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1.
Int J Mol Sci ; 22(5)2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33803361

RESUMO

Radionuclide imaging of HER2 expression in tumours may enable stratification of patients with breast, ovarian, and gastroesophageal cancers for HER2-targeting therapies. A first-generation HER2-binding affibody molecule [99mTc]Tc-ZHER2:V2 demonstrated favorable imaging properties in preclinical studies. Thereafter, the affibody scaffold has been extensively modified, which increased its melting point, improved storage stability, and increased hydrophilicity of the surface. In this study, a second-generation affibody molecule (designated ZHER2:41071) with a new improved scaffold has been prepared and characterized. HER2-binding, biodistribution, and tumour-targeting properties of [99mTc]Tc-labelled ZHER2:41071 were investigated. These properties were compared with properties of the first-generation affibody molecules, [99mTc]Tc-ZHER2:V2 and [99mTc]Tc-ZHER2:2395. [99mTc]Tc-ZHER2:41071 bound specifically to HER2 expressing cells with an affinity of 58 ± 2 pM. The renal uptake for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 was 25-30 fold lower when compared with [99mTc]Tc-ZHER2:2395. The uptake in tumour and kidney for [99mTc]Tc-ZHER2:41071 and [99mTc]Tc-ZHER2:V2 in SKOV-3 xenografts was similar. In conclusion, an extensive re-engineering of the scaffold did not compromise imaging properties of the affibody molecule labelled with 99mTc using a GGGC chelator. The new probe, [99mTc]Tc-ZHER2:41071 provided the best tumour-to-blood ratio compared to HER2-imaging probes for single photon emission computed tomography (SPECT) described in the literature so far. [99mTc]Tc-ZHER2:41071 is a promising candidate for further clinical translation studies.


Assuntos
Antineoplásicos Imunológicos , Rim , Neoplasias Experimentais , Compostos Radiofarmacêuticos , Receptor ErbB-2/metabolismo , Tecnécio , Tomografia Computadorizada de Emissão de Fóton Único , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Rim/diagnóstico por imagem , Rim/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Tecnécio/química , Tecnécio/farmacocinética , Tecnécio/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Methods Mol Biol ; 2265: 363-376, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33704727

RESUMO

The lymph node microenvironment is extremely dynamic and responds to immune stimuli in the host by reprogramming immune, stromal, and endothelial cells. In normal physiological conditions, the lymph node will initiate an appropriate immune response to clear external threats that the host may experience. However, in metastatic disease, cancer cells often colonize local lymph nodes, disrupt immune function, and even leave the lymph node to create additional metastases. Understanding how cancer cells enter, colonize, survive, proliferate, and interact with other cell types in the lymph node is challenging. Here, we describe the use of photoconvertible fluorescent proteins to label and trace the fate of cancer cells once they enter the lymph node.


Assuntos
Rastreamento de Células , Proteínas de Fluorescência Verde/metabolismo , Linfonodos , Neoplasias Experimentais , Células Neoplásicas Circulantes , Imagem Óptica , Animais , Linhagem Celular Tumoral , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática , Camundongos , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Microambiente Tumoral
3.
Nat Commun ; 12(1): 1912, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771989

RESUMO

Glioblastoma (GB) is a highly invasive type of brain cancer exhibiting poor prognosis. As such, its microenvironment plays a crucial role in its progression. Among the brain stromal cells, the microglia were shown to facilitate GB invasion and immunosuppression. However, the reciprocal mechanisms by which GB cells alter microglia/macrophages behavior are not fully understood. We propose that these mechanisms involve adhesion molecules such as the Selectins family. These proteins are involved in immune modulation and cancer immunity. We show that P-selectin mediates microglia-enhanced GB proliferation and invasion by altering microglia/macrophages activation state. We demonstrate these findings by pharmacological and molecular inhibition of P-selectin which leads to reduced tumor growth and increased survival in GB mouse models. Our work sheds light on tumor-associated microglia/macrophage function and the mechanisms by which GB cells suppress the immune system and invade the brain, paving the way to exploit P-selectin as a target for GB therapy.


Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Macrófagos/metabolismo , Microglia/metabolismo , Selectina-P/genética , Animais , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Selectina-P/antagonistas & inibidores , Selectina-P/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
4.
Mol Cell ; 81(6): 1216-1230.e9, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33606996

RESUMO

Interferon-γ (IFN-γ)-mediated adaptive resistance is one major barrier to improving immunotherapy in solid tumors. However, the mechanisms are not completely understood. Here, we report that IFN-γ promotes nuclear translocation and phase separation of YAP after anti-PD-1 therapy in tumor cells. Hydrophobic interactions of the YAP coiled-coil domain mediate droplet initiation, and weak interactions of the intrinsically disordered region in the C terminus promote droplet formation. YAP partitions with the transcription factor TEAD4, the histone acetyltransferase EP300, and Mediator1 and forms transcriptional hubs for maximizing target gene transcriptions, independent of the canonical STAT1-IRF1 transcription program. Disruption of YAP phase separation reduced tumor growth, enhanced immune response, and sensitized tumor cells to anti-PD-1 therapy. YAP activity is negatively correlated with patient outcome. Our study indicates that YAP mediates the IFN-γ pro-tumor effect through its nuclear phase separation and suggests that YAP can be used as a predictive biomarker and target of anti-PD-1 combination therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Interferon gama/metabolismo , Neoplasias Experimentais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células HEK293 , Humanos , Interferon gama/genética , Camundongos , Camundongos Knockout , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Fatores de Transcrição/genética
5.
Eur J Med Chem ; 214: 113249, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33561608

RESUMO

Built upon the 4-acrylamido quinoline derivative 4, a previously discovered PI3K/mTOR dual inhibitor, structural modification was undertaken in this study with the attempt to improve its oral exposure via introducing steric hindrance to the 4-acrylamido functionality. Consequently, 14d, as the representative among the synthesized compounds, exhibited IC50 values of 0.80, 0.67, 1.30, 1.30 and 5.0 nM against PI3Kα, PI3Kß, PI3Kγ, PI3Kδ and mTOR, respectively. Besides, 14d displayed comparable anti-proliferative activity against both PC3 and U87MG cell lines to that of the positive reference GSK2126458 with respective GI50 value of 0.36 and 0.14 µM. Kinase selectivity assay showed that 14d was selective to PI3K family. In U87MG cells, 14d can strongly down-regulate PI3K/Akt/mTOR pathway via blocking both PI3K and mTOR signaling at the concentration as low as 25 nM. Importantly, following a PO dose of 5 mg/kg in male SD rats, 14d displayed favorable oral exposure (AUC0-t = 1336.16 h × ng/mL, AUC0-∞ = 1447.63 h × ng/mL) and high maximum plasma concentration (Cmax = 903.00 ng/mL). In a U87MG glioblastoma xenograft model, tumor growth inhibition of 93.5% and tumor regression were observed at PO dose of 30 and 60 mg/kg, respectively. Meanwhile, no overt loss of body weight was observed in the 14d-treated groups. Taken together, 14d, by virtue of its attractive performance, merits further development as a potential anti-tumor candidate.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Quinolinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Quinolinas/síntese química , Quinolinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismo
6.
Eur J Med Chem ; 214: 113256, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33581556

RESUMO

Multiple-target drugs may achieve better therapeutic effect via different pathways than single-target ones, especially for complex diseases. Tubulin and DNA are well-characterized molecular targets for anti-cancer drug development. A novel class of diaryl substituted 2H-azirines were designed based on combination of pharmacophores from Combretastatin A-4 (CA-4) and aziridine-type alkylating agents, which are known tubulin polymerization inhibitor and DNA damaging agents, respectively. The antitumor activities of these compounds were evaluated in vitro and 6h showed the most potent activities against four cancer cell lines with IC50 values ranging from 0.16 to 1.40 µM. Further mechanistic studies revealed that 6h worked as a bifunctional agent targeting both tubulin and DNA. In the nude mice xenograft model, 6h significantly inhibited the tumor growth with low toxicity, demonstrating the promising potential for further developing novel cancer therapy with a unique mechanism.


Assuntos
Antineoplásicos/farmacologia , Azirinas/farmacologia , DNA/efeitos dos fármacos , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Azirinas/síntese química , Azirinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
7.
ACS Appl Mater Interfaces ; 13(7): 8026-8041, 2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33577301

RESUMO

Photodynamic therapy (PDT) is a promising strategy for cancer treatment. It can not only generate reactive oxygen species (ROS) to cause the chemical damage of tumor cells in the presence of enough oxygen but also promote the antitumor immunity of T cells through enhancing the production of interferon γ (IFN-γ). However, one phenomenon is ignored so far that the enhanced production of IFN-γ caused by PDT may significantly increase the expression of programmed death-ligand 1 (PD-L1) on the tumor cell membrane and thus could inhibit the immune killing effects of T cells. Herein, we report the construction of a composite by loading metformin (Met) and IR775 into a clinically usable liposome as a two-in-one nanoplatform (IR775@Met@Lip) to solve this problem. The IR775@Met@Lip could reverse tumor hypoxia to enhance ROS production to elicit more chemical damage. Besides, the overexpression of PD-L1 by PDT was also effectively down-regulated. These therapeutic benefits including decreased PD-L1 expression, alleviated T cell exhaustion, and reversed tumor hypoxia successfully suppressed both the primary and abscopal tumor growth in bladder and colon cancers, respectively. Combining with its excellent biocompatibility, our results indicate that this IR775@Met@Lip system has great potential to become a highly effective cancer therapy modality.


Assuntos
Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Imunoterapia , Metformina/farmacologia , Fotoquimioterapia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Antígeno B7-H1/análise , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Indóis/química , Indóis/farmacologia , Lipossomos/química , Lipossomos/farmacologia , Masculino , Metformina/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Imagem Óptica , Tamanho da Partícula , Propriedades de Superfície , Hipóxia Tumoral/efeitos dos fármacos
8.
Nat Commun ; 12(1): 759, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536421

RESUMO

The malignancy of colorectal cancer (CRC) is connected with inflammation and tumor-associated macrophages (TAMs), but effective therapeutics for CRC are limited. To integrate therapeutic targeting with tumor microenvironment (TME) reprogramming, here we develop biocompatible, non-covalent channel-type nanoparticles (CNPs) that are fabricated through host-guest complexation and self-assemble of mannose-modified γ-cyclodextrin (M-γ-CD) with Regorafenib (RG), RG@M-γ-CD CNPs. In addition to its carrier role, M-γ-CD serves as a targeting device and participates in TME regulation. RG@M-γ-CD CNPs attenuate inflammation and inhibit TAM activation by targeting macrophages. They also improve RG's anti-tumor effect by potentiating kinase suppression. In vivo application shows that the channel-type formulation optimizes the pharmacokinetics and bio-distribution of RG. In colitis-associated cancer and CT26 mouse models, RG@M-γ-CD is proven to be a targeted, safe and effective anti-tumor nanomedicine that suppresses tumor cell proliferation, lesions neovascularization, and remodels TME. These findings indicate RG@M-γ-CD CNPs as a potential strategy for CRC treatment.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Nanopartículas/administração & dosagem , Neoplasias Experimentais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , gama-Ciclodextrinas/administração & dosagem , Animais , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Manose/química , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/química , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Compostos de Fenilureia/química , Piridinas/química , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , gama-Ciclodextrinas/química
9.
Nat Commun ; 12(1): 773, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536439

RESUMO

Macrophages are plastic and, in response to different local stimuli, can polarize toward multi-dimensional spectrum of phenotypes, including the pro-inflammatory M1-like and the anti-inflammatory M2-like states. Using a high-throughput phenotypic screen in a library of ~4000 FDA-approved drugs, bioactive compounds and natural products, we find ~300 compounds that potently activate primary human macrophages toward either M1-like or M2-like state, of which ~30 are capable of reprogramming M1-like macrophages toward M2-like state and another ~20 for the reverse repolarization. Transcriptional analyses of macrophages treated with 34 non-redundant compounds identify both shared and unique targets and pathways through which the tested compounds modulate macrophage activation. One M1-activating compound, thiostrepton, is able to reprogram tumor-associated macrophages toward M1-like state in mice, and exhibit potent anti-tumor activity. Our compound-screening results thus help to provide a valuable resource not only for studying the macrophage biology but also for developing therapeutics through modulating macrophage activation.


Assuntos
Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Produtos Biológicos/química , Linhagem Celular Tumoral , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Macrófagos/classificação , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Fenótipo , Células THP-1 , Tioestreptona/química , Tioestreptona/farmacologia
10.
Eur J Med Chem ; 212: 113019, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33429247

RESUMO

Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFRL858R/T790M inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC50 value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC50 value of 0.008 µM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFRL858R/T790M-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Masculino , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 212: 113142, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33450619

RESUMO

We established a large-scale separation and purification platform to obtain kilogram amounts of natural compounds from the extraction of the fruiting bodies of C. militaris. Seven monomeric compounds, N6-(2-hydroxyethyl) adenosine (HEA), ergosterol (E), ergosta-7,22-diene-3,5,6-triol (EI), 5α,8α-epidioxy-(22E,24R)-ergosta-6,22-dien-3ß-ol (ED),ergosta-7,22-dien-3ß,5α-dihydroxy-6-one (EO), (20S,22E,24R)-Eegosta-7,22-dien-3ß,5α,6ß,9α-tetraol (ET), and (24S)-5,22-stigmastadien-3ß-ol (SE), were harvested using different solvents, and the structure of each compound was identified. The activities and functions of the isolated compounds were tested by label-free, real-time cell analysis methods at the cellular level, and their antitumor effects were verified using mouse models of Lewis and H22 tumors. The anti-insomnia effect of HEA was tested in an anti-insomnia mouse model. The interactions between E and 8 A549 cell proteins were determined. The biosynthetic pathways of HEA and E, which possess pharmacologically active monomers, were determined. This platform can provide a theoretical basis for the further development and discovery of novel natural medicines.


Assuntos
Antineoplásicos/farmacologia , Cordyceps/química , Medicamentos de Ervas Chinesas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cordyceps/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Humanos , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 212: 113150, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33453602

RESUMO

Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valuable for further investigation.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Sulfonas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química , Células Tumorais Cultivadas
13.
Eur J Med Chem ; 213: 113163, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33482599

RESUMO

Discovering novel small molecules for cancer immunotherapy represents a promising but challenging strategy in future cancer treatment. Herein, we designed the first theranostic fluorescent probes to efficiently detect and inhibit the enzymatic activity of 2,3-dioxygenase 1 (IDO1). Probe 6b is a highly active IDO1 inhibitor (IC50 = 12 nM, Cellular IC50 = 10 nM), which can sensitively and specifically detect endogenous IDO1 in living cells. Furthermore, as a theranostic probe, 6b showed excellent in vivo antitumor efficacy in the CT26 xenograft mouse model as well. Therefore, it can be applied as a valuable chemical tool for better understanding the immunotherapy mechanism of IDO1 and improving the therapeutic efficiency.


Assuntos
Neoplasias do Colo/terapia , Inibidores Enzimáticos/farmacologia , Corantes Fluorescentes/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores , Neoplasias Experimentais/terapia , Bibliotecas de Moléculas Pequenas/farmacologia , Neoplasias do Colo do Útero/terapia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias Experimentais/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Nanomedicina Teranóstica , Neoplasias do Colo do Útero/metabolismo
14.
ACS Appl Mater Interfaces ; 13(5): 5999-6010, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33506682

RESUMO

Cellular FLIP (cFLIP) is a crucial player of apoptosis-regulated pathways that is frequently overexpressed in solid cancers. To inhibit c-FLIP, pre- and post-transcriptionally, a multifunctional nanoparticle (NP) was created to deliver cFLIP-specific small interfering RNA (siRNA) into cancer cells. Specifically, Vorinostat (Vor)-loaded mesoporous silica nanoparticles (MSN) were conjugated with polyethylenimine-biotin (PB), followed by electrostatically binding with cFLIP siRNA (Vor/siR@MSN-PB). To stabilize and prolong the circulation time of nanoparticles, a bialdehyde-modified poly(ethylene glycol) (PEG) was cross-linked onto the polyethylenimine (PEI) backbone via the formation of the imine linkage (Schiff base) (Vor/siR@MSN-PB-PEG). The Schiff base is highly stable at physiological pH 7.4 but labile under slightly acidic pH conditions. In the acidic tumor microenvironment (TME), the PEG outer layer could be rapidly cleaved, resulting in the switching of the nanoparticle surface charge to positive, which specifically enhances internalization of the NPs to the biotin-positive tumor cells. Our results demonstrated the successful preparation of Vor/siR@MSN-PB-PEG NPs, in which the siRNA was effectively protected in serum and regulated the expression of cFlip, post-transcriptionally. The presence of the PEG layer resulted in high tumor accumulation and high efficacy in tumor inhibition, which was a result of the efficient cFLIP suppression. Furthermore, in the low-dose regimen of Vorinostat-the pre-transcriptional cFLIP suppressor, treatment with Vor/siR@MSN-PB-PEG NPs was found to be safe with the treated mice, indicating a promising combination regimen for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/antagonistas & inibidores , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Nanopartículas/química , RNA Interferente Pequeno/farmacologia , Vorinostat/farmacologia , Animais , Antineoplásicos/química , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Polietilenoglicóis/química , RNA Interferente Pequeno/química , Propriedades de Superfície , Vorinostat/química
15.
Eur J Med Chem ; 210: 113080, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33310286

RESUMO

NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation.


Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Anilidas/síntese química , Anilidas/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Proteínas Repressoras/metabolismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
16.
Angew Chem Int Ed Engl ; 60(7): 3603-3610, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33314603

RESUMO

CD22, a member of Siglec family of sialic acid binding proteins, has restricted expression on B cells. Antibody-based agents targeting CD22 or CD20 on B lymphoma and leukemia cells exhibit clinical efficacy for treating these malignancies, but also attack normal B cells leading to immune deficiency. Here, we report a chemoenzymatic glycocalyx editing strategy to introduce high-affinity and specific CD22 ligands onto NK-92MI and cytokine-induced natural killer cells to achieve tumor-specific CD22 targeting. These CD22-ligand modified cells exhibited significantly enhanced tumor cell binding and killing in vitro without harming healthy B cells. For effective lymphoma cell killing in vivo, we further functionalized CD22 ligand-modified NK-92MI cells with the E-selectin ligand sialyl Lewis X to promote trafficking to bone marrow. The dual-functionalized cells resulted in the efficient suppression of B lymphoma in a xenograft model. Our results suggest that natural killer cells modified with glycan ligands to CD22 and selectins promote both targeted killing of B lymphoma cells and improved trafficking to sites where the cancer cells reside, respectively.


Assuntos
Células Matadoras Naturais/metabolismo , Linfoma de Células B/metabolismo , Engenharia Metabólica , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Animais , Configuração de Carboidratos , Linhagem Celular Tumoral , Células HEK293 , Humanos , Ligantes , Linfoma de Células B/terapia , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/terapia , Polissacarídeos/metabolismo
17.
Methods Mol Biol ; 2185: 241-258, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33165852

RESUMO

Acute myeloid leukemia (AML) is a highly frequent hematological malignancy, characterized by clinical and biological diversity, along with high relapse and mortality rates. The inherent functional and genetic intra-tumor heterogeneity in AML is thought to play an important role in disease recurrence and resistance to chemotherapy. Patient-derived xenograft (PDX) models preserve important features of the original tumor, allowing, at the same time, experimental manipulation and in vivo amplification of the human cells. Here we present a detailed protocol for the generation of fluorescently labeled AML PDX models to monitor cell proliferation kinetics in vivo, at the single-cell level. Although experimental protocols for cell proliferation studies are well established and widespread, they are not easily applicable to in vivo contexts, and the analysis of related time-series data is often complex to achieve. To overcome these limitations, model-driven approaches can be exploited to investigate different aspects of cell population dynamics. Among the existing approaches, the ProCell framework is able to perform detailed and accurate stochastic simulations of cell proliferation, relying on flow cytometry data. In particular, by providing an initial and a target fluorescence histogram, ProCell automatically assesses the validity of any user-defined scenario of intra-tumor heterogeneity, that is, it is able to infer the proportion of various cell subpopulations (including quiescent cells) and the division interval of proliferating cells. Here we explain the protocol in detail, providing a description of our methodology for the conditional expression of H2B-GFP in human AML xenografts, data processing by flow cytometry, and the final elaboration in ProCell.


Assuntos
Simulação por Computador , Leucemia Mieloide Aguda , Transplante de Neoplasias , Neoplasias Experimentais , Animais , Feminino , Xenoenxertos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia
18.
Mol Cell ; 81(4): 767-783.e11, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33333017

RESUMO

Chromatin is a barrier to efficient DNA repair, as it hinders access and processing of certain DNA lesions. ALC1/CHD1L is a nucleosome-remodeling enzyme that responds to DNA damage, but its precise function in DNA repair remains unknown. Here we report that loss of ALC1 confers sensitivity to PARP inhibitors, methyl-methanesulfonate, and uracil misincorporation, which reflects the need to remodel nucleosomes following base excision by DNA glycosylases but prior to handover to APEX1. Using CRISPR screens, we establish that ALC1 loss is synthetic lethal with homologous recombination deficiency (HRD), which we attribute to chromosome instability caused by unrepaired DNA gaps at replication forks. In the absence of ALC1 or APEX1, incomplete processing of BER intermediates results in post-replicative DNA gaps and a critical dependence on HR for repair. Hence, targeting ALC1 alone or as a PARP inhibitor sensitizer could be employed to augment existing therapeutic strategies for HRD cancers.


Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/metabolismo , Nucleossomos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , DNA Helicases/genética , Replicação do DNA/efeitos dos fármacos , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Proteínas de Ligação a DNA/genética , Recombinação Homóloga/efeitos dos fármacos , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Nucleossomos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/genética
19.
Pharm Res ; 37(10): 196, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32944844

RESUMO

PURPOSE: Hypoxia-inducible factor (HIF) is one of the critical components of the tumor microenvironment that is involved in tumor development. HIF-1α functionally and physically interacts with CDK1, 2, and 5 and stimulates the cell cycle progression and Cyclin-Dependent Kinase (CDK) expression. Therefore, hypoxic tumor microenvironment and CDK overexpression lead to increased cell cycle progression and tumor expansion. Therefore, we decided to suppress cancer cell expansion by blocking HIF-1α and CDK molecules. METHODS: In the present study, we used the carboxylated graphene oxide (CGO) conjugated with trimethyl chitosan (TMC) and hyaluronate (HA) nanoparticles (NPs) loaded with HIF-1α-siRNA and Dinaciclib, the CDK inhibitor, for silencing HIF-1α and blockade of CDKs in CD44-expressing cancer cells and evaluated the impact of combination therapy on proliferation, metastasis, apoptosis, and tumor growth. RESULTS: The results indicated that the manufactured NPs had conceivable physicochemical properties, high cellular uptake, and low toxicity. Moreover, combination therapy of cancer cells using CGO-TMC-HA NPs loaded with HIF-1α siRNA and Dinaciclib (SCH 727965) significantly suppressed the CDKs/HIF-1α and consequently, decreased the proliferation, migration, angiogenesis, and colony formation in tumor cells. CONCLUSIONS: These results indicate the ability of CGO-TMC-HA NPs for dual drug/gene delivery in cancer treatment. Furthermore, the simultaneous inhibition of CDKs/HIF-1α can be considered as a novel anti-cancer treatment strategy; however, further research is needed to confirm this treatment in vivo. Graphical Abstract The suppression of HIF-1α and CDKs inhibits cancer growth. HIF-1α is overexpressed by the cells present in the tumor microenvironment. The hypoxic environment elevates mitochondrial ROS production and increases p38 MAP kinase, JAK/STAT, ERK, JNK, and Akt/PI3K signaling, resulting in cyclin accumulation and aberrant cell cycle progression. Furthermore, the overexpression of HIF-1α/CDK results in increased expression of genes such as BCL2, Bcl-xl, Ki-67, TGFß, VEGF, FGF, MMP2, MMP9, and, HIF-1α and consequently raise the survival, proliferation, angiogenesis, metastasis, and invasion of tumor cells. In conclusion, HIF-1α-siRNA/Dinaciclib-loaded CGO-TMC-HA NPs can inhibit the tumor expansion by blockage of CDKs and HIF-1α (JAK: Janus kinase, STAT: Signal transducer and activator of transcription, MAPK: mitogen-activated protein kinase, ERK: extracellular signal-regulated kinase, JNK: c-Jun N-terminal kinase, PI3K: phosphatidylinositol 3-kinase).


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Experimentais/terapia , Compostos de Piridínio/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Quitosana/química , Grafite/química , Ácido Hialurônico/química , Camundongos , Nanopartículas/química , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Compostos de Piridínio/química , Compostos de Piridínio/farmacocinética , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética
20.
J Environ Pathol Toxicol Oncol ; 39(3): 247-260, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32865916

RESUMO

The anticancer activity of malvidin was studied in Dalton's lymphoma ascites (DLA)-induced solid and ascitic tumor mice models. Malvidin is a natural compound belonging to the family of O-methylated anthocyanidin and plays a predominant role in regulating both short- and long-term cellular activities. Animals were injected with DLA cells (1.5 × 106 cells/animal) to induce solid and ascitic tumors. The administration of malvidin (5 mg/kg bw and 10 mg/kg bw) was carried out for 10 consecutive days from the day of tumor induction for both solid and ascitic tumors. Cyclophosphamide, CTX (25 mg/kg bw), used as the standard drug, was also administered for 10 consecutive days. Treatment with malvidin showed a significant reduction in tumor volume and elevated white blood cell (WBC) count when compared to the DLA-bearing control animals. The treatment also maintained the body weight and hemoglobin level, and decreases in aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) were also noted. This investigation also reported the decreased levels of cellular glutathione (GSH) in ascitic tumor groups. Malvidin reduced inflammatory mediator and cytokine levels, such as tumor necrosis factor level alpha (TNF-α) and interleukin-6 (IL-6), which serve as molecular targets for cancer prevention. A decrease in the level of reactive oxygen species (ROS), like nitric oxide (NO), was observed. Histopathological examination revealed altered morphological changes in tumor tissue and the alleviation of hepatic architecture due to DLA. Immunohistochemical analysis revealed the inhibition of iNOS. This study demonstrated that malvidin exhibited significant in vivo antitumor activity and that it was reasonably imputable to its increasing endogenous mechanism. We accent the pertinence of malvidin as a potential naturally derived drug target for tumor control.


Assuntos
Antocianinas/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Ascite/tratamento farmacológico , Citocinas/sangue , Linfoma/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Animais , Antocianinas/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Ascite/metabolismo , Ascite/patologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Linfoma/metabolismo , Linfoma/patologia , Masculino , Camundongos , Transplante de Neoplasias , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Estresse Oxidativo/imunologia
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