized with the diagnosis of AM. Eighty-four percent (N = 272) of the patients were males. When compared to females, male patients were younger (36 ± 14 vs 45 ± 17 years, p <0.001), more likely to present with ST segment elevation (75% vs 44%. p <0.001) as well as PR depression upon ECG, and have higher admission troponin levels (7.6 ± 11 vs 2.3 ± 4 µg/L, p <0.001). Moreover, males were more likely to have late gadolinium enhancement upon cardiac magnetic resonance. While male patients were more likely to have ventricular arrhythmias during hospitalization (7% vs 0%, p = 0.05), there were no differences in the incidence of in-hospital mortality or the need for escalation therapy during hospitalization between both groups. There were no episodes of mortality upon all patients among a follow-up of 1 year. In conclusion, male patients, which constitute the majority of patients admitted with AM were younger, more likely to present with ST elevation, had higher troponin levels at admission, and had a higher rate of ventricular arrhythmias compared to females. There were no differences in post-discharge mortality rates between males and females.


Assuntos
Arritmias Cardíacas/epidemiologia , Mortalidade Hospitalar , Miocardite/epidemiologia , Doença Aguda , Corticosteroides/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Distribuição por Idade , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/uso terapêutico , Colchicina/uso terapêutico , Diuréticos/uso terapêutico , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Israel/epidemiologia , Tempo de Internação , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocardite/diagnóstico por imagem , Miocardite/tratamento farmacológico , Miocardite/fisiopatologia , Fatores Sexuais , Volume Sistólico , Troponina/sangue , Moduladores de Tubulina/uso terapêutico , Adulto Jovem
14.
Nat Rev Clin Oncol ; 17(6): 349-359, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152484

RESUMO

Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody-drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices.


Assuntos
Antineoplásicos/uso terapêutico , Receptor 1 de Folato/metabolismo , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imagem Molecular , Neoplasias/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/terapia , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/terapia , Feminino , Corantes Fluorescentes , Ácido Fólico , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Imunoterapia Adotiva , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Mesotelioma/diagnóstico por imagem , Mesotelioma/metabolismo , Mesotelioma/terapia , Terapia de Alvo Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Imagem Óptica , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Cintilografia , Nanomedicina Teranóstica , Moduladores de Tubulina/uso terapêutico
15.
Cell Prolif ; 53(4): e12749, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32167212

RESUMO

OBJECTIVES: Given that autophagy inhibition is a feasible way to enhance sensitivity of cancer cells towards chemotherapeutic agents, identifying potent autophagy inhibitor has obvious clinical relevance. Here, we investigated ability of TN-16, a microtubule disrupting agent, on modulation of autophagic flux and its significance in promoting in vitro and in vivo cancer cell death. MATERIALS AND METHODS: The effect of TN-16 on cancer cell proliferation, cell division, autophagic process and apoptotic signalling was assessed by various biochemical (Western blot and SRB assay), morphological (TEM, SEM, confocal microscopy) and flowcytometric assays. In vivo anti-tumour efficacy of TN-16 was investigated in syngeneic mouse model of breast cancer. RESULTS: TN-16 inhibited cancer cell proliferation by impairing late-stage autophagy and induction of apoptosis. Inhibition of autophagic flux was demonstrated by accumulation of autophagy-specific substrate p62 and lack of additional LC3-II turnover in the presence of lysosomotropic agent. The effect was validated by confocal micrographs showing diminished autophagosome-lysosome fusion. Further studies revealed that TN-16-mediated inhibition of autophagic flux promotes apoptotic cell death. Consistent with in vitro data, results of our in vivo study revealed that TN-16-mediated tumour growth suppression is associated with blockade of autophagic flux and enhanced apoptosis. CONCLUSIONS: Our data signify that TN-16 is a potent autophagy flux inhibitor and might be suitable for (pre-) clinical use as standard inhibitor of autophagy with anti-cancer activity.


Assuntos
Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Pirrolidinonas/uso terapêutico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Microtúbulos/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Pirrolidinonas/farmacologia , Moduladores de Tubulina/farmacologia
16.
Nat Rev Neurol ; 16(4): 213-228, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203398

RESUMO

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive executive, behavioural and language dysfunction. The various FTD spectrum disorders are associated with brain accumulation of different proteins: tau, the transactive response DNA binding protein of 43 kDa (TDP43), or fused in sarcoma (FUS) protein, Ewing sarcoma protein and TATA-binding protein-associated factor 15 (TAF15) (collectively known as FET proteins). Approximately 60% of patients with FTD have autosomal dominant mutations in C9orf72, GRN or MAPT genes. Currently available treatments are symptomatic and provide limited benefit. However, the increased understanding of FTD pathogenesis is driving the development of potential disease-modifying therapies. Most of these drugs target pathological tau - this category includes tau phosphorylation inhibitors, tau aggregation inhibitors, active and passive anti-tau immunotherapies, and MAPT-targeted antisense oligonucleotides. Some of these therapeutic approaches are being tested in phase II clinical trials. Pharmacological approaches that target the effects of GRN and C9orf72 mutations are also in development. Key results of large clinical trials will be available in a few years. However, clinical trials in FTD pose several challenges, and the development of specific brain imaging and molecular biomarkers could facilitate the recruitment of clinically homogenous groups to improve the chances of positive clinical trial results.


Assuntos
Anticorpos/uso terapêutico , Afasia Primária Progressiva/tratamento farmacológico , Desenvolvimento de Medicamentos , Demência Frontotemporal/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/genética , Esclerose Amiotrófica Lateral/metabolismo , Afasia Primária Progressiva/genética , Afasia Primária Progressiva/metabolismo , Proteína C9orf72/genética , Proteínas de Ligação a DNA/metabolismo , Demência Frontotemporal/genética , Demência Frontotemporal/metabolismo , Humanos , Imunização Passiva , Imunoterapia Ativa , Terapia de Alvo Molecular , Progranulinas/genética , Proteína EWS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Paralisia Supranuclear Progressiva/tratamento farmacológico , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/metabolismo , Fatores Associados à Proteína de Ligação a TATA/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
19.
Eur J Med Chem ; 189: 112041, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954880

RESUMO

A series of novel conjugates comprising tublin and IDO inhibitors were designed, synthesized and evaluated for their antiproliferative activity. Among them, HI5, composed of combretastatin A-4 (CA-4) and (D)-1-methyltryptophan (D-MT) by a linker, exhibited the most potent antitumor activity, in particular with higher IC50 value (0.07 µM) than CA-4 (0.21 µM) against HeLa cancer cell line. Mechanism studies indicated that HI5 can inhibit tubulin polymerization and cell migration, cause G2/M phase arrest, concurrent induce apoptosis via the mitochondrial dependent apoptosis pathway and cause reactive oxidative stress generation in HeLa cells. Furthermore, HI5 can inhibit IDO expression and decrease kynurenine production, leading to stimulating T cells activation and proliferation to enhance antitumor immunity in vitro. Interestingly, HI5 can effectively limit the tumor growth in the HeLa xenograft mice models without causing significant loss of body weight. Consequently, such a conjugation can be a potent and safe immunochemotherapeutic method for improving cancer therapy.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Moduladores de Tubulina/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HeLa , Humanos , Cinurenina/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T/efeitos dos fármacos , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Ital J Pediatr ; 46(1): 7, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941537

RESUMO

Familial Mediterranean Fever, a monogenic autoinflammatory disease secondary to MEFV gene mutations in the chromosome 16p13, is characterized by recurrent self-limiting attacks of fever, arthritis, aphthous changes in lips and/or oral mucosa, erythema, serositis. It is caused by dysregulation of the inflammasome, a complex intracellular multiprotein structure, commanding the overproduction of interleukin 1. Familial Mediterranean Fever can be associated with other multifactorial autoinflammatory diseases, as vasculitis and Behçet disease.Symptoms frequently start before 20 years of age and are characterized by a more severe phenotype in patients who begin earlier.Attacks consist of fever, serositis, arthritis and high levels of inflammatory reactants: C-reactive protein, erythrocyte sedimentation rate, serum amyloid A associated with leucocytosis and neutrophilia. The symptom-free intervals are of different length.The attacks of Familial Mediterranean Fever can have a trigger, as infections, stress, menses, exposure to cold, fat-rich food, drugs.The diagnosis needs a clinical definition of the disease and a genetic confirmation. An accurate differential diagnosis is mandatory to exclude infective agents, autoimmune diseases, etc.In many patients there is no genetic confirmation of the disease; furthermore, some subjects with the relieve of MEFV mutations, show a phenotype not in line with the diagnosis of Familial Mediterranean Fever. For these reasons, diagnostic criteria were developed, as Tel Hashomer Hospital criteria, the "Turkish FMF Paediatric criteria", the "clinical classification criteria for autoinflammatory periodic fevers" formulated by PRINTO.The goals of the treatment are: prevention of attacks recurrence, normalization of inflammatory markers, control of subclinical inflammation in attacks-free intervals and prevention of medium and long-term complications, as amyloidosis. Colchicine is the first step in the treatment; biological drugs are effective in non-responder patients.The goal of this paper is to give a wide and broad review to general paediatricians on Familial Mediterranean Fever, with the relative diagnostic, clinical and therapeutic aspects.


Assuntos
Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/terapia , Biomarcadores/sangue , Criança , Colchicina/uso terapêutico , Diagnóstico Diferencial , Febre Familiar do Mediterrâneo/genética , Humanos , Fenótipo , Moduladores de Tubulina/uso terapêutico
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