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1.
Zhonghua Zhong Liu Za Zhi ; 42(8): 624-628, 2020 Aug 23.
Artigo em Chinês | MEDLINE | ID: mdl-32867452

RESUMO

Small cell lung cancer (SCLC), a special type of lung cancer, is a highly malignant neuroendocrine tumor with strong invasiveness and rapid progression. SCLC is sensitive to radiotherapy and chemotherapy, so radiotherapy and chemotherapy have been the main first-line treatment of SCLC. However, it is easy to develop drug resistance after treatment. Therefore, the study of anti-angiogenic therapy has attracted more and more attention. At present, anti-angiogenic drugs mainly focus on four categories: monoclonal antibodies (such as bevacizumab), endogenous angiogenesis inhibitors (such as endostar), anti-angiogenic fusion protein (such as aflibercept) and small molecular tyrosine kinase inhibitors (such as anlotinib). There are still some bottlenecks in the research and clinical application of antiangiogenic drugs. It is the right direction to explore better combination therapy and effective dual-field and multi-target drugs.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Neovascularização Patológica/patologia , Medicina de Precisão , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento
2.
Anticancer Res ; 40(9): 5049-5057, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878793

RESUMO

BACKGROUND/AIM: Studies with acridine compounds have reported anticancer effects. Herein, we evaluated the toxicity and antitumor effect of the (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a promising anticancer spiro-acridine compound. MATERIALS AND METHODS: The toxicity of AMTAC-06 was evaluated on zebrafish and mice. Antitumor activity was assessed in Ehrlich ascites carcinoma model. Effects on angiogenesis, cytokine levels and cell cycle were also investigated. RESULTS: AMTAC-06 did not induce toxicity on zebrafish and mice (LD50 approximately 5000 mg/kg, intraperitoneally). No genotoxicity was observed on micronucleus assay. AMTAC-06 significantly reduced the total viable Ehrlich tumor cells and increased sub-G1 peak, suggesting apoptosis was triggered. Moreover, the compound significantly decreased the density of peritumoral microvessels, indicating an anti-angiogenic action, possibly dependent on the cytokine modulation (TNF-α, IL-1ß and IFN-γ). No significant toxicological effects were recorded for AMTAC-06 on tumor transplanted animals. CONCLUSION: AMTAC-06 has low toxicity and a significant antitumor activity.


Assuntos
Acridinas/farmacologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Compostos de Espiro/farmacologia , Acridinas/química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/química , Imunomodulação/efeitos dos fármacos , Camundongos , Estrutura Molecular , Compostos de Espiro/química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
3.
Life Sci ; 259: 118183, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32781058

RESUMO

Cancer, being a multifactorial disease has diverse presentation in different subgroups which is mainly attributed to heterogenous presentation of tumor cells. This cancer cell heterogeneity is the major reason for variable response to standard chemotherapeutic regimes owing to which high relapse rate and multi-drug resistance has increasingly been reported over the past decade. Interestingly, the research on natural compounds in combination with standard therapies have reported with interesting and promising results from the pre-clinical trials and few of which have also been tested in other phases of clinical trials. This review focusses on baicalein, an emerging anti-cancerous natural compound, its chemistry and mechanism of action. In view of promising pre-clinical this review is mainly motivated by the results observed from baicalein treatment of different cancer cell population. With the advancing scientific evidence on the anti-malignant potential of baicalein with respect to its pharmacological activities encompassing from anti-inflammatory to anti-angiogenic/anti-metastatic effects, the focus is mainly directed to understanding the precise mechanism of action of baicalein. In the process of understanding the underlying signaling cascades, the role of mitogen activated protein kinase (MAPK), mammalian target of rapamycin (mTOR), AKT serine/threonine protein kinase B (AKT), poly(ADP-ribose) polymerase (PARP), matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9) and caspase-3/-8,-9 have been highlighted as the major players for baicalein anti-malignant potential. This is also supported by the interesting pre-clinical findings which cumulatively pave the way ahead for development of baicalein as an adjunct anti-cancer treatment with chemotherapeutic agents.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Flavanonas/farmacologia , Flavanonas/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Apoptose/efeitos dos fármacos , Humanos , Metástase Neoplásica/prevenção & controle , Neoplasias/patologia
4.
Int J Nanomedicine ; 15: 4523-4540, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606692

RESUMO

Purpose: Selenium nanoparticles (SeNP) have several applications in the field of biotechnology, including their use as anti-cancer drugs. The purpose of the present study is to analyze the efficacy of green synthesis on the preparation of SeNP and its effect on their anti-cancer properties. Methods: A bacterial strain isolated from a freshwater source was shown to efficiently synthesize SeNP with potential therapeutic properties. The quality and stability of the NP were studied by scanning electron microscopy, X-ray diffraction, zeta-potential and FTIR analysis. A cost-effective medium formulation from biowaste having 6% banana peel extract enriched with 0.25 mM tryptophan was used to synthesize the NP. The NP after optimization was used to analyze their anti-tumor and anti-angiogenic activity. For this purpose, first, the cytotoxicity of the NP against cancer cells was analyzed by MTT assay and then chorioallantoic membrane assay was performed to assess anti-angiogenic activity. Further, cell migration assay and clonogenic inhibition assay were performed to test the anti-tumor properties of SeNP. To assess the cytotoxicity of SeNP on healthy RBC, hemolysis assay was performed. Results: The strain identified as Pseudomonas stutzeri (MH191156) produced phenazine carboxylic acid, which aids the conversion of Se oxyanions to reduced NP state, resulting in particles in the size range of 75 nm to 200 nm with improved stability and quality of SeNP, as observed by zeta (ξ) potential of the particles which was found to be -46.2 mV. Cytotoxicity of the SeNP was observed even at low concentrations such as 5 µg/mL against cervical cancer cell line, ie, HeLa cells. Further, neovascularization was inhibited by upto 30 % in CAMs of eggs coinoculated with SeNp when compared with untreated controls, indicating significant anti-angiogenic activity of SeNP. The NP also inhibited the invasiveness of HeLa cells as observed by decreased cell migration and clonogenic proliferation. These observations indicate significant anti-tumor and anti-angiogenic activity of the SeNP in cervical cancer cells. Conclusion: P. stutzeri (MH191156) is an efficient source of Se NP production with potential anti-angiogenic and anti-tumor properties, particularly against cervical cancer cells.


Assuntos
Inibidores da Angiogênese/farmacologia , Nanopartículas Metálicas/química , Pseudomonas stutzeri/metabolismo , Selênio/farmacologia , Animais , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Embrião de Galinha , Custos e Análise de Custo , Feminino , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/ultraestrutura , Fenazinas/química , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Neoplasias do Colo do Útero/irrigação sanguínea , Neoplasias do Colo do Útero/patologia , Difração de Raios X
5.
Nat Commun ; 11(1): 3704, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709869

RESUMO

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRß-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRß ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.


Assuntos
Inibidores da Angiogênese/farmacologia , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/metabolismo , Neoplasias/tratamento farmacológico , Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Animais , Biomarcadores Tumorais , Pressão Sanguínea , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Permeabilidade Capilar , Proliferação de Células , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas , Transdução de Sinais/efeitos dos fármacos , Hipóxia Tumoral , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
J Nat Med ; 74(4): 732-740, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32643027

RESUMO

AG36 is a triterpenoid saponin from Ardisia gigantifolia stapf. Our recent studies proved that AG36 displayed prominent cytotoxicity against breast cancer cells both in vitro and in vivo. However, whether AG36 has antiangiogenic properties is unknown. Therefore, in the present study, we evaluated the antiangiogenic effect of AG36 and the underlying mechanism. The results indicated that AG36 could significantly inhibit the proliferation, migration and invasion of human umbilical vein endothelial cells (HUVEC). Further antiangiogenic molecular mechanism investigation showed that AG36 significantly suppressed phosphorylated FAK and AKT, and downregulated the expressions of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) in HUVECs. PI3K inhibitor (LY294002) and FAK inhibitor (PF562271) pretreatment could markedly enhance AG36-induced inhibition of HUVEC proliferation and p-FAK suppression, respectively. In addition, AG36 inhibited the tumor growth in xenograft model and expressions of p-VEGFR2 and p-Akt in vivo. Molecular docking simulation indicated that AG36 formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic potency and related underlying molecular of AG36, demonstrating that AG36 maybe a potential antiangiogenic cancer therapy agent or lead candidate.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Ardisia/química , Medicina Tradicional Chinesa/métodos , Saponinas/química , Inibidores da Angiogênese/farmacologia , Animais , Humanos
7.
Life Sci ; 256: 118011, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32592723

RESUMO

Melatonin is recognized as an anti-angiogenic agent, but its function in the tumor microenvironment especially in osteosarcoma remains uncertain. Among the selected miRNAs, miR-205, miR-424, miR-140, miR-106, and miR-519 were upregulated by melatonin in osteosarcoma cells. The functional role of miR-424-5p in osteosarcoma was further analyzed using miR-424-5p mimic/inhibitor. VEGFA mRNA and protein expression were altered by miR-424-5p mimic/inhibitor transfection with and without melatonin treatment and it was further identified that the VEGFA 3'UTR is directly targeted by miR-424-5p using the luciferase reporter gene system. The conditioned medium from SaOS2 and MG63 cells treated with melatonin and/or transfected with miR-424-5p mimic/inhibitor was exposed to endothelial cells, and cell proliferation and migration was analyzed. MG-63 and SaOS2 cells are also transfected with miR-424-5p inhibitors and positioned on CAM vascular bed to study the angiogenic activity at both morphological and molecular level under melatonin treatment. Our observations demonstrate for the first time that, melatonin upregulated the expression of miR-424-5p in osteosarcoma inhibiting VEGFA. Furthermore, it suppresses tumor angiogenesis, modulating surrounding endothelial cell proliferation and migration as well as the morphology of blood vessels, and angiogenic growth factors. These findings suggest that melatonin could play a pivotal role in tumor suppression via miR-424-5p/VEGFA axis.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Melatonina/farmacologia , Osteossarcoma/tratamento farmacológico , Animais , Neoplasias Ósseas/irrigação sanguínea , Linhagem Celular Tumoral , Galinhas , Gema de Ovo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Osteossarcoma/irrigação sanguínea , RNA Mensageiro/genética , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Int J Nanomedicine ; 15: 2717-2732, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368051

RESUMO

Background: Phototherapy is a potential new candidate for glioblastoma (GBM) treatment. However inadequate phototherapy due to stability of the photosensitizer and low target specificity induces the proliferation of neovascular endothelial cells for angiogenesis and causes poor prognosis. Methods: In this study, we constructed c(RGDfk)-modified glycolipid-like micelles (cRGD-CSOSA) encapsulating indocyanine green (ICG) for dual-targeting neovascular endothelial cells and tumor cells, and cRGD-CSOSA/ICG mediated dual effect of PDT/PTT with NIR irradiation. Results: In vitro, cRGD-CSOSA/ICG inhibited cell proliferation and blocked angiogenesis with NIR irradiation. In vivo, cRGD-CSOSA/ICG exhibited increased accumulation in neovascular endothelial cells and tumor cells. Compared with that of CSOSA, the accumulation of cRGD-CSOSA in tumor tissue was further improved after dual-targeted phototherapy pretreatment. With NIR irradiation, the tumor-inhibition rate of cRGD-CSOSA/ICG was 80.00%, significantly higher than that of ICG (9.08%) and CSOSA/ICG (42.42%). Histological evaluation showed that the tumor vessels were reduced and that the apoptosis of tumor cells increased in the cRGD-CSOSA/ICG group with NIR irradiation. Conclusion: The cRGD-CSOSA/ICG nanoparticle-mediated dual-targeting phototherapy could enhance drug delivery to neovascular endothelial cells and tumor cells for anti-angiogenesis and improve the phototherapy effect of glioblastoma, providing a new strategy for glioblastoma treatment.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Glioblastoma/terapia , Verde de Indocianina/administração & dosagem , Nanopartículas/administração & dosagem , Neovascularização Patológica/tratamento farmacológico , Fototerapia/métodos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Glioblastoma/patologia , Glicolipídeos/química , Humanos , Verde de Indocianina/química , Camundongos Nus , Micelas , Nanopartículas/química , Oligopeptídeos/química , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Chem Biol Interact ; 325: 109127, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32437695

RESUMO

Inhibition of mouse double minute 2 homolog (MDM2)-p53 interaction and reactivation of p53 signaling have been explored as effective anticancer therapeutic strategy. The potent and specific antitumor activity shown by Nutlins, first class of MDM2-p53 inhibitors discovered, has made these compounds potential antitumor candidates. To this end, we synthesized Nutlin-1 and Nutlin-2 analogs through molecular simplification and selected the compound with the most efficient antitumoral activity. Cytotoxicity of Nutlin-2 analog LQFM126 on B16F10 melanoma cells induced intense cytoplasmic vacuolization, reduction of cell size, chromatin condensation, cytoplasmic degeneration and nuclear fragmentation. LQFM126 antiproliferative effects mediated cell cycle retention in G0/G1 phase and increased the levels of cell cycle regulatory proteins p21 and p27. This Nutlin analog increased mitochondrial membrane potential, activated caspase-8, -9 and -3/7 and reduced VEGF levels in B16F10 cells. Therefore, LQFM126 promoted alterations suggestive of apoptosis, G0/G1 cell cycle arrest and suppression of angiogenesis through modulation of VEGF expression in B16F10 cells. Additionally, LQFM126 was classified as UN GHS category 4 (LD50 > 300-2000 mg/kg), suggesting it has low acute systemic toxicity. LQFM126 can be a promising prototype for anticancer therapy.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Melanoma Experimental/patologia , Pirazóis/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imidazóis/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Piperazinas/química , Pirazóis/síntese química , Pirazóis/química , Pirazóis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo
10.
Pharm Res ; 37(6): 91, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385723

RESUMO

PURPOSE: Bevacizumab (BCZ) is a recombinant monoclonal antibody that inhibits the biological activity of the vascular endothelial growth factor, which has an important role in angiogenesis for tumoral growth and progression. In this way, our objective was to develop chitosan-coated lipid-core nanocapsules functionalized with BCZ by an organometallic complex using gold-III. METHODS: The formulation was produced and characterized in relation to physicochemical characteristics. Furthermore, the antitumoral and antiangiogenic activities were evaluated against C6 glioma cell line and chicken embryo chorioallantoic membrane (CAM), respectively. RESULTS: Final formulation showed nanometric size, narrow polydispersity, positive zeta potential and gold clusters size lower than 2 nm. BCZ in aqueous solution (0.01-0.10 µmol L-1) did not show cytotoxic activity in vitro against C6 glioma cell line; although, MLNC-Au-BCZ showed cytotoxicity with a median inhibition concentration of 30 nmol L-1 of BCZ. Moreover, MLNC-Au-BCZ demonstrated cellular internalization dependent on incubation time and BCZ concentration. BCZ solution did not induce significant apoptosis as compared to MLNC-Au-BCZ within 24 h of treatment. CAM assay evidenced potent antiangiogenic activity for MLNC-Au-BCZ, representing a decrease of 5.6 times in BCZ dose comparing to BCZ solution. CONCLUSION: MLNC-Au-BCZ is a promising product for the treatment of solid tumors.


Assuntos
Inibidores da Angiogênese/química , Bevacizumab/química , Quitosana/química , Glioma/tratamento farmacológico , Ouro/química , Lipídeos/química , Nanocápsulas/química , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bevacizumab/metabolismo , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Embrião de Galinha , Membrana Corioalantoide/efeitos dos fármacos , Complexos de Coordenação/química , Relação Dose-Resposta a Droga , Composição de Medicamentos/métodos , Hexoses/química , Humanos , Lectinas de Plantas/química , Polissorbatos/química , Proteínas de Soja/química , Propriedades de Superfície , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
Medicine (Baltimore) ; 99(19): e20011, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384458

RESUMO

BACKGROUND: Glioblastoma is the most common malignant primary brain tumor which has highly expressed vascular endothelial growth factor. To date, various antiangiogenic drugs have been investigated in clinical trials but with no overall conclusion, especially for newly diagnosed glioblastoma (nGBM). In this study, Bayesian network meta-analysis will be used to conduct a comprehensive analysis of the results of different clinical trials, and assess the efficacy of different antiangiogenic drugs on nGBM. METHODS: In order to find more comprehensive information about the application of antiangiogenic drugs in nGBM patients, we searched the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials. We also reviewed their reference lists to avoid omissions. Cochrane risk of bias tool (V.1.4.3) and Stata (V.15.0) will be used to assess the methodological quality of this review. RESULTS: This study will provide reliable evidence for different antiangiogenic therapies in nGBM patients. CONCLUSION: We will evaluate the relative effectiveness of different antiangiogenic drugs and rank each intervention in nGBM patients through prognosis to provide decision-making reference on which method to choose for clinicians. PROTOCOL REGISTRATION NUMBER: CRD42019146537.


Assuntos
Inibidores da Angiogênese , Glioblastoma , Inibidores da Angiogênese/classificação , Inibidores da Angiogênese/farmacologia , Protocolos Clínicos , Glioblastoma/diagnóstico , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Humanos , Metanálise em Rede , Seleção de Pacientes , Prognóstico , Revisões Sistemáticas como Assunto , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/análise
12.
Medicine (Baltimore) ; 99(17): e19955, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32332680

RESUMO

The aim of this study was to identify any changes that occur in the retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) in patients with exudative age-related macular degeneration (AMD) during treatment with anti-vascular endothelial growth factor (VEGF) injections.Patients were enrolled in this retrospective study if they had exudative AMD, had received at least 3 injections of ranibizumab or aflibercept, and had a minimum of 12 months of follow-up. We analyzed the changes in the RNFL and GC-IPL using spectral-domain optical coherence tomography in rescan mode.Fifty-two eyes of 52 patients who had been treated with repeated anti-VEGF injections for exudative AMD were included. At the final visit, there was no significant between-group difference in best-corrected visual acuity or intraocular pressure. There was a significant decrease in central macular thickness in all groups (P < .05). There was a decrease in RNFL thickness that was only statistically significant in the ranibizumab group and when the ranibizumab or aflibercept groups were combined (P = .036 and .044, respectively). The thickness of the GC-IPL layer was significantly decreased in the aflibercept and total group (P = .035 and P = .048, respectively).The thicknesses of the RNFL and GC-IPL decreased in patients with exudative AMD who underwent repeated anti-VEGF injections.


Assuntos
Degeneração Macular/tratamento farmacológico , Retina/patologia , Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Pesos e Medidas , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ranibizumab/farmacologia , Ranibizumab/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Retina/fisiopatologia , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Crescimento do Endotélio Vascular/farmacologia
13.
Cancer Treat Rev ; 86: 102017, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32335505

RESUMO

When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.


Assuntos
Bevacizumab/administração & dosagem , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Bevacizumab/farmacologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Terapia de Alvo Molecular , Neoplasias/irrigação sanguínea , Neovascularização Patológica/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Life Sci ; 252: 117670, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32298741

RESUMO

Deregulation of angiogenesis is a key reason for tumor growth and progression. Several anti-angiogenic drugs in clinical practice attempt to normalize abnormal tumor vasculature. Unfortunately, these drugs are ineffective due to the development of resistance in patients after drug holidays. A sizable literature suggests that resistance to these anti-angiogenic drugs occurs due to various compensatory mechanisms of tumor angiogenesis. Therefore, we describe different compensatory mechanisms of tumor angiogenesis, and explain why intussusceptive angiogenesis (IA), is a crucial mechanism of compensatory angiogenesis in tumors which resist anti-VEGF (vascular endothelial growth factor) therapies. IA is often overlooked due to the scarcity of experimental models. Therefore, we examine data from existing experimental models and our novel ex-ovo model of angiogenesis in chick embryos, and explain the important genes and signaling pathways driving IA. Using bio-informatic analyses of major genes regulating conventional sprouting angiogenesis (SA) and intussusceptive angiogenesis, we provide fresh insights on the 'angiogenic switch' which regulates the transition from SA to IA. Finally, we examine the interplay between molecules regulating SA, IA, and molecules known to promote tumor progression. Based on these analyses, we conclude that intussusceptive angiogenesis (IA) is a promising therapeutic target for developing effective anti-cancer treatment regimes.


Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Animais , Embrião de Galinha , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/irrigação sanguínea , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
15.
World Neurosurg ; 139: e136-e143, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32251821

RESUMO

OBJECTIVE: Vasospasm after subarachnoid hemorrhage (SAH) plays a vital role in the development of delayed cerebral ischemia. Anti- vascular endothelial growth factor (VEGF) antibodies, like bevacizumab (BEV), may attenuate VEGF-stimulated angiogenesis, reduced vascular cell proliferation, and improve vasospasm after SAH. METHODS: Thirty-two adult male New Zealand white rabbits were randomly divided into 4 groups of 8 rabbits in each group: group 1 (control); group 2 (SAH); group 3 (SAH + vehicle); and group 4 (SAH + BEV). BEV (5 mg/kg, intraperitoneally) was administered 5 minutes after the intracisternal blood injection and continued for 72 hours once per day in the same dose for group 4. Animals were sacrificed 72 hours after SAH. Basilar artery cross-sectional areas, arterial wall thicknesses, and hippocampal degeneration scores were evaluated in all groups. RESULTS: VEGF is associated with the narrowing of the basilar artery. Treatment with BEV statistically significantly increased the cross-sectional area of the basilar artery when compared with the SAH and the vehicle groups. Basilar artery wall thicknesses in the BEV group was statistically significant smaller than in the SAH and vehicle groups. The hippocampal degeneration scores for the BEV and control groups were similar and significantly lower than those for the SAH and vehicle groups. CONCLUSIONS: Cellular proliferation and subsequent vessel wall thickening is a reason to delay cerebral ischemia and deterioration of the neurocognitive function. Intraperitoneal administration of BEV was found to attenuate cerebral vasospasm and prevent delayed cerebral ischemia and improve neurocognitive function after SAH in rabbits.


Assuntos
Inibidores da Angiogênese/farmacologia , Bevacizumab/farmacologia , Hemorragia Subaracnóidea/complicações , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Vasoespasmo Intracraniano/etiologia , Animais , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Masculino , Coelhos
16.
Nat Commun ; 11(1): 1204, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32139674

RESUMO

Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositides consumed during intracellular transduction of pro-angiogenic signals in endothelial cells (EC), thus harnessing the tumor's own production of excess stimulatory ligands to deplete adjacent ECs of the capacity to respond to these signals. Using zebrafish and human endothelial cells in vitro, we show ECs deficient in CDP-diacylglycerol synthase 2 are uniquely sensitive to increased vascular endothelial growth factor (VEGF) stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PIP2), resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling. Using murine tumor allograft models, we show that systemic or EC specific suppression of phosphoinositide recycling results in reduced tumor growth and tumor angiogenesis. Our results suggest inhibition of phosphoinositide recycling provides a useful anti-angiogenic approach.


Assuntos
Inibidores da Angiogênese/farmacologia , Endotélio Vascular/metabolismo , Fosfatidilinositóis/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Aloenxertos/efeitos dos fármacos , Animais , Bovinos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diacilglicerol Colinofosfotransferase/deficiência , Diacilglicerol Colinofosfotransferase/metabolismo , Endotélio Vascular/efeitos dos fármacos , Deleção de Genes , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos Knockout , Modelos Biológicos , Neovascularização Fisiológica/efeitos dos fármacos , Especificidade de Órgãos , Transdução de Sinais , Peixe-Zebra
17.
Life Sci ; 247: 117402, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32035930

RESUMO

AIMS: Gastric cancer (GC) is one of the most common malignant tumors in the world. Anti-angiogenic therapy is a useful strategy for the treatment of advanced GC. This study was aimed to systemically compare the anti-angiogenesis, anti-cancer efficacy, as well as the safety of four known anti-angiogenic drugs, namely ramucirumab, apatinib, regorafenib and cabozantinib. MAIN METHODS: Anti-angiogenic effect was evaluated for the intersegmental vessels (ISVs) and subintestinal veins (SIVs) formation in the Tg (fli-1: EGFP) zebrafish embryos. Anti-cancer efficacy was tested for the in vivo cell proliferation in cell line derived tumor xenograft (CDX) model based on Tg (fli-1: EGFP) zebrafish embryos. KEY FINDINGS: All four drugs exhibited anti-angiogenic abilities and tumor inhibition effects in fli-1: EGFP transgenic zebrafish. Using zebrafish xenografted model, we found that effectiveness of ramucirumab in anti-GC-proliferation is better than apatinib, regorafenib and cabozantinib. The combination of anti-angiogenic drugs and cisplatin showed no significant benefit in tumors. Meanwhile, toxicity assay showed that all tested anti-angiogenic drugs could cause cardiovascular-related side effects. The therapeutic index (LD50/ED50) of cabozantinib is higher than apatinib and regorafenib, suggesting a potential as an anti-GC drug. SIGNIFICANCE: The comparison of GC-related anti-angiogenic drugs was first reported. It was found that cabozantinib had a potential as an anti-GC drug. Zebrafish model was an ideal animal model for the research of anti-angiogenic behaviors.


Assuntos
Inibidores da Angiogênese/farmacologia , Anilidas/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Feminino , Masculino , Neovascularização Fisiológica/efeitos dos fármacos , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/tratamento farmacológico , Peixe-Zebra/embriologia
18.
Microvasc Res ; 129: 103986, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32017943

RESUMO

Wet age-related macular degeneration (AMD) and diabetic retinopathy are the leading causes of blindness through increased angiogenesis. Although VEGF-neutralizing proteins provide benefit, inconsistent responses indicate a need for new therapies. We previously identified the Fibulin-7 C-terminal fragment (Fbln7-C) as an angiogenesis inhibitor in vitro. Here we show that Fbln7-C inhibits neovascularization in vivo, in both a model of wet AMD involving choroidal neovascularization (CNV) and diabetic retinopathy involving oxygen-induced ischemic retinopathy. Furthermore, a short peptide sequence from Fbln7-C is responsible for the anti-angiogenic properties of Fbln7-C. Our work suggests Fbln7-C as a therapeutic candidate for wet AMD and ischemic retinopathy.


Assuntos
Inibidores da Angiogênese/farmacologia , Proteínas de Ligação ao Cálcio/farmacologia , Corioide/irrigação sanguínea , Neovascularização de Coroide/prevenção & controle , Fragmentos de Peptídeos/farmacologia , Neovascularização Retiniana/prevenção & controle , Vasos Retinianos/efeitos dos fármacos , Degeneração Macular Exsudativa/prevenção & controle , Animais , Proteínas de Ligação ao Cálcio/síntese química , Proteínas de Ligação ao Cálcio/genética , Neovascularização de Coroide/genética , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/síntese química , Neovascularização Retiniana/genética , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Degeneração Macular Exsudativa/genética , Degeneração Macular Exsudativa/metabolismo , Degeneração Macular Exsudativa/patologia
19.
Cancer Genomics Proteomics ; 17(2): 131-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32108035

RESUMO

BACKGROUND/AIM: Pazopanib (PAZ) can inhibit tumor progression, but whether PAZ inhibits lymph node metastasis and lymphangiogenesis in colorectal cancer is still unknown. The aim of the present study was to determine the efficacy of PAZ on tumor growth, lymph node metastasis and lymphangiogenesis in an orthotopic nude mouse model in colorectal cancer. MATERIALS AND METHODS: CT-26-green fluorescence protein (GFP)-expressing mouse colon cancer cells were injected into nude mice to establish a subcutaneous colorectal cancer model and were treated with saline and PAZ. Additionals subcutaneous tumors were harvested and cut into 5 mm3 fragments, then tumor fragments were implanted orthotopically in the cecum to establish an orthotopic colorectal-cancer nude mouse model. Orthotopic mice were randomized into two groups for the treatment with saline and PAZ, respectively. Tumor width, length and mouse body weight was measured twice a week. The Fluor Vivo imaging system was used to image the GFP. Hematoxylin & eosin staining and immunohistochemical staining was used for histological analysis. RESULTS: PAZ inhibited the growth of subcutaneous colorectal cancer, as wells as orthotopic transplanted colorectal cancer tumors. PAZ suppressed lymph node metastasis and lymphangiogenesis in the orthotopic colon cancer model. No significant changes were observed in the body weight between the control and the mice treated with PAZ. CONCLUSION: PAZ can inhibit the growth of colorectal cancer and inhibit lymph node metastasis and lymphangiogenesis in orthotopic colon cancer nude mouse models.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Linfangiogênese/efeitos dos fármacos , Metástase Linfática/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Nus , Pirimidinas/farmacologia , Sulfonamidas/farmacologia
20.
Mol Biol Rep ; 47(3): 2279-2288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32040707

RESUMO

Liver fibrosis affects over 100 million people in the world; it represents a multifactorial, fibro-inflammatory disorder characterized by exacerbated production of extracellular matrix with consequent aberration of hepatic tissue. The aetiology of this disease is very complex and seems to involve a broad spectrum of factors including the lifestyle, environment factors, genes and epigenetic changes. More evidences indicate that angiogenesis, a process consisting in the formation of new blood vessels from pre-existing vessels, plays a crucial role in the progression of liver fibrosis. Central to the pathogenesis of liver fibrosis is the hepatic stellate cells (HSCs) which represent a crossroad among inflammation, fibrosis and angiogenesis. Quiescent HSCs can be stimulated by a host of growth factors, pro-inflammatory mediators produced by damaged resident liver cell types, as well as by hypoxia, contributing to neoangiogenesis, which in turn can be a bridge between acute and chronic inflammation. As matter of fact, studies demonstrated that neutralization of vascular endothelial growth factor as well as other proangiogenic agents can attenuate the progression of liver fibrosis. With this review, our intent is to discuss the cause and the role of angiogenesis in liver fibrosis focusing on the current knowledge about the impact of anti-angiogenetic therapies in this pathology.


Assuntos
Cirrose Hepática/patologia , Neovascularização Patológica , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças , Biomarcadores Ambientais , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Terapia de Alvo Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo
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