Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.817
Filtrar
1.
Medicine (Baltimore) ; 100(25): e26471, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160456

RESUMO

RATIONALE: Advanced hepatocellular carcinoma (HCC) remains a deadly disease in part due to decades of limited therapeutic options. With recent advances in our understanding of the tumor biology, several promising treatment strategies involving targeted and immunotherapies have emerged. However, enhancing their modest efficacy in HCC and other gastrointestinal malignancies is essential to improving survival. PATIENT CONCERNS: A man in his late 50s with a history of type 2 diabetes mellitus and morbid obesity initially presented with progressive abdominal pain and anorexia prompting an abdominal computed tomography scan that revealed a large solitary liver mass with extensive local involvement. DIAGNOSES: Although there were features consistent with a primary gastric tumor on subsequent endoscopic evaluation leading to early diagnostic uncertainty, his clinical picture, including a dominant liver mass, immunohistochemical staining profile, and significantly elevated alpha fetoprotein ultimately favored HCC. INTERVENTIONS: The patient received palliative systemic therapy with infusional fluorouracil for a presumed gastric primary, however restaging scans after 3 cycles demonstrated disease progression. The consensus from a multidisciplinary discussion was that his pathology was more consistent with primary HCC. He was subsequently started on nivolumab with a partial response, although after 5 months, he progressed prompting initiation of second-line atezolizumab and bevacizumab with a favorable response. OUTCOMES: The addition of atezolizumab and bevacizumab led to a sustained biochemical and radiographic response that appeared to overcome the resistance to nivolumab monotherapy. Aside from several mild immune-related adverse effects, his quality of life has greatly improved and he has tolerated treatment well to date. LESSONS: Our findings suggest that vascular endothelial growth factor inhibition can overcome resistance to checkpoint inhibition in advanced HCC by resulting in a unique synergy that has never before been described in patients. The biological rationale for this response is likely attributable to the immunomodulatory effects of antiangiogenic agents, promoting an immunostimulatory microenvironment that can be exploited by immune checkpoint inhibitors for more effective antitumor activity. Given the considerable benefit patients may derive following progression on first-line treatment, it is important to consider this strategic combination of therapies which can ultimately lead to improved patient outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fígado/diagnóstico por imagem , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
2.
Int J Nanomedicine ; 16: 4001-4016, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135585

RESUMO

Background: Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy. Methods: Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel "BEL-7402+HUVEC" co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test. Results: The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery. Conclusion: CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Lipossomos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Curcumina/administração & dosagem , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Ligantes , Lipossomos/administração & dosagem , Lipossomos/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Estilbenos/administração & dosagem , Estilbenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Molecules ; 26(9)2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-34063635

RESUMO

Tea is one of the most widely consumed beverages worldwide after water, and green tea accounts for 20% of the total tea consumption. The health benefits of green tea are attributed to its natural antioxidants, namely, catechins, which are phenolic compounds with diverse beneficial effects on human health. The beneficial effects of green tea and its major bioactive component, (-)-epigallocatechin-3-gallate (EGCG), on health include high antioxidative, osteoprotective, neuroprotective, anti-cancer, anti-hyperlipidemia and anti-diabetic effects. However, the review of green tea's benefits on female reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis and dysmenorrhea, remains scarce. Thus, this review summarises current knowledge on the beneficial effects of green tea catechins on selected female reproductive disorders. Green tea or its derivative, EGCG, improves endometriosis mainly through anti-angiogenic, anti-fibrotic, anti-proliferative and proapoptotic mechanisms. Moreover, green tea enhances ovulation and reduces cyst formation in PCOS while improving generalised hyperalgesia, and reduces plasma corticosterone levels and uterine contractility in dysmenorrhea. However, information on clinical trials is inadequate for translating excellent findings on green tea benefits in animal endometriosis models. Thus, future clinical intervention studies are needed to provide clear evidence of the green tea benefits with regard to these diseases.


Assuntos
Catequina/farmacologia , Dismenorreia/tratamento farmacológico , Endometriose/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Chá/química , Inibidores da Angiogênese/farmacologia , Animais , Antioxidantes/uso terapêutico , Apoptose , Camellia sinensis , Catequina/análogos & derivados , Proliferação de Células , Corticosterona/sangue , Estudos Transversais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Extratos Vegetais/farmacologia , Útero/patologia
4.
Food Chem ; 360: 129999, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33989880

RESUMO

In this study, cherry fruits and petioles from six ancient Italian Prunus avium L. varieties (Ferrovia, Capellina, Morellina, Ciambellana, Napoletana, and Bianca), were compared by chemical and bioinformatic analyses and evaluated for their antiangiogenic activity. The highest levels of total phenols and flavonoids were found in Napoletana petioles, and Morellina and Capellina fruits. HPLC-PDA-MS analyses showed similar phenolic profiles for all fruit extracts, with cyanidin-3-O-rutinoside, flavonols glycosides, and quinic acid derivatives as major components. Flavonoid glycosides were found in all petiole extracts, while proanthocyanidins B type were predominant in Capellina, Napoletana and Bianca. Accordingly to their higher polyphenolic content, petiole extracts exhibited stronger radical scavenging activity compared to the fruits. The best antiangiogenic response was exhibited by Morellina, Ferrovia, and Ciambellana petiole extracts, and by Ferrovia, Morellina, and Capellina fruit extracts; by bioinformatic studies rutin and cyanidin 3-O-rutinoside were recognised as the best candidate bioactive compounds. In conclusion, sweet cherry varietes were confirmed as valuable sources of phenols, showing also potential angiomodulator properties.


Assuntos
Inibidores da Angiogênese/análise , Extratos Vegetais/química , Prunus avium/química , Fosfatase Alcalina/metabolismo , Inibidores da Angiogênese/farmacologia , Animais , Antocianinas/análise , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Análise por Conglomerados , Embrião não Mamífero/diagnóstico por imagem , Embrião não Mamífero/metabolismo , Flavonoides/análise , Frutas/química , Frutas/metabolismo , Itália , Fenóis/análise , Extratos Vegetais/farmacologia , Prunus avium/metabolismo , Espectrometria de Massas por Ionização por Electrospray , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/metabolismo
5.
Sci Rep ; 11(1): 11130, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: covidwho-1246392

RESUMO

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.


Assuntos
Inibidores da Angiogênese/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Pulmão/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Serina Endopeptidases/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios , Enzima de Conversão de Angiotensina 2/genética , Animais , Benzamidas/farmacologia , COVID-19/genética , Linhagem Celular Tumoral , Sequenciamento de Cromatina por Imunoprecipitação , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Serina Endopeptidases/genética , Fumantes
6.
Sci Rep ; 11(1): 11130, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34045511

RESUMO

The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.


Assuntos
Inibidores da Angiogênese/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Pulmão/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Serina Endopeptidases/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Androgênios , Enzima de Conversão de Angiotensina 2/genética , Animais , Benzamidas/farmacologia , COVID-19/genética , Linhagem Celular Tumoral , Sequenciamento de Cromatina por Imunoprecipitação , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Pulmão/metabolismo , Pulmão/virologia , Masculino , Camundongos , Nitrilas/farmacologia , Feniltioidantoína/farmacologia , Serina Endopeptidases/genética , Fumantes
7.
Front Immunol ; 12: 616837, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33854498

RESUMO

Vascular endothelial growth factor A is known to play a central role in tumor angiogenesis. Several studies showed that VEGF-A is also an immunosuppressive factor. In tumor-bearing hosts, VEGF-A can modulate immune cells (DC, MDSC, TAM) to induce the accumulation of regulatory T-cells while simultaneously inhibiting T-cell functions. Furthermore, VEGFR-2 expression on activated T-cells and FoxP3high regulatory T-cells also allow a direct effect of VEGF-A. Anti-angiogenic agents targeting VEGF-A/VEGFR contribute to limit tumor-induced immunosuppression. Based on interesting preclinical studies, many clinical trials have been conducted to investigate the efficacy of anti-VEGF-A/VEGFR treatments combined with immune checkpoint blockade leading to the approvement of these associations in different tumor locations. In this review, we focus on the impact of VEGF-A on immune cells especially regulatory and effector T-cells and different therapeutic strategies to restore an antitumor immunity.


Assuntos
Inibidores da Angiogênese/farmacologia , Imunomodulação/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Ensaios Clínicos como Assunto , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Terapia de Alvo Molecular , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
Biochem Biophys Res Commun ; 555: 13-18, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33812053

RESUMO

Propofol, a commonly used intravenous anesthetic in tumor surgery, has recently garnered attention for its anti-cancer activity. We previously demonstrated that propofol inhibits migration and invasion of esophageal squamous cell carcinoma cells. However, the effects of propofol in tumor angiogenesis are inconclusive. The current study investigated the effects of propofol on the biological functions of lung cancer associated endothelial cells (LC-EC) and colon cancer associated endothelial cells (CC-EC) that represent in vitro tumor angiogenesis. We showed that propofol inhibited tubular structure formation of both LC-EC and CC-EC, particularly the early stages of angiogenesis. In addition, propofol inhibited migration, adhesion, proliferation, and survival of tumor associated endothelial cells. Mechanism studies revealed that propofol disrupted tumor angiogenesis microenvironment via suppressing expression and secretion of multiple pro-angiogenic factors by tumor cells. Propofol also inhibited VEGF/VEGFR2-and mTOR/eIF4E-mediated signaling pathways in endothelial cells. Our findings demonstrate the inhibitory effects of propofol on tumor angiogenesis and support the anti-cancer properties of propofol. Our work provides preclinical evidence into the potential mechanisms by which propofol may negatively affect tumor growth and metastasis.


Assuntos
Inibidores da Angiogênese/farmacologia , Neovascularização Patológica/tratamento farmacológico , Propofol/farmacologia , Células A549 , Proliferação de Células/efeitos dos fármacos , Fator de Iniciação 4E em Eucariotos/metabolismo , Células HCT116 , Humanos , Neovascularização Patológica/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Chemistry ; 27(38): 9885-9897, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-33860585

RESUMO

A new class of emissive cyclometallated IrIII -AuI complexes with a bis(diphenylphosphino) methanide bridging ligand was successfully synthesised from the diphosphino complex [Ir(N^C)2 (dppm)]+ (1). The different gold ancillary ligand, a triphenylphosphine (2), a chloride (3) or a thiocytosine (4) did not reveal any significant effect on the photophysical properties, which are mainly due to metal-to-ligand charge-transfer (3 MLCT) transitions based on IrIII . However, the AuI fragment, along with the ancillary ligand, seemed crucial for the bioactivity in A549 lung carcinoma cells versus endothelial cells. Both cell types display variable sensitivities to the complexes (IC50 =0.6-3.5 µM). The apoptotic pathway is activated in all cases, and paraptotic cell death seems to take place at initial stages in A549 cells. Species 2-4 showed at least dual lysosomal and mitochondrial biodistribution in A549 cells, with an initial lysosomal localisation and a possible trafficking process between both organelles with time. The bimetallic IrIII -AuI complexes disrupted the mitochondrial transmembrane potential in A549 cells and increased reactive oxygen species (ROS) generation and thioredoxin reductase (TrxR) inhibition in comparison with that displayed by the monometallic complex 1. Angiogenic activity assays performed in endothelial cells revealed the promising antimetastatic potential of 1, 2 and 4.


Assuntos
Antineoplásicos , Irídio , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Células Endoteliais , Irídio/farmacologia , Potencial da Membrana Mitocondrial , Distribuição Tecidual
10.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802884

RESUMO

Novel therapeutic strategies for ovarian cancer treatment are in critical need due to the chemoresistance and adverse side effects of platinum-based chemotherapy. Theasaponin E1 (TSE1) is an oleanane-type saponin from Camellia sinensis seeds. Its apoptosis-inducing, cell cycle arresting and antiangiogenesis activities against platinum-resistant ovarian cancer cells were elucidated in vitro and using the chicken chorioallantoic membrane (CAM) assay. The results showed that TSE1 had more potent cell growth inhibitory effects on ovarian cancer OVCAR-3 and A2780/CP70 cells than cisplatin and was lower in cytotoxicity to normal ovarian IOSE-364 cells. TSE1 significantly induced OVCAR-3 cell apoptosis via the intrinsic and extrinsic apoptotic pathways, slightly arresting cell cycle at the G2/M phase, and obviously inhibited OVCAR-3 cell migration and angiogenesis with reducing the protein secretion and expression of vascular endothelial growth factor (VEGF). Western bolt assay showed that Serine/threonine Kinase (Akt) signaling related proteins including Ataxia telangiectasia mutated kinase (ATM), Phosphatase and tensin homolog (PTEN), Akt, Mammalian target of rapamycin (mTOR), Ribosome S6 protein kinase (p70S6K) and e IF4E-binding protein 1(4E-BP1) were regulated, and Hypoxia inducible factor-1α (HIF-1α) protein expression was decreased by TSE1 in OVCAR-3 cells. Moreover, TSE1 treatment potently downregulated protein expression of the Notch ligands including Delta-like protein 4 (Dll4) and Jagged1, and reduced the protein level of the intracellular domain (NICD) of Notch1. Combination treatment of TSE1 with the Notch1 signaling inhibitor tert-butyl (2S)-2-[[(2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoyl]amino]-2-phenylacetate (DAPT), or the Akt signaling inhibitor wortmannin, showed a stronger inhibition toward HIF-1α activation compared with single compound treatment. Taken together, TSE1 might be a potential candidate compound for improving platinum-resistant ovarian cancer treatment via Dll4/Jagged1-Notch1-Akt-HIF-1α axis.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Neoplasias Ovarianas/tratamento farmacológico , Saponinas/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Camellia sinensis/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Membrana Corioalantoide/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Ácido Oleanólico/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sementes/química , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
11.
J Med Chem ; 64(9): 5535-5550, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33902285

RESUMO

Diabetic retinopathy is the leading cause of blindness which is associated with excessive angiogenesis. Using the structure of wondonin marine natural products, we previously created a scaffold to develop a novel type of antiangiogenesis agent that possesses minimized cytotoxicity. To overcome its poor pharmaceutical properties, we further modified the structure. A new scaffold was derived in which the stereogenic carbon was changed to nitrogen and the 1,2,3-triazole ring was replaced by an alkyl chain. By comparing the bioactivity versus cytotoxicity, compound 31 was selected, which has improved aqueous solubility and an enhanced selectivity index. Mechanistically, 31 suppressed angiopoietin-2 (ANGPT2) expression induced by high glucose in retinal cells and exhibited in vivo antiangiogenic activity in choroidal neovascularization and oxygen-induced retinopathy mouse models. These results suggest the potential of 31 as a lead to develop antiangiogenic small-molecule drugs to treat diabetic retinopathy and as a chemical tool to elucidate new mechanisms of angiogenesis.


Assuntos
Inibidores da Angiogênese/farmacologia , Desenho de Fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/uso terapêutico , Angiopoietina-2/genética , Angiopoietina-2/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Estabilidade de Medicamentos , Glucose/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Relação Estrutura-Atividade , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacologia , Triazóis/uso terapêutico
12.
Mar Drugs ; 19(4)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805447

RESUMO

Fish oil (FO) and selenium (Se) possess antiangiogenic potential in malignant tumors. This study aimed to determine whether combination of FO and Se enhanced treatment efficacy of low-dose antiangiogenic agent Avastin (bevacizumab) in a dose-dependent manner and targeted multiple signaling pathways in triple-negative breast cancer (TNBC)-bearing mice. Randomized into five groups, mice received treatment with either physiological saline (control), Avastin alone, or Avastin in combination with low, medium, and high doses of FO/Se. The target signaling molecules for anticancer were determined either by measuring protein or mRNA expression. Avastin-treated mice receiving FO/Se showed lower tumor growth and metastasis than did mice treated with Avastin alone. Combination-treated mice exhibited lower expressions in multiple proangiogenic (growth) factors and their membrane receptors, and altered cytoplasmic signaling molecules (PI3K-PTEN-AKT-TSC-mTOR-p70S6K-4EBP1, Ras-Raf-MEK-ERK, c-Src-JAK2-STAT3-TMEPAI-Smad, LKB1-AMPK, and GSK3ß/ß-catenin). Dose-dependent inhibition of down-stream targets including epithelial-to-mesenchymal transition transcription factors, nuclear cyclin and cyclin-dependent kinases, cancer stem cell markers, heat shock protein (HSP-90), hypoxia-inducible factors (HIF-1α/-2α), matrix metalloprotease (MMP-9), and increased apoptosis were observed. These results suggest that combination treatment with FO and Se increases the therapeutic efficacy of Avastin against TNBC in a dose-dependent manner through multiple signaling pathways in membrane, cytoplasmic, and nucleic targets.


Assuntos
Inibidores da Angiogênese/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/farmacologia , Óleos de Peixe/farmacologia , Compostos de Selênio/farmacologia , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Camundongos Endogâmicos BALB C , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Carga Tumoral/efeitos dos fármacos
13.
Mar Drugs ; 19(4)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805470

RESUMO

Fucoidans, sulfated polysaccharides extracted from brown algae, are marine products with the potential to modulate bone formation and vascularization processes. The bioactivity and safety of fucoidans are highly associated with their chemical structure, which may vary with algae species and extraction method. Thus, in depth evaluation of fucoidan extracts in terms of endotoxin content, cytotoxicity, and their detailed molecular biological impact on the individual cell types in bone is needed. In this study, we characterized fucoidan extracts from three different Fucus species including Fucus vesiculosus (Fv), Fucus serratus (Fs), and Fucus distichus subsp. evanescens (Fe) for their chemical features, endotoxin content, cytotoxicity, and bioactive effects on human outgrowth endothelial cells (OEC) and human mesenchymal stem cells (MSC) as in vitro models for bone function and vascularization. Extracts contained mainly high molecular weight (HMW) fucoidans and were free of endotoxins that may cause inflammation or influence vascularization. OEC tolerated fucoidan concentrations up to 200 µg/mL, and no indication of cytotoxicity was observed. The inflammatory response, however, investigated by real-time PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) and endothelial barrier assessed by impedance measurement differed for the individual extracts. MSC in comparison with endothelial cells were more sensitive to fucoidans and showed partly reduced metabolic activity and proliferation at higher doses of fucoidans. Further results for MSC indicated impaired osteogenic functions in alkaline phosphatase and calcification assays. All tested extracts consistently lowered important molecular mediators involved in angiogenesis, such a VEGF (vascular endothelial growth factor), ANG-1 (angiopoietin 1), and ANG-2 (angiopoietin 2), as indicated by RT-PCR and ELISA. This was associated with antiangiogenic effects at the functional level using selected extracts in co-culture models to mimic bone vascularization processes during bone regeneration or osteosarcoma.


Assuntos
Inibidores da Angiogênese/farmacologia , Células Endoteliais/efeitos dos fármacos , Fucus/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Polissacarídeos/farmacologia , Inibidores da Angiogênese/isolamento & purificação , Proteínas Angiogênicas/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Células Endoteliais/metabolismo , Metabolismo Energético/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , Peso Molecular , Polissacarídeos/isolamento & purificação , Transdução de Sinais
14.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916166

RESUMO

The Euterpe oleracea fruit (açaí) is a promising source of polyphenols with health-promoting properties. To our knowledge, few studies have focused on the influence of açaí phytochemicals on angiogenesis, with a significant impact on cancer. This study aimed at investigating the phytochemical profile of a purple açaí hydroethanolic extract (AHE) obtained from a commercial dietary powder supplement by high-performance liquid chromatography coupled to diode array detection and electrospray ionization mass spectrometry, and evaluate its in vitro effects on distinct angiogenic steps during vessel growth and on oxidative markers in human microvascular endothelial cells (HMEC-1). The phenolic profile of AHE revealed the presence of significant levels of anthocyanins, mainly cyanidin-3-O-rutinoside, and other flavonoids with promising health effects. The in vitro studies demonstrated that AHE exerts antiangiogenic activity with no cytotoxic effect. The AHE was able to decrease HMEC-1 migration and invasion potential, as well as to inhibit the formation of capillary-like structures. Additionally, AHE increased antioxidant defenses by upregulating superoxide dismutase and catalase enzymatic activities, accompanied by a reduction in the production of reactive oxygen species. These data bring new insights into the potential application of angiogenic inhibitors present in AHE on the development of novel therapeutic approaches for angiogenesis-dependent diseases.


Assuntos
Inibidores da Angiogênese/farmacologia , Antioxidantes/farmacologia , Suplementos Nutricionais , Euterpe/química , Extratos Vegetais/farmacologia , Pós , Inibidores da Angiogênese/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão/métodos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Humanos , Fenóis/análise , Extratos Vegetais/química , Espécies Reativas de Oxigênio/análise , Espectrometria de Massas por Ionização por Electrospray
15.
BMC Cancer ; 21(1): 336, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33789622

RESUMO

BACKGROUND: Pazopanib, a multitargeted tyrosine kinase inhibitor, is recommended as the standard treatment for refractory soft tissue sarcoma (STS). However, there are comparatively few molecular determinants for predicting pazopanib efficacy. Based on correlative studies regarding the predictive impact of PD-L1, we investigated the clinical relevance of PD-L1 expression and evaluated its value for predicting pazopanib efficacy. METHODS: Tumour tissues from patients with advanced STS who went on to receive pazopanib were assessed for PD-L1 expression. Immunohistochemistry was performed using an anti-PD-L1 antibody, and the PD-L1 tumour proportion score (TPS) was calculated as the percentage of at least 100 viable cells with positive expression, defined as TPS ≥ 1%. RESULTS: Among the 67 patients, 8 (11.9%) achieved partial response and a median progression-free survival (PFS) of 4.8 months (95% CI 3.8-5.7). PD-L1 expression in tumour cells was detected in 13 (19.4%) cases and the TPS scores ranged from 1 to 100%, as follows: 0 (n = 54, 80.6%), 1-9% (n = 3, 4.5%), 10-49% (n = 9, 13.4%), and ≥ 50% (n = 1, 1.5%). PD-L1 positive tumours exhibited a poorer response to pazopanib treatment than the PD-L1 negative tumours (0% vs 14.8%, P = 0.07). PD-L1-positive tumours had significantly shorter PFS than the PD-L1-negative tumours (median PFS 2.8 vs 5.1 months, P = 0.003), and PD-L1 positivity was an independent predictor of poor response to pazopanib treatment (HR 2.77, 95% CI; 1.45-5.56, P = 0.006). CONCLUSION: We identified that PD-L1 expression can help predict the clinical outcome of patients with advanced STS treated with pazopanib. Based on our study, stratification should be actively considered in order to identify patients who will benefit from pazopanib or further therapeutic strategies for future clinical trials.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Antígeno B7-H1/metabolismo , Pirimidinas/uso terapêutico , Sarcoma/tratamento farmacológico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pirimidinas/farmacologia , Estudos Retrospectivos , Sulfonamidas/farmacologia
16.
Int J Mol Sci ; 22(6)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33810078

RESUMO

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/química , Biomarcadores Tumorais , Linhagem Celular Tumoral , Descoberta de Drogas/métodos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas de Checkpoint Imunológico/genética , Proteínas de Checkpoint Imunológico/metabolismo , Imunomodulação/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/etiologia , Melanoma/metabolismo , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/farmacologia
17.
Eur J Pharmacol ; 901: 174061, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33766618

RESUMO

It has been previously demonstrated by our group that genetic inhibition of thioredoxin-interacting-protein (TXNIP) preserved retinal neuronal function in chemically-induced retinopathy. Moreover, elevated intracellular levels of TXNIP and calcium ions play important roles in hyperglycemia-induced oxidative stress and inflammation. Current study aimed to appraise the potential therapeutic benefits of pharmacological inhibition of TXNIP using verapamil in diabetic retinopathy. Diabetic retinopathy was assessed in type-1 diabetes rat model induced by a single intravenous injection of streptozotocin (45 mg/kg), with or without daily treatment with verapamil (10 mg/kg, oral) for 4 months. Verapamil treatment commenced 48 h post-streptozotocin insult and continued for 16 weeks. Untreated diabetic rats exhibited higher expression of toll-like-receptor-4 (TLR4), TXNIP, nucleotide-binding domain-like receptor protein-3 (NLRP3), caspase-1, cytochrome-c, and ssDNA as assessed immunohistochemically in both retinal and pancreatic tissues 16 weeks post-diabetes induction. This was associated with a reduced thioredoxin reductase (Trx-R) activity, increased release of TNF-α and IL-1ß into vitreous fluid along with retinal ganglion cell (RGC) loss, pancreatic islets shrinkage, and enhanced CD34 expression. The treatment with verapamil enhanced Trx-R activity, significantly inhibited TLR4 mediated NLRP3-inflammasome assembly with subsequent diminishing of inflammatory markers (TNF-α and IL-1ß) release into the vitreous, suppression of pathological angiogenesis, and preservation of RGC count and pancreatic islets diameter. Current study showed that using the calcium channel blocker, verapamil, interferes with the pathogenesis of diabetic retinopathy and pancreatic islets damage at multiple levels mainly through the inhibition of TLR4, TXNIP and NLRP3-inflammasome, suggesting its promising role as an anti-diabetic and a neuroprotective agent.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Retinopatia Diabética/tratamento farmacológico , Inflamassomos/efeitos dos fármacos , Pancreatopatias/tratamento farmacológico , Verapamil/uso terapêutico , Inibidores da Angiogênese/farmacologia , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ratos , Ratos Wistar , Células Ganglionares da Retina/efeitos dos fármacos , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Perda de Peso/efeitos dos fármacos
18.
Inorg Chem ; 60(6): 3939-3951, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33657313

RESUMO

Palladacycles are versatile organometallic compounds that show potential for therapeutic use. Here are described the synthesis and characterization of mono- and dinuclear palladacycles bearing diphosphines. Their biological effect was investigated in A2780, an ovarian-derived cancer line, and in normal dermal fibroblasts. The compounds displayed selective cytotoxicity toward the A2780 cell line. Compound 3 decreased the cell viability through cell cycle retention in G0/G1, triggered apoptosis through the intrinsic pathway, and induced autophagy in A2780 cells. Compound 9 also induced cell cycle retention, apoptosis, and cellular detachment. Notably, compound 9 induced the production of intracellular reactive oxygen species (ROS). Our work demonstrated that compound 3 enters A2780 cells via active transport, which requires energy, while compound 9 enters A2780 cells mostly passively. The potential effect of palladacycles in angiogenesis was investigated for the first time in an in vivo chorioallantoic membrane model, showing that while compound 3 displayed an antiangiogenic effect crucial to fighting cancer progression, compound 9 promoted angiogenesis. These results show that palladacycles may be used in different clinical applications where pro- or antiangiogenic effects may be desirable.


Assuntos
Inibidores da Angiogênese/farmacologia , Complexos de Coordenação/farmacologia , Compostos Organometálicos/farmacologia , Inibidores da Angiogênese/síntese química , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Galinhas , Complexos de Coordenação/síntese química , Embrião não Mamífero/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Compostos Organometálicos/síntese química , Neoplasias Ovarianas/tratamento farmacológico , Paládio/química , Espécies Reativas de Oxigênio/metabolismo
19.
Chem Biol Interact ; 343: 109433, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33689707

RESUMO

Pancreatic cancer is one of the most malignant cancers around the world. The co-occurrence of mutation in KRAS and p53 makes it highly aggressive, proliferative, metastatic, and resistant to apoptotic cell death. Therefore, there is a need to trigger an alternate mechanism of cancer cell death in apoptosis-resistant pancreatic cancer. Autophagic cell death could be an alternate viable option for treatment in such cases. Thus, the identification of small molecules as autophagy modulators with potent anticancer efficacy would be of great importance in pancreatic cancer. The present study investigates fluorinated thiazolidionol (FTZ) driven autophagy modulation, underlying mechanism, and regulation of critical sentinels of oncogenic signaling in pancreatic cancer cells. We identified that FTZ triggered autophagic cell death in pancreatic cancer cells, independent of apoptosis evidenced by an increase in cytoplasmic vacuoles formation, autophagy flux, LC3-II expression, and p62 degradation. Further, the crucial events of apoptosis i.e., Caspase-3 activation and PARP cleavage, were not observed, indicating the non-occurrence of apoptotic cell death. Moreover, FTZ was able to activate AMPK and suppress PI3k/Akt/mTOR as well as MEK/ERK, the key oncogenic signaling pathways in cancer cells. Furthermore, treatment with FTZ suppressed migration, invasion, and angiogenesis in pancreatic cancer cells. Studies in vivo revealed significant regression of tumors by FTZ in nude mice model. Overall, our study demonstrates that FTZ induces autophagic cell death in pancreatic cancer cells independent of apoptosis, which is accompanied by AMPK activation and suppression of critical sentinels of oncogenic signaling in pancreatic cancer cells.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/uso terapêutico , Morte Celular Autofágica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Tiazóis/uso terapêutico , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos Nus , Tiazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Sci ; 112(6): 2223-2232, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33743555

RESUMO

Oral tongue squamous cell carcinoma (OTSCC) is one of the most common cancers worldwide and is characterized by early metastasis and poor prognosis. Recently, we reported that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in OTSCC patients and has promising anticancer effects in vitro. Vasculogenic mimicry (VM) is the formation of an alternative vasculogenic system by aggressive tumor cells, which is implicated in treatment failure and poor survival of cancer patients. We sought to confirm the formation of VM in OTSCC and to investigate the effect of IL-17F on VM formation. Here, we showed that highly invasive OTSCC cells (HSC-3 and SAS) form tube-like VM on Matrigel similar to those formed by human umbilical vein endothelial cells. Interestingly, the less invasive cells (SCC-25) did not form any VM structures. Droplet-digital PCR, FACS, and immunofluorescence staining revealed the presence of CD31 mRNA and protein in OTSCC cells. Additionally, in a mouse orthotopic model, HSC-3 cells expressed VE-cadherin (CD144) but lacked Von Willebrand Factor. We identified different patterns of VM structures in patient samples and in an orthotopic OTSCC mouse model. Similar to the effect produced by the antiangiogenic drug sorafenib, IL-17F inhibited the formation of VM structures in vitro by HSC-3 and reduced almost all VM-related parameters. In conclusion, our findings indicate the presence of VM in OTSCC and the antitumorigenic effect of IL-17F through its effect on the VM. Therefore, targeting IL-17F or its regulatory pathways may lead to promising therapeutic strategies in patients with OTSCC.


Assuntos
Interleucina-17/farmacologia , Neovascularização Patológica/prevenção & controle , Carcinoma de Células Escamosas de Cabeça e Pescoço/irrigação sanguínea , Neoplasias da Língua/irrigação sanguínea , Inibidores da Angiogênese/farmacologia , Animais , Antígenos CD/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias da Língua/metabolismo , Neoplasias da Língua/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...