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1.
Anticancer Res ; 40(1): 229-238, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892571

RESUMO

BACKGROUND/AIM: We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells. MATERIALS AND METHODS: Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel. RESULTS: Curcumin combined with Rau 008 elicited marked cytotoxic effects in MCF-7 cells compared with the individual treatments, whereas when it was combined with Rau 015 and with Rau 018, it displayed similar effects in MDA-MB-231 cells. The anti-angiogenic effect of Rau 015 plus curcumin in MCF-7 cells and Rau 018 plus curcumin in MDA-MB-231 cells was more effective than individual treatments, while the metastatic capability of MDA-MB-231 cells was significantly reduced after treatment with the aminonaphthoquinone-curcumin combinations. CONCLUSION: Aminonaphthoquinones may offer significant promise as therapeutic agents against breast cancer, particularly when combined with curcumin.


Assuntos
Neoplasias da Mama/patologia , Curcumina/farmacologia , Progressão da Doença , Naftoquinonas/farmacologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/química , Curcumina/uso terapêutico , Matriz Extracelular/metabolismo , Feminino , Humanos , Células MCF-7 , Naftoquinonas/química , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Anticancer Res ; 40(1): 121-132, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892560

RESUMO

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (pNETs) are rare pancreatic neoplasms, and therapeutic options for pNETs are limited. Metformin is an anti-hypoglycemic drug that appears to have anticancer effects. However, little is known about the effect of metformin on pNETs. In this study, we investigated the anti-proliferative effect of metformin on a human pNET cell line. MATERIALS AND METHODS: The anti-proliferative properties of metformin were evaluated in QGP-1 and NCI-H727 cells using a cell counting kit-8 assay. Xenograft mouse models were used to assess the tumor effect in vivo. RESULTS: Metformin inhibited the proliferation and anti-tumor growth of QGP-1 cells, accompanied by their arrest during the cell cycle at the G0/G1 phase. Immunohistochemical analysis of tumor tissues revealed down-regulation of cyclin D1 and proliferating cell nuclear antigen in the metformin-treated group. Additionally, metformin induced apoptosis, and the expression of survivin and claspin were decreased in metformin-treated QGP-1 cells according to the apoptosis array. Furthermore, the angiogenic related protein TIMP-1 was down-regulated, and its miRNA expression was altered by metformin in QGP-1 cells. CONCLUSION: Taken together, our study demonstrated the therapeutic potential of metformin and provides molecular mechanistic insights into its anti-tumoral effect on pNETs. This study is the first one describing anti-tumoral effects in pNETs.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Metformina/farmacologia , Biomarcadores , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , MicroRNAs/genética , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Int J Cancer ; 146(6): 1730-1740, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31840816

RESUMO

Immune checkpoint blockade (ICB) has shown long-term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show that anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) treatment-induced tumor vessel normalization was accompanied by an increased infiltration of eosinophils into breast tumors. Eosinophil accumulation was positively correlated with the responsiveness of a breast tumor to anti-CTLA4 therapy. Depletion of eosinophils subsequently negated vessel normalization, reduced antitumor immunity and attenuated tumor growth inhibition by anti-CTLA4 therapy. Moreover, intratumoral accumulation of eosinophils relied on T lymphocytes and interferon γ production. Together, these results suggest that eosinophils partially mediate the antitumor effects of CTLA4 blockade through vascular remodeling. Our findings uncover an unidentified role of eosinophils in anti-CTLA4 therapy, providing a potential new target to improve ICB therapy and to predict its efficacy.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Antígeno CTLA-4/antagonistas & inibidores , Eosinófilos/efeitos dos fármacos , Eosinófilos/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores , Linhagem Celular Tumoral , Eosinófilos/imunologia , Feminino , Humanos , Imunidade , Imunomodulação/efeitos dos fármacos , Imunofenotipagem , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Depleção Linfocítica , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Life Sci ; 239: 117018, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678280

RESUMO

Angiogenesis-targeted therapy of cancer is considered a promising strategy for therapeutic management of cancer progression. Over the last two decades, a few anti-angiogenesis monoclonal antibodies (mAbs) blocking VEGF signaling have been developed and approved by the FDA. The most widely used anti-angiogenesis drug is bevacizumab which binds VEGFA and prevents its interaction with VEGF receptor leading to suppression of angiogenesis. Despite the remarkable success in development of angiogenesis inhibitory mAbs, their clinical application is limited by the high-cost of mAbs-based regimen which includes multiple doses of mAbs due to their short biological half-life. Antibody gene therapy is an alternative system of antibody production. In this study, we have developed a gene-based anti-VEGF mAb system which is expected to produce a high concentration of anti-VEGFA mAb upon a single administration in cancer patients. The full-length cDNA bevacizumab light and heavy chains joint with T2A sequence were cloned in pCDH lentivirus vector. The lentiviral particles expressing bevacizumab was produced in HEK-293T cells. Recombinant lentiviral particles containing bevacizumab (rLV-bev) efficiently transduced HEK-293cells and produced functional bevacizumab mAb. Bevacizumab expression in the transduced cell was assessed by qRT-PCR and western blot at both the mRNA and protein level, respectively. The functionality of the recombinant bevacizumab was confirmed using the tube formation assay in the co-culture system of endothelial cells and HT-29cells transduced with rLV-bev viral particles. Our results show that rLV-bev gene therapy can be useful for angiogenesis-targeted therapy of cancer.


Assuntos
Terapia Genética/métodos , Neoplasias/genética , Neoplasias/terapia , Neovascularização Patológica/genética , Neovascularização Patológica/terapia , Anticorpos Monoclonais/uso terapêutico , Bevacizumab/farmacologia , Células Endoteliais/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Células HT29 , Humanos , Lentivirus/genética , Microtúbulos/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
5.
Expert Opin Ther Pat ; 29(12): 987-1009, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31722579

RESUMO

Introduction: The ubiquitously expressed 37 kDa/67 kDa high-affinity laminin receptor (laminin receptor precursor/laminin receptor, LRP/LR) is a protein found to play several roles within cells. The receptor is located in the nucleus, cytosol and the cell surface. LRP/LR mediates cell proliferation, cell adhesion and cell differentiation. As a result, it is seen to enhance tumor angiogenesis as well as invasion and adhesion, key steps in the metastatic cascade of cancer. Recent findings have shown that LRP/LR is involved in the maintenance of cell viability through apoptotic evasion, allowing for tumor progression. Thus, several patented therapeutic approaches targeting the receptor for the prevention and treatment of cancer have emerged.Areas covered: The several roles that LRP/LR plays in cancer progression as well as an overview of the current therapeutic patented strategies targeting LRP/LR and cancer to date.Expert opinion: Small molecule inhibitors, monoclonal antibodies and small interfering RNAs might act used as powerful tools in preventing tumor angiogenesis and metastasis through the induction of apoptosis and telomere erosion in several cancers. This review offers an overview of the roles played by LRP/LR in cancer progression, while providing novel patented approaches targeting the receptor as potential therapeutic routes for the treatment of cancer as well as various other diseases.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Receptores de Laminina/antagonistas & inibidores , Proteínas Ribossômicas/antagonistas & inibidores , Animais , Progressão da Doença , Desenho de Drogas , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Patentes como Assunto , Receptores de Laminina/metabolismo , Proteínas Ribossômicas/metabolismo
6.
Int J Nanomedicine ; 14: 7643-7663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31571869

RESUMO

Angiogenesis is the formation of new blood vessels from pre-existing vessels. It is a highly regulated process as determined by the interplay between pro-angiogenic and anti-angiogenic factors. Under certain conditions the balance between angiogenesis stimulators and inhibitors is altered, which results in a shift from physiological to pathological angiogenesis. Therefore, the goal of therapeutic targeting of angiogenic process is to normalize vasculature in target tissues by enhancing angiogenesis in disease conditions of reduced vascularity and blood flow, such as tissue ischemia, or alternatively to inhibit excessive and abnormal angiogenesis in disorders like cancer. Gold nanoparticles (AuNPs) are special particles that are generated by nanotechnology and composed of an inorganic core containing gold which is encircled by an organic monolayer. The ability of AuNPs to alter vasculature has captured recent attention in medical literature as potential therapeutic agents for the management of pathologic angiogenesis. This review provides an overview of the effects of AuNPs on angiogenesis and the molecular mechanisms and biomedical applications associated with their effects. In addition, the main synthesis methods, physical properties, uptake mechanisms, and toxicity of AuNPs are briefly summarized.


Assuntos
Tecnologia Biomédica/métodos , Ouro/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Endocitose , Ouro/toxicidade , Humanos , Nanopartículas Metálicas/toxicidade
7.
Chem Soc Rev ; 48(21): 5381-5407, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31495856

RESUMO

The ever-growing use of inorganic nanoparticles (NPs) in biomedicine provides an exciting approach to develop novel imaging and drug delivery systems, owing to the ease with which these NPs can be functionalized to cater to various applications. In cancer therapeutics, nanomedicine generally relies on the enhanced permeability and retention (EPR) effect observed in tumour vasculature to deliver anti-cancer drugs across the endothelium. However, such a phenomenon is dependent on the tumour microenvironment and is not consistently observed in all tumour types, thereby limiting drug transport to the tumour site. On the other hand, there is a rise in utilizing inorganic NPs to intentionally induce endothelial leakiness, creating a window of opportunity to control drug delivery across the endothelium. While this active targeting approach creates a similar phenomenon compared to the EPR effect arising from tumour tissues, its drug delivery applications extend beyond cancer therapeutics and into other vascular-related diseases. In this review, we summarize the current findings of the EPR effect and assess its limitations in the context of anti-cancer drug delivery systems. While the EPR effect offers a possible route for drug passage, we further explore alternative uses of NPs to create controllable endothelial leakiness within short exposures, a phenomenon we coined as nanomaterial-induced endothelial leakiness (NanoEL). Furthermore, we discuss the main mechanistic features of the NanoEL effect that make it unique from conventionally established endothelial leakiness in homeostatic and pathologic conditions, as well as examine its potential applicability in vascular-related diseases, particularly cancer. Therefore, this new paradigm changes the way inorganic NPs are currently being used for biomedical applications.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Nanomedicina , Nanopartículas/química , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias/patologia , Neovascularização Patológica/patologia
8.
Int J Nanomedicine ; 14: 6357-6369, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496691

RESUMO

Background: Diabetic retinopathy (DR) is a complication of diabetes that affects the eyes and vision. It is a leading cause of visual impairment and blindness in working-age people. Vascular endothelial growth factor-A (VEGF-A) is a primary initiator and potential mediator of DR. Matrix metalloproteinase-9 (MMP-9) plays a progressive role in the onset and severity of DR. Interleukin-12 (IL-12) is a cytokine of the chemokine family that could reduce the levels of MMP-9 and VEGF-A and suppress tumor angiogenesis. We hypothesize that IL-12 may also have superior therapeutic efficacy against DR. However, protein drugs are prone to degradation by various proteases after drug injection. Therefore, they have short half-lives and low blood concentrations. The objective of this study was to develop IL-12-loaded nanoparticles for long-term and sustained DR treatment. Methods: IL-12-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (IL-12-PNP) were developed by double emulsion. The characteristics, anti-DR activity, and mechanisms of IL-12-PNP were examined in vitro and in vivo. Results: The nanoparticles had suitable particle size (~132.8 nm), drug encapsulation efficiency (~34.7%), and sustained drug release profile. Compared with IL-12 and blank nanoparticles, IL-12-PNP showed better inhibitory efficacy against VEGF-A and MMP-9 expression in rat endothelial cells and DR mouse retina. Intraocular IL-12-PNP administration significantly reduced retinal damage in DR mice as they presented with increased thickness and decreased neovascularization after treatment. Conclusion: These data indicate that IL-12-PNP is an effective drug delivery platform for DR therapy. It restores the thickness and reduces neovascularization of the retinas of DR mice.


Assuntos
Retinopatia Diabética/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Interleucina-12/administração & dosagem , Interleucina-12/uso terapêutico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Preparações de Ação Retardada/farmacologia , Retinopatia Diabética/patologia , Células Endoteliais/metabolismo , Injeções Intravítreas , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Nanopartículas/ultraestrutura , Neovascularização Patológica/tratamento farmacológico , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Curr Top Med Chem ; 19(22): 2069-2078, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31385773

RESUMO

BACKGROUND: Disintegrins from snake venoms bind with high specificity cell surface integrins, which are important pharmacological targets associated with cancer development and progression. OBJECTIVE: In this study, we isolated a disintegrin from the Porthidium lansbergii lansbergii venom and evaluated its antitumoral effects on breast cancer cells. METHODS: The isolation of the disintegrin was performed on RP-HPLC and the inhibition of platelet aggregation was evaluated on human platelet-rich plasma. The inhibition of cell adhesion was also evaluated in vitro on cultures of cell lines by the MTT method as well as the inhibition of breast cancer cell migration by the wound healing assay. The binding of the disintegrin to integrin subunits was verified by flow cytometry and confocal microscopy. Finally, inhibition of angiogenesis was assessed in vitro on HUVEC cells and the concentration of VEGF was measured in the cellular supernatants. RESULTS: The disintegrin, named Lansbermin-I, is a low molecular weight protein (< 10 kDa) that includes an RGD on its sequence identified previously. Lansbermin-I showed potent inhibition of ADP and collagen-induced platelet aggregation on human plasma and also displayed inhibitory effects on the adhesion and migration of breast cancer MCF7 and MDA-MB 231cell lines, without affecting nontumorigenic breast MCF-10A and lung BEAS cells. Additionally, Lansbermin-I prevented MCF7 cells to adhere to fibronectin and collagen, and also inhibited in vitro angiogenesis on human endothelial HUVEC cells. CONCLUSION: Our results display the first report on the antitumor and anti-metastatic effects of an RGDdisintegrin isolated from a Porthidium snake venom by possibly interfering with α2 and/or ß1-containing integrins. Thus, Lansbermin-I could be an attractive model to elucidate the role of disintegrins against breast cancer development.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Venenos de Crotalídeos/farmacologia , Desintegrinas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Venenos de Crotalídeos/química , Venenos de Crotalídeos/isolamento & purificação , Desintegrinas/química , Desintegrinas/isolamento & purificação , Relação Dose-Resposta a Droga , Feminino , Humanos , Integrinas/análise , Integrinas/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Relação Estrutura-Atividade , Viperidae , Cicatrização/efeitos dos fármacos
11.
Phytother Res ; 33(11): 2849-2861, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31407422

RESUMO

Silymarin is a complex extract isolated from the plant Silybum marianum, widely known for its prominent antioxidant and hepatoprotective effects, although increasing evidences have reported extraordinary antiproliferative and apoptotic abilities. As a result, several signaling pathways involved in cell cycle control, cell proliferation, and cell death have been deconvoluted as critical mechanisms. In this regard, cyclin and cyclin-dependent pathways have been the most studied ones. Following that, apoptotic pathways, such as p53, Akt, STAT-3, Ras, and caspases pathways, have been extensively studied, although other mechanisms involved in inflammation and angiogenesis have also been highlighted as silymarin-likely targets in cancer therapy. Therefore, the main challenge of this review is to discuss the diverse molecular mechanisms for silymarin antiproliferative and apoptotic effects; most of them largely studied in various types of cancers so far. Clinical trials and combination therapies related to silymarin application in cancer prevention and treatment are presented as well.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias/patologia , Silimarina/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Humanos , Cardo Mariano/química , Neoplasias/classificação , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Silimarina/uso terapêutico
12.
Future Oncol ; 15(22): 2571-2576, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31407939

RESUMO

Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases. It inhibits VEGF-induced VEGFR2 phosphorylation, endothelial cell proliferation and tubule formation. Currently, it has been approved for the treatment of metastatic colorectal cancer in patients who have failed at least two prior systemic antineoplastic therapies in China. However, it is not approved outside China, and there is another similar small molecular VEGFR multitarget drug approved in China, USA, Europe, etc. Here, we summarize the mechanism characteristics and clinical development of fruquintinib supporting its use in the treatment of metastastic colorectal cancer as well as explorations in other tumor types.


Assuntos
Benzofuranos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Inibidores da Angiogênese/uso terapêutico , Proliferação de Células/efeitos dos fármacos , China , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Europa (Continente) , Humanos , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Fosforilação/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética
13.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370155

RESUMO

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.


Assuntos
Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Sobrevivência Celular/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/crescimento & desenvolvimento , Helicobacter pylori/patogenicidade , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Inativação Metabólica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Microambiente Tumoral/efeitos dos fármacos
14.
Molecules ; 24(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370204

RESUMO

Some polyphenols have been shown to inhibit, at physiological levels, the VEGF-induced VEGF receptor-2 signaling that causes angiogenesis, allegedly by direct interaction with VEGF and reducing the binding to its receptor VEGFR2. Surface plasmon resonance was used to measure the parameters of binding between VEGF and polyphenols as well as the nature of the interactions by assessing the effect of physico-chemical changes in the solution. CD spectrometry was used to determine any change in the secondary structure of the protein upon binding. The kinetic parameters (ka, kd, and KD) that characterise the binding to VEGF were measured for both inhibitor and non-inhibitor polyphenolic molecules. The effect of changes in the physico-chemical conditions of the solution where the binding occurred indicated that the nature of the interactions between VEGF and EGCG was predominantly of a hydrophobic nature. CD studies suggested that a change in the secondary structure of the protein occurred upon binding. Direct interaction and binding between VEGF and polyphenol molecules acting as inhibitors of the signaling of VEGFR2 has been measured for the first time. The binding between VEGF and EGCG seemed to be based on hydrophobic interactions and caused a change in the secondary structure of the protein.


Assuntos
Neovascularização Patológica/tratamento farmacológico , Polifenóis/química , Fator A de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Catequina/análogos & derivados , Catequina/química , Catequina/farmacologia , Proliferação de Células/efeitos dos fármacos , Dicroísmo Circular , Flavonoides/química , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Cinética , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Polifenóis/farmacologia , Ligação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína/efeitos dos fármacos , Transdução de Sinais/genética , Ressonância de Plasmônio de Superfície , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
15.
Int J Nanomedicine ; 14: 5135-5146, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371952

RESUMO

Nanoparticles appear to be one of the most promising agents that offer efficacy in angiogenesis-related disease therapy. The objective of this research is to systematically review studies that have probed into the effect of nanoparticles on angiogenesis. Selected inclusion criteria were used to extract articles, references that were cited in the initial search were sought to identify more potential articles, and articles that did not meet the inclusion criteria and duplicates were discarded. The spherical shape was shown to be the most common shape employed to investigate the role of nanoparticles in angiogenesis therapy. The size of nanoparticles appears to play a crucial role for efficacy on angiogenesis, in which 20 nm emerged as the preferred size. Gold nanoparticles exhibit the most promise as an antiangiogenesis agent, and the toxicity was adjustable based on the dosages applied.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Nanopartículas/uso terapêutico , Humanos , Nanopartículas/toxicidade , Neovascularização Patológica/tratamento farmacológico , Tamanho da Partícula
16.
Int J Mol Sci ; 20(17)2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31455001

RESUMO

The purpose of this study was to investigate whether Ger-Gen-Chyn-Lian-Tang (GGCLT) suppresses oxidative stress, inflammation, and angiogenesis during experimental liver fibrosis through the hypoxia-inducible factor-1α (HIF-1α)-mediated pathway. Male C57BL/6 mice were randomly assigned to a sham-control or bile duct ligation (BDL) group with or without treatment with GGCLT at 30, 100, and 300 mg/kg. Plasma alanine aminotransferase (ALT) levels were analyzed using a diagnostic kit. Liver histopathology and hepatic status parameters were measured. Compared to control mice, the BDL mice exhibited an enlargement in liver HIF-1α levels, which was suppressed by 100 and 300 mg/kg GGCLT treatments (control: BDL: BDL + GGCLT-100: BDL + GGCLT-300 = 0.95 ± 0.07: 1.95 ± 0.12: 1.43 ± 0.05: 1.12 ± 0.10 fold; p < 0.05). GGCLT restrained the induction of hepatic hydroxyproline and malondialdehyde levels in the mice challenged with BDL, further increasing the hepatic glutathione levels. Furthermore, in response to increased hepatic inflammation and fibrogenesis, significant levels of ALT, nuclear factor kappa B, transforming growth factor-ß, α-smooth muscle actin, matrix metalloproteinase-2 (MMP-2), MMP-9, and procollagen-III were found in BDL mice, which were attenuated with GGCLT. In addition, GGCLT reduced the induction of angiogenesis in the liver after BDL by inhibiting vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. In conclusion, the anti-liver fibrosis effect of GGCLT, which suppresses hepatic oxidative stress and angiogenesis, may be dependent on an HIF-1α-mediated pathway.


Assuntos
Colestase/complicações , Medicamentos de Ervas Chinesas/farmacologia , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Animais , Biomarcadores , Biópsia , Colestase/patologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Masculino , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Resultado do Tratamento
17.
Carbohydr Polym ; 223: 115034, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31426965

RESUMO

Fucoidan is a marine-origin sulfated polysaccharide that can show anticancer activity, to which both pro- and anti-angiogenic responses have been reported. Due to this unpredictability, the angiogenic potential of an effective anticancer crude fucoidan (CF), at a concentration of 0.5 mg mL-1, was evaluated. Tube formation assays demonstrated that CF, either administered while endothelial cells seeding or after their adhesion, migration and organization, inhibited or disrupted the formation of tubular-like structures, respectively. Although CF did not significantly reduced vascular endothelial growth factor (VEGF) secretion, it significantly reduced the expression of platelet-derived growth factor (PDGF), compromising the blood vessels maturation. Two chicken embryo chorioallantoic membrane (CAM) assays were performed: one without tumor (CAM I) and the other with an onplanted tumor mass (CAM II); the CF injection reduced the number of blood of vessels and significantly decreased the tumor size, respectively. In vitro and in vivo results support the effectiveness of fucoidan as a natural antitumor therapeutic agent.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Fucus/química , Neovascularização Patológica/tratamento farmacológico , Polissacarídeos/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Humanos , Polissacarídeos/farmacologia , Microambiente Tumoral/efeitos dos fármacos
18.
Int J Mol Sci ; 20(16)2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434286

RESUMO

There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional Prunella vulgaris plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and Caenorhabditis elegans. According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.


Assuntos
Neovascularização Patológica/tratamento farmacológico , Pirazinas/química , Pirazinas/uso terapêutico , Triterpenos/química , Triterpenos/uso terapêutico , Animais , Caenorhabditis elegans/efeitos dos fármacos , Membrana Corioalantoide/efeitos dos fármacos , Descoberta de Drogas , Células Endoteliais da Veia Umbilical Humana , Humanos , Metabolômica/métodos
19.
Molecules ; 24(16)2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31416271

RESUMO

Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent ß-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin-murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 µM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent ß-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Carbolinas/síntese química , Carbolinas/farmacologia , Desenho de Drogas , Hidrazonas/química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Carbolinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Embrião de Galinha , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Neovascularização Patológica/tratamento farmacológico , Relação Estrutura-Atividade
20.
Recenti Prog Med ; 110(7): 330-337, 2019.
Artigo em Italiano | MEDLINE | ID: mdl-31379367

RESUMO

Riassunto. L'angiogenesi svolge un ruolo importante sia nei tessuti epiteliali normali sia in quelli maligni. Negli ultimi anni questo fenomeno è stato ampiamente studiato in oncologia sperimentale e clinica perché ci sono evidenze che sia coinvolto nella diffusione e nella diffusione metastatica del carcinoma ovarico. Il fattore di crescita dell'endotelio vascolare (vascular endothelial growth factor - VEGF) è l'attore principale nel meccanismo di angiogenesi e svolge un ruolo strategico nella proliferazione e migrazione delle cellule neoplastiche, con un impatto significativo sulla sopravvivenza e sull'outcome clinico. Secondo quanto emerge da molti studi sperimentali e clinici, le nostre conoscenze sulla biologia dell'angiogenesi e del VEGF sono aumentate portando allo sviluppo farmacologico di specifici agenti in grado di targeting VEGF. Questo nuovo campo di indagine offre agli scienziati l'opportunità di testare nuove possibilità terapeutiche nei pazienti con carcinoma ovarico con nuovi agenti mirati. Il bevacizumab, un anticorpo monoclonale anti-VEGF umanizzato, è stato il primo farmaco anti-VEGF scoperto ed è usato oggi per il trattamento di diversi tumori solidi. Negli ultimi anni questo agente è stato ampiamente testato nei pazienti con carcinoma ovarico, mostrando un'attività clinica interessante e un profilo di tossicità tollerabile sia nelle pazienti giovani sia in quelle anziane. Il bevacizumab, combinato con carboplatino e paclitaxel e successivamente utilizzato come agente singolo, è indicato per il trattamento del carcinoma epiteliale dell'ovaio di stadio III o IV, tuba di Falloppio o carcinoma peritoneale primario dopo iniziale resezione chirurgica. Il bevacizumab è anche usato per il trattamento di pazienti con carcinoma ovarico epiteliale ricorrente e resistente al platino, delle tube di Falloppio o dal tumore peritoneale primario che hanno ricevuto non più di 2 regimi precedenti di chemioterapia. Inoltre, il bevacizumab, combinato con carboplatino e paclitaxel o con carboplatino e gemcitabina (e usato come agente singolo), è indicato per il trattamento di pazienti con carcinoma epiteliale dell'ovario sensibile al platino, tuba di Falloppio o tumore peritoneale primario. Le linee guida più accreditate suggeriscono quando bevacizumab deve essere usato nel trattamento del carcinoma ovarico avanzato e ricorrente. Altri agenti anti-VEGF, come gli inibitori della tirosin-chinasi del recettore VEGF (VEGFR), sono stati ampiamente testati nel carcinoma ovarico e molti altri sono in corso di studi al fine di testare la loro attività e sicurezza rispetto a bevacizumab. Gli agenti anti-VEGF e gli inibitori di PARP svolgono oggi un ruolo strategico nel trattamento del cancro ovarico con agenti mirati in associazione con la chemioterapia e la chirurgia in un'ottica multidisciplinare e personalizzata.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Inibidores da Angiogênese/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Feminino , Humanos , Terapia de Alvo Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Neoplasias Ovarianas/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo
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