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1.
Pharmacol Res Perspect ; 12(4): e1241, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38992911

RESUMO

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6ß-hydroxycortisol, deoxycholic acid, and 1ß-hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography-tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three-compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.


Assuntos
Biomarcadores , Citocromo P-450 CYP3A , Monitoramento de Medicamentos , Compostos de Fenilureia , Quinolinas , Humanos , Compostos de Fenilureia/urina , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/sangue , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/administração & dosagem , Feminino , Quinolinas/urina , Quinolinas/uso terapêutico , Quinolinas/sangue , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Idoso , Pessoa de Meia-Idade , Masculino , Biomarcadores/urina , Biomarcadores/sangue , Monitoramento de Medicamentos/métodos , Adulto , Idoso de 80 Anos ou mais , Antineoplásicos/urina , Antineoplásicos/uso terapêutico , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Inibidores de Proteínas Quinases/urina , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias/tratamento farmacológico , Neoplasias/sangue , Neoplasias/urina , Espectrometria de Massas em Tandem/métodos , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/urina , Neoplasias do Endométrio/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/urina , Cromatografia Líquida/métodos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/urina , Neoplasias da Glândula Tireoide/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/urina , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/urina , Carcinoma de Células Renais/sangue
2.
Int J Biol Sci ; 20(9): 3269-3284, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38993552

RESUMO

Background: Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. Methods: We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study. Results: We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance in vitro and in vivo. Mechanistically, USP14 directly interacts with and stabilizes calcium- and integrin-binding protein 1 (CIB1) by reversing K48-linked proteolytic ubiquitination at K24, thus facilitating the P21-activated kinase 1 (PAK1)-ERK1/2 signaling axis. Moreover, in vivo adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. Conclusions: These findings provide new insights into the role of CIB1/PAK1-ERK1/2 signaling in lenvatinib resistance in HCC. Targeting CIB1 and its pathways may be a novel pharmaceutical intervention for the treatment of lenvatinib-resistant HCC.


Assuntos
Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Ubiquitina Tiolesterase , Quinases Ativadas por p21 , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Humanos , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Animais , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/genética , Camundongos , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases , Camundongos Nus , Ubiquitinação
3.
Neoplasma ; 71(3): 297-305, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38958712

RESUMO

Currently, there is a lack of effective second-line and subsequent treatments for patients with extensive-stage small-cell lung cancer (ES-SCLC), and the establishment of a standardized treatment protocol is still underway. Considering the potential synergistic therapeutic effects of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs), combination therapy could be a viable option for treating lung cancer. This research concentrates on assessing the efficacy and safety of anlotinib in combination with ICIs for the treatment of ES-SCLC. We undertook a retrospective analysis of patients with extensive-stage SCLC who received anlotinib in combination with ICIs as second-line and subsequent treatment at Zhejiang Cancer Hospital between April 2020 and April 2023. Survival rates were analyzed using the Kaplan-Meier method. Among the 43 patients who received combination therapy, there were no cases of complete response (CR), 16 patients who achieved partial response (PR), 21 patients who had stable disease (SD), and 6 patients who experienced disease progression (PD). This resulted in an overall response rate (ORR) of 37.2% (16/43) and a disease control rate (DCR) of 86.0% (34/43). The median progression-free survival (PFS) was 4.0 months (95% CI: 2.74-5.26), and the median overall survival (OS) time was 10 months (95% CI: 4.8-15.2). Cox multifactorial regression analysis disclosed that the performance score (PS) and the number of metastatic organs were independent factors influencing PFS in ES-SCLC (p<0.001). The combination therapy demonstrated acceptable toxicity, with a total grade 3/4 toxicity rate of 30.2%. The combination therapy showed a notable association with several adverse events, including hand-foot syndrome, hypertension, and fatigue, which were the most significant. Combining anlotinib with immune checkpoint inhibitors has demonstrated favorable efficacy and safety in the treatment of second-line and subsequent extensive-stage small-cell lung cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores de Checkpoint Imunológico , Indóis , Neoplasias Pulmonares , Quinolinas , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Indóis/administração & dosagem , Indóis/efeitos adversos , Indóis/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Quinolinas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Masculino , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Taxa de Sobrevida , Intervalo Livre de Progressão , Estadiamento de Neoplasias , Idoso de 80 Anos ou mais
4.
Arch Dermatol Res ; 316(7): 447, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958761

RESUMO

Malignant melanoma presents a formidable challenge due to its aggressive metastatic behavior and limited response to current treatments. To address this, our study delves into the impact of anlotinib on angiogenesis and vasculogenic mimicry using malignant melanoma cells and human umbilical vein endothelial cells. Evaluating tubular structure formation, cell proliferation, migration, invasion, and key signaling molecules in angiogenesis, we demonstrated that anlotinib exerts a dose-dependent inhibition on tubular structures and effectively suppresses cell growth and invasion in both cell types. Furthermore, in a mouse xenograft model, anlotinib treatment resulted in reduced tumor growth and vascular density. Notably, the downregulation of VEGFR-2, FGFR-1, PDGFR-ß, and PI3K underscored the multitargeted antitumor activity of anlotinib. Our findings emphasize the therapeutic potential of anlotinib in targeting angiogenesis and vasculogenic mimicry, contributing to the development of novel strategies for combating malignant melanoma.


Assuntos
Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana , Indóis , Melanoma , Neovascularização Patológica , Quinolinas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Ensaios Antitumorais Modelo de Xenoenxerto , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Animais , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Camundongos Nus , Angiogênese
5.
BMC Pulm Med ; 24(1): 307, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38956524

RESUMO

Liver-related side effects are a known complication of treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for cystic fibrosis (CF). Gilbert's syndrome is caused by a genetic mutation that reduces activity of the enzyme UDP glucuronosyltransferase 1 polypeptide A1 (UGT1A1), causing elevated levels of unconjugated bilirubin in the blood and duodenal bile. The presence of Gilbert's syndrome and CF might represent additive risk factors for liver-related adverse events during ETI treatment. This case series describes six people with CF (pwCF) in whom previously unknown Gilbert's syndrome was unmasked after initiation of treatment with ETI. Although all patients had some level of hepatic dysfunction and/or elevated levels of bilirubin after initiation of ETI, the clinical course varied. Only one patient had to stop ETI therapy altogether, while the others were able to continue treatment (some at a reduced dosage and others at the full recommended daily dosage). All patients, even those using a lower dosage, experienced clinical benefit during ETI therapy. Gilbert's syndrome is not a contraindication for ETI therapy but may be mistaken for a risk factor for liver-related adverse events in pwCF. This is something that physicians need to be aware of in pwCF who show liver adverse events during ETI therapy.


Assuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Doença de Gilbert , Hiperbilirrubinemia , Indóis , Pirazóis , Piridinas , Quinolonas , Humanos , Doença de Gilbert/genética , Doença de Gilbert/tratamento farmacológico , Masculino , Aminofenóis/efeitos adversos , Aminofenóis/uso terapêutico , Feminino , Adulto , Fibrose Cística/tratamento farmacológico , Fibrose Cística/complicações , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Indóis/efeitos adversos , Benzodioxóis/efeitos adversos , Benzodioxóis/uso terapêutico , Quinolonas/efeitos adversos , Quinolonas/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Hiperbilirrubinemia/induzido quimicamente , Adulto Jovem , Pirróis/efeitos adversos , Adolescente , Glucuronosiltransferase/genética , Pirrolidinas , Quinolinas
6.
Molecules ; 29(13)2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38998949

RESUMO

Newly synthesized 7-chloro-4-aminoquinoline-benzimidazole hybrids were characterized by NMR and elemental analysis. Compounds were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts) and carcinoma (HeLa and CaCo-2), leukemia, and lymphoma (Hut78, THP-1, and HL-60) cell lines. The obtained results, expressed as the concentration at which 50% inhibition of cell growth is achieved (IC50 value), show that the tested compounds affect cell growth differently depending on the cell line and the applied dose (IC50 ranged from 0.2 to >100 µM). Also, the antiplasmodial activity of these hybrids was evaluated against two P. falciparum strains (Pf3D7 and PfDd2). The tested compounds showed potent antiplasmodial activity, against both strains, at nanomolar concentrations. Quantitative structure-activity relationship (QSAR) analysis resulted in predictive models for antiplasmodial activity against the 3D7 strain (R2 = 0.886; Rext2 = 0.937; F = 41.589) and Dd2 strain (R2 = 0.859; Rext2 = 0.878; F = 32.525) of P. falciparum. QSAR models identified the structural features of these favorable effects on antiplasmodial activities.


Assuntos
Antimaláricos , Antineoplásicos , Benzimidazóis , Desenho de Fármacos , Plasmodium falciparum , Relação Quantitativa Estrutura-Atividade , Humanos , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Antimaláricos/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/crescimento & desenvolvimento , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Estrutura Molecular , Aminoquinolinas
7.
Molecules ; 29(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38999028

RESUMO

Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed to inhibit InhA, an essential enzyme for Mycobacterium tuberculosis survival. Over twenty molecules were synthesized and the results showed modest inhibitory efficacy against the protein. Docking experiments were carried out to show how these molecules could interact with the protein's substrate binding site. Disappointingly, unlike triazolophthlazines, these imidazoquinoline derivatives showed an absence of inhibition on mycobacterial growth.


Assuntos
Antituberculosos , Proteínas de Bactérias , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis , Oxirredutases , Quinolinas , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/síntese química , Quinolinas/química , Quinolinas/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Imidazóis/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana , Sítios de Ligação , Estrutura Molecular
8.
Molecules ; 29(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38999109

RESUMO

In the presented work, a series of 22 hybrids of 8-quinolinesulfonamide and 1,4-disubstituted triazole with antiproliferative activity were designed and synthesised. The title compounds were designed using molecular modelling techniques. For this purpose, machine-learning, molecular docking, and molecular dynamics methods were used. Calculations of the pharmacokinetic parameters (connected with absorption, distribution, metabolism, excretion, and toxicity) of the hybrids were also performed. The new compounds were synthesised via a copper-catalysed azide-alkyne cycloaddition reaction (CuAAC). 8-N-Methyl-N-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}quinolinesulfonamide was identified in in silico studies as a potential strong inhibitor of Rho-associated protein kinase and as a compound that has an appropriate pharmacokinetic profile. The results obtained from in vitro experiments confirm the cytotoxicity of derivative 9b in four selected cancer cell lines and the lack of cytotoxicity of this derivative towards normal cells. The results obtained from silico and in vitro experiments indicate that the introduction of another quinolinyl fragment into the inhibitor molecule may have a significant impact on increasing the level of cytotoxicity toward cancer cells and indicate a further direction for future research in order to find new substances suitable for clinical applications in cancer treatment.


Assuntos
Antineoplásicos , Aprendizado de Máquina , Simulação de Acoplamento Molecular , Quinolinas , Sulfonamidas , Triazóis , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Estrutura Molecular
9.
Molecules ; 29(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38999167

RESUMO

Organometallic complexes of the formula [Ru(N^N)(p-cymene)Cl][X] (N^N = bidentate polypyridyl ligands, p-cymene = 1-methyl-4-(1-methylethyl)-benzene, X = counter anion), are currently studied as possible candidates for the potential treatment of cancer. Searching for new organometallic compounds with good to moderate cytotoxic activities, a series of mononuclear water-soluble ruthenium(II)-arene complexes incorporating substituted pyridine-quinoline ligands, with pending -CH2OH, -CO2H and -CO2Me groups in the 4-position of quinoline ring, were synthesized, for the first time, to study their possible effect to modulate the activity of the ruthenium p-cymene complexes. These include the [Ru(η6-p-cymene)(pqhyme)Cl][X] (X = Cl- (1-Cl), PF6- (1-PF6), pqhyme = 4-hydroxymethyl-2-(pyridin-2-yl)quinoline), [Ru(η6-p-cymene)(pqca)Cl][Cl] ((2-Cl), pqca = 4-carboxy-2-(pyridin-2-yl)quinoline), and [Ru(η6-p-cymene)(pqcame)Cl][X] (X = Cl- (3-Cl), PF6- (3-PF6), pqcame = 4-carboxymethyl-2-(pyridin-2-yl)quinoline) complexes, respectively. Identification of the complexes was based on multinuclear NMR and ATR-IR spectroscopic methods, elemental analysis, conductivity measurements, UV-Vis spectroscopic, and ESI-HRMS techniques. The solid-state structures of 1-PF6 and 3-PF6 have been elucidated by single-crystal X-ray diffraction revealing a three-legged piano stool geometry. This is the first time that the in vitro cytotoxic activities of these complexes are studied. These were conducted in HEK293T (human embryonic kidney cells) and HeLa cells (cervical cancer cells) via the MTT assay. The results show poor in vitro anticancer activities for the HeLa cancer cell lines and 3-Cl proved to be the most potent (IC50 > 80 µΜ). In both cell lines, the cytotoxicity of the ligand precursor pqhyme is significantly higher than that of cisplatin.


Assuntos
Antineoplásicos , Complexos de Coordenação , Cimenos , Piridinas , Quinolinas , Rutênio , Humanos , Rutênio/química , Quinolinas/química , Quinolinas/síntese química , Quinolinas/farmacologia , Ligantes , Cimenos/química , Cimenos/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Piridinas/química , Piridinas/síntese química , Piridinas/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/síntese química , Estrutura Molecular , Linhagem Celular Tumoral , Cristalografia por Raios X , Sobrevivência Celular/efeitos dos fármacos
11.
BMC Pharmacol Toxicol ; 25(1): 38, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38978151

RESUMO

BACKGROUND: Dihydroartemisinin-piperaquine (DHP) recently showed superior effectiveness over sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in pregnancy (IPTp). We investigated day 7 piperaquine pharmacokinetics and its therapeutic efficacy in preventing malaria during pregnancy. METHODS: Malaria-free (mRDT) pregnant women (n = 400) who received monthly IPTp-DHP were enrolled and followed till delivery. Day 7 Plasma piperaquine concentrations were determined after each IPTp dose using UPLC/MS/MS. IPTp outcomes (symptomatic malaria and parasitemia during pregnancy, placental malaria, and maternal malaria at delivery) were monitored. Linear mixed model and Cox regression were used to assess predictors of day 7 piperaquine concentration and treatment outcome, respectively. RESULTS: The incidences of symptomatic malaria and parasitemia during pregnancy per 100 person-year at risk were 2 and 33, respectively. The prevalence of histopathologically confirmed placental malaria and maternal malaria at delivery were 3% and 9.8%, respectively. Repeated monthly IPTp-DHP resulted in significantly increased day 7 plasma piperaquine concentration (p < 0.001). Following the 1st, 2nd, and 3rd monthly IPTp-DHP doses, the proportions of women with day 7 piperaquine concentration below the therapeutic threshold (< 30 ng/mL) were 6.1%, 4.1% and 3.6%, respectively. Factors such as maternal age, body weight and trimester were not significant predictors of day 7 piperaquine concentration. However, having a low day 7 piperaquine plasma concentration (< 30 ng/mL) was significantly associated with a higher risk of parasitemia during pregnancy (p = 0.004). CONCLUSION: Lower day 7 piperaquine plasma concentration is a risk factor for parasitemia during pregnancy. Single plasma sampling at day 7 can be used to monitor piperaquine effectiveness during IPTp-DHP. TRIAL REGISTRATION: Registered 09/12/2016, PACTR201612001901313.


Assuntos
Antimaláricos , Malária , Complicações Parasitárias na Gravidez , Quinolinas , Humanos , Feminino , Gravidez , Quinolinas/farmacocinética , Quinolinas/sangue , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Antimaláricos/farmacocinética , Antimaláricos/uso terapêutico , Antimaláricos/sangue , Antimaláricos/administração & dosagem , Adulto , Complicações Parasitárias na Gravidez/prevenção & controle , Complicações Parasitárias na Gravidez/sangue , Adulto Jovem , Malária/prevenção & controle , Malária/tratamento farmacológico , Artemisininas/farmacocinética , Artemisininas/uso terapêutico , Artemisininas/administração & dosagem , Artemisininas/sangue , Parasitemia/sangue , Parasitemia/prevenção & controle , Resultado do Tratamento , Combinação de Medicamentos , Adolescente , Piperazinas
12.
Cancer Med ; 13(13): e7415, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38953381

RESUMO

BACKGROUND: Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B. METHODS: Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis. RESULTS: Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001). CONCLUSIONS: In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Compostos de Fenilureia , Quinolinas , Sorafenibe , Humanos , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Quinolinas/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Sorafenibe/uso terapêutico , Estudos Retrospectivos , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Progressão , Bevacizumab/uso terapêutico , Resultado do Tratamento , Imunoterapia/métodos
13.
Clin Nucl Med ; 49(8): 754-756, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38967508

RESUMO

ABSTRACT: Currently, monoamine oxidase B is recognized as the primary target of 18F-THK5351, although 18F-THK5351 was initially developed to target neurofibrillary tangles (NFTs) in Alzheimer disease. When clinically applying 18F-THK5351 PET to visualize ongoing astrogliosis via estimating monoamine oxidase B levels, a crucial concern is how much degree 18F-THK5351 uptake reflects NFTs in in vivo images. To unravel this concern, a head-to-head comparison between 18F-THK5351 and 18F-MK-6240 (estimating NFT) images in the NFT lesion ideally without accompanying astrogliosis is essential. Here, we present such a case suggesting that 18F-THK5351 uptake may not estimate NFTs in in vivo images.


Assuntos
Emaranhados Neurofibrilares , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Humanos , Tomografia por Emissão de Pósitrons , Aminopiridinas , Transporte Biológico , Idoso , Masculino , Feminino , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Isoquinolinas , Quinolinas
14.
Cell Death Dis ; 15(7): 484, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969639

RESUMO

An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells' competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.


Assuntos
Carcinoma Hepatocelular , Resistencia a Medicamentos Antineoplásicos , Metabolismo Energético , Neoplasias Hepáticas , Proteínas de Membrana , Mitofagia , Compostos de Fenilureia , Quinolinas , Humanos , Quinolinas/farmacologia , Mitofagia/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Proteínas de Membrana/metabolismo , Metabolismo Energético/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas/metabolismo , Camundongos , Camundongos Nus , Proliferação de Células/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos BALB C , Reprogramação Metabólica
15.
Sci Rep ; 14(1): 15522, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969677

RESUMO

A series of benzoquinoline-employing heterocycles was synthesized by treating 3-chlorobenzo[f]quinoline-2-carbaldehyde with N-phenyl-3-methylpyrazolone, 4-aminoacetophenone, 1,2-diaminoethane, and 2-cyanoethanohydrazide. Also, pyridine, chromene, α,ß-unsaturated nitrile, thiosemicarbazone, and 1,2-bis-aryl hydrazine derivatives were prepared from the cyanoethanohydrazone obtained. The DFT calculations and experiment outcomes were consistent. In vitro screening of their antiproliferative efficacy was examined against HCT116 and MCF7 cancer cell lines. The pyrazolone 2 and cyanoethanohydrazone 5 derivatives exhibited the most potency, which was demonstrated by their molecular docking towards the CDK-5 enzyme. The binding energies of compounds 2 and 5 were - 6.6320 kcal/mol (with RMSD of 0.9477 Å) and - 6.5696 kcal/mol (with RMSD of 1.4889 Å), respectively, which were near to that of co-crystallized ligand (EFP). This implies a notably strong binding affinity towards the CDK-5 enzyme. Thus, pyrazolone derivative 2 would be considered a promising candidate for further optimization to develop new chemotherapeutic agents. In addition, the ADME (absorption, distribution, metabolism, and excretion) analyses displayed its desirable drug-likeness and oral bioavailability properties.


Assuntos
Antineoplásicos , Simulação de Acoplamento Molecular , Quinolinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Quinolinas/química , Quinolinas/síntese química , Quinolinas/farmacologia , Células MCF-7 , Proliferação de Células/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Simulação por Computador , Células HCT116 , Linhagem Celular Tumoral , Relação Estrutura-Atividade
16.
Medicine (Baltimore) ; 103(27): e38459, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38968520

RESUMO

BACKGROUND: Maintenance therapy could significantly improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Anlotinib is effective, tolerable, and convenient in administration as a third-line treatment for NSCLC. This study aimed to evaluate the efficacy and safety of maintenance therapy with anlotinib after platinum-based induction chemotherapy for patients with advanced NSCLC. METHODS: This pooled analysis of 2 multicenter, open-label, single-arm, phase 2 clinical trials (ALTER-L014 and ALTER-L011) enrolled patients with locally advanced or metastatic NSCLC and without known sensitive mutations in China between September 2018 and January 2021. The primary outcome was progression-free survival. The secondary outcomes were objective response rate, disease control rate, overall survival, and safety. RESULTS: The data of 23 patients were pooled, with 15 from ALTER-L014 and 8 from ALTER-L011. At the cutoff date of June 13, 2021, the median progression-free survival since the start of maintenance therapy was 5.95 (95% confidence interval, 4.30-8.80) months. Nineteen patients had stable disease, 1 had a partial response and 3 had progressive disease. The objective response rate was 4.35%, while disease control rate was 86.96%. The median overall survival of the patients since the start of maintenance therapy was 18.60 (95% confidence interval, 6.87-22.80) months. The incidence of adverse events of grade ≥ 3 was 21.7%. CONCLUSION: Anlotinib might offer a new option for maintenance treatment in patients with locally advanced or metastatic NSCLC without known sensitive mutations after standard first-line platinum-based chemotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Indóis , Quimioterapia de Indução , Neoplasias Pulmonares , Quinolinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Indóis/uso terapêutico , Indóis/administração & dosagem , Indóis/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Idoso , Quimioterapia de Indução/métodos , Quimioterapia de Manutenção/métodos , Adulto , Intervalo Livre de Progressão , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
17.
Eur J Med Chem ; 275: 116561, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38870832

RESUMO

Quinolones, a key class of heterocyclics, are gaining popularity among organic and medicinal chemists due to their promising properties. Quinoline, with its broad spectrum of action, plays a primordial role in chemotherapy for cancer. Drugs include lenvatinib and its structural derivatives carbozantinib and bosutinib, and tipifarnib are the popular anticancer agents. Owing to the importance of quinoline, there are several classical methods for the synthesis such as, such as Gould-Jacobs, Conrad-Limpach, Camps cyclization, Skraup, Doebnervon Miller, Combes, Friedlander, Pfitzinger, and Niementowski synthesis. These methods are well-commended for developing an infinite variety of quinoline analogues. However, these procedures are associated with several drawbacks such as long reaction times, use of hazardous chemicals or stoichiometric proportions, difficulty of working up conditions, high temperatures, organic solvents, and the presence of numerous steps, all of which have an impact on the environment and the economy. As a result, researchers are working hard to develop green quinoline compounds in the hopes of making groundbreaking discoveries in the realm of cancer. In this review, we have highlighted significant research on quinoline-based compounds and their structure-activity relationship (SAR). Furthermore, because of the significant economic and environmental health and safety (EHS) concerns, more research is being dedicated to the green synthesis of quinolone derivatives. The current review offers recent advances in quinoline derivatives as anticancer agents for green synthesis using microwave, ultrasound, and one-pot synthesis. We believe that our findings will provide useful insight and inspire more green research on this framework to produce powerful and selective quinoline derivatives.


Assuntos
Antineoplásicos , Química Verde , Quinolinas , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Quinolinas/química , Quinolinas/síntese química , Quinolinas/farmacologia , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
18.
Eur J Med Chem ; 275: 116534, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38870830

RESUMO

Combination therapy proven to be an effective therapeutic approach for estrogen receptor (ER)-positive breast cancer. Currently, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are combined with aromatase inhibitors (AIs) or selective estrogen receptor degraders (SERDs) as first-line therapy for advanced ER-positive breast cancer. Herein, a new family of quinoline scaffold SERDs was synthesized and evaluated in MCF-7 cells. Among them, compounds 18j and 24d exhibited remarkable MCF-7 inhibition, both alone and in combination with ribociclib (CDK4/6 inhibitor), in vitro and in vivo. Meanwhile, compounds 18j and 24d effectively degraded ER and inhibited ER downstream signaling pathways. Interestingly, compounds 18j and 24d induced endoplasmic reticulum stress (ERS) and triggered immunogenic cell death (ICD) via damage-associated molecular patterns (DAMPs) in MCF-7 cells. These findings highlight the immune-related and enhanced antiproliferative effects of oral SERDs in ER positive breast cancer treatment.


Assuntos
Antineoplásicos , Neoplasias da Mama , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Quinolinas , Receptores de Estrogênio , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Quinolinas/farmacologia , Quinolinas/química , Quinolinas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Feminino , Receptores de Estrogênio/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Animais , Morte Celular Imunogênica/efeitos dos fármacos , Descoberta de Drogas , Relação Dose-Resposta a Droga , Células MCF-7 , Camundongos , Estresse do Retículo Endoplasmático/efeitos dos fármacos
19.
Mol Med Rep ; 30(2)2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38904207

RESUMO

Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triple­negative breast cancer MDA­MB­231 cells. By contrast, only zafirlukast induces G0/G1 cell cycle arrest. The present study compared the effects of these drugs on proteins regulating cell proliferation, apoptosis, autophagy, and endoplasmic reticulum (ER) and oxidative stress using reverse transcription­quantitative PCR, western blotting and flow cytometry. The expression of proliferating markers, Ki­67 and proliferating cell nuclear antigen, was decreased by both drugs. Zafirlukast, but not montelukast, decreased the expression of cyclin D1 and CDK4, disrupting progression from G1 to S phase. Zafirlukast also increased the expression of p27, a cell cycle inhibitor. Both drugs decreased the expression of anti­apoptotic protein Bcl­2 and ERK1/2 phosphorylation, and increased levels of the autophagy marker LC3­II and DNA damage markers, including cleaved PARP­1, phosphorylated (p)­ATM and p­histone H2AX. The number of caspase 3/7­positive cells was greater in montelukast­treated cells compared with zafirlukast­treated cells. Montelukast induced higher levels of the ER stress marker CHOP compared with zafirlukast. Montelukast activated PERK, activating transcription factor 6 (ATF6) and inositol­requiring enzyme type 1 (IRE1) pathways, while zafirlukast only stimulated ATF6 and IRE1 pathways. GSK2606414, a PERK inhibitor, decreased apoptosis mediated by montelukast, but did not affect zafirlukast­induced cell death. The knockdown of CHOP by small interfering RNA reduced apoptosis triggered by montelukast and zafirlukast. In conclusion, the effects on cell cycle regulator proteins may contribute to cell cycle arrest caused by zafirlukast. The greater apoptotic effects of montelukast may be caused by the higher levels of activated caspase enzymes and the activation of three pathways of ER stress: PERK, ATF6, and IRE1.


Assuntos
Acetatos , Apoptose , Autofagia , Ciclopropanos , Dano ao DNA , Estresse do Retículo Endoplasmático , Indóis , Quinolinas , Sulfetos , Sulfonamidas , Humanos , Sulfetos/farmacologia , Ciclopropanos/farmacologia , Quinolinas/farmacologia , Apoptose/efeitos dos fármacos , Acetatos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Linhagem Celular Tumoral , Autofagia/efeitos dos fármacos , Sulfonamidas/farmacologia , Indóis/farmacologia , Feminino , Dano ao DNA/efeitos dos fármacos , Fenilcarbamatos/farmacologia , Compostos de Tosil/farmacologia , Proliferação de Células/efeitos dos fármacos , eIF-2 Quinase/metabolismo , eIF-2 Quinase/genética , Endorribonucleases/metabolismo , Endorribonucleases/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo , Fator de Transcrição CHOP/genética , Ciclo Celular/efeitos dos fármacos , Antagonistas de Leucotrienos/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética
20.
Int J Biol Sci ; 20(8): 3046-3060, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38904018

RESUMO

Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. As a first-line treatment for advanced HCC, Lenvatinib has been applicated in clinic since 2018. Resistance to Lenvatinib, however, has severely restricted the clinical benefits of this drug. Therefore, it is urgent to explore the potential resistance mechanisms of Lenvatinib and identify appropriate methods to reduce resistance for the treatment of HCC. We identified SAHA, a HDAC inhibitor, to have effective anti-tumor activity against Lenvatinib-resistant HCC organoids by screening a customized drug library. Mechanism analysis revealed that SAHA upregulates PTEN expression and suppresses AKT signaling, which contributes to reversing Lenvatinib resistance in liver cancer cells. Furthermore, combinational application of Lenvatinib and HDAC inhibitor or AKT inhibitor synergistically inhibits HCC cell proliferation and induces cell apoptosis. Finally, we confirmed the synergistic effects of Lenvatinib and SAHA, or AZD5363 in primary liver cancer patient derived organoids. Collectively, these findings may enable the development of Lenvatinib combination therapies for HCC.


Assuntos
Carcinoma Hepatocelular , Inibidores de Histona Desacetilases , Neoplasias Hepáticas , Compostos de Fenilureia , Proteínas Proto-Oncogênicas c-akt , Quinolinas , Quinolinas/farmacologia , Compostos de Fenilureia/farmacologia , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Animais , Vorinostat/farmacologia , Sinergismo Farmacológico , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos
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