RESUMO
Tumor cells trigger angiogenesis through the expression of angiogenic factors. Vasohibins (VASHs) are a family of peptides that regulate angiogenesis. Flavonoids have antiproliferative antitumor properties; however, few studies have highlighted their antiangiogenic potential. This study evaluated the flavonoid isoquercetin (Q3G) as an antitumor compound related to colon cancer vascularization and regulation of VASH1 and 2. Mice bearing xenogeneic colon cancer (n = 15) were divided into 3 groups: Q3G-treated (gavage, daily over a week), bevacizumab-treated (intraperitoneal, single dose), or untreated animals. Tumor growth, histological characteristics, blood vessel volume, and VASH1 and 2 expressions were analyzed. Q3G impaired tumor growth and vascularization, upregulated VASH1, and downregulated VASH2 in comparison to untreated animals. Mice treated with Q3G showed approximately 65% fewer blood vessels than untreated animals and 50% fewer blood vessels than mice treated with bevacizumab. Thus, we show that Q3G has antitumor activity, impairs vascularization, and differentially modulates VASH1 and 2 expressions in colon cancer.
Assuntos
Neoplasias do Colo , Neovascularização Patológica , Proteínas Angiogênicas/metabolismo , Animais , Bevacizumab/farmacologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias do Colo/tratamento farmacológico , Camundongos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Quercetina/análogos & derivados , Quercetina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This review was based on a literature search of PubMed and Scielo databases using the keywords "quercetin, rutin, isoquercitrin, isoquercitin (IQ), quercetin-3-glucoside, bioavailability, flavonols and favonoids, and cancer" and combinations of all the words. We collected relevant scientific publications from 1990 to 2015 about the absorption, bioavailability, chemoprevention activity, and treatment effects as well as the underlying anticancer mechanisms of isoquercitin. Flavonoids are a group of polyphenolic compounds widely distributed throughout the plant kingdom. The subclass of flavonols receives special attention owing to their health benefits. The main components of this class are quercetin, rutin, and IQ, which is a flavonoid and although mostly found as a glycoside, is an aglycone (lacks a glycoside side chain). This compound presents similar therapeutic profiles to quercetin but with superior bioavailability, resulting in increased efficacy compared to the aglycone form. IQ has therapeutic applications owing to its wide range of pharmacological effects including antioxidant, antiproliferative, anti-inflammatory, anti-hypertensive, and anti-diabetic. The protective effects of IQ in cancer may be due to actions on lipid peroxidation. In addition, the antitumor effect of IQ and its underlying mechanism are related to interactions with Wnt signaling pathway, mixed-lineage protein kinase 3, mitogen-activated protein kinase, apoptotic pathways, as well proinflammatory protein signaling. This review contributed to clarifying the mechanisms of absorption, metabolism, and actions of IQ and isoquercitrin in cancer.
RESUMO
Aged and adult populations have differences in the structural, biological, and healing properties of skin. Comparative studies of healing under the influence of retinoids in both these populations are very important and, to the best of our knowledge, have not been performed to date. The purpose of this study was to compare the activities of topical tretinoin in aged and adult animal models of wound healing by secondary intention. Male aged rats (24 months old, n = 7) and adult rats (6 months old, n = 8) were used. The rats were assigned to the following groups according to the dates on which wound samples were excised (day 14 or 21 after model creation): treated group, control group, and naive group. Topical application of tretinoin cream was used only on the proximal wound and was applied daily for 7 days. Wound healing areas were measured using metal calipers, and morphological analysis was performed. Slides were stained with Hematoxylin and Eosin, Masson's trichrome, and periodic acid-Schiff stains. Statistical analysis adopted a 5% coefficient for rejection of the null hypothesis. Although aged animals showed skin repair, complete reepithelialization was found on day 21 in some animals of both groups (treated and control). In aged rats, the wound area was significantly smaller in treated wounds than in untreated wounds, resulting in a larger scar area compared with the adult group. When treated wounds were compared, no differences were found between the wound areas in adult and aged rats. As expected, the collagen concentration was higher in normal skin from adult rats than in normal skin from aged animals, but there was no difference when aged skin was treated with tretinoin. These results indicate that tretinoin increases collagen synthesis in aged skin and returns the healing process to a normal state of skin healing.
Assuntos
Ceratolíticos/farmacologia , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/patologia , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Tecido de Granulação/metabolismo , Ceratolíticos/uso terapêutico , Masculino , Ratos , Ratos Wistar , Reepitelização/efeitos dos fármacos , Ferimentos e Lesões/patologiaRESUMO
The present study aims to identify differences between left and right colon adenocarcinoma arising from identical clonal cell and to find out if microenvironment has any influence on matrix metalloproteinase-2 (MMP2), p53 and ß-catenin tumor expressions. MATERIAL AND METHODS. Rats (RNU) were submitted to cecostomy to obtain the orthotopic model of right colon tumor (n = 10), while for the left colon model (n = 10), a colon diversion and distal mucous fistula in the descending colon was used. Cultivated human colon adenocarcinoma cells (WiDr) were inoculated in stomas submucosa. Histopathological analysis, real-time reverse transcription-PCR for ß-catenin, p53 and MMP2, as well as immunohistochemical analysis for p53 and ß-catenin expression were conducted. Central tendency, variance analysis and the Livak delta-delta-CT method were used for statistical analysis, adopting a 5% significance level. RESULTS. All tumors from the left colon exhibited infiltrative ulceration, while in the right colon tumor growth was predominantly exophytic (67%). In the left colon, tumor growth was undifferentiated (100%), while it was moderately differentiated in the right colon (83%). In right colon tumors, MMP2, p53, and ß-catenin gene expressions were higher than compared to left colon (p = 4.59354E-05, p = 0.0035179, p = 0.00093798, respectively, for MMP2, p53 and ß-catenin). ß-catenin and p53 results obtained by real-time polymerase chain reaction were confirmed by immunohistochemistry assay (p = 0.01 and p = 0.001, respectively, for ß-catenin and p53). CONCLUSION. Left and right human colon adenocarcinomas developed in animal models have distinct phenotypes even when they have the same clonal origin. Microenvironment has influenced p53, ß-catenin, and MMP2 expression in animal models of colon cancer.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Microambiente Tumoral , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/genética , Fenótipo , Ratos , Ratos Nus , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/genética , beta Catenina/genéticaRESUMO
AIM: To investigate the relationship between beta-catenin and E-cadherin tissue quantitative expression (content) in tumors and clinical prognostic factors in patients with left colon cancer. MATERIAL AND METHODS: Twenty nine patients with colon adenocarcinoma located distal to the splenic flexure were studied. Diagnosis and histological variables related to adenocarcinoma prognosis were evaluated using hematoxylin-eosin. Beta-catenin and E-cadherin were analysed by immunohistochemistry with specific anti-beta-catenin and anti-E-cadherin monoclonal antibodies. Tissue quantitative expression (content) was determined by computer assisted image analysis method. Results were analysed with statistical tests, adopting a significance level of 5%. RESULTS: There are correlations between beta-catenin and TNM stage (p< 0.01). There are progressively greater amounts of beta-catenin in patients with deeper invasion of the tumor in colon layers (p=0.03), progressive lymph node involvement (p=0.05), as well as in patients with distant metastasis (p=0.04). Worse histological grades are related to lower expression of E-cadherin in tumor tissue (p=0.01). CONCLUSIONS: E-cadherin can be used as an indicator of tumor differentiation degree, whereas beta-catenin can be used as a predictor of invasion depth and spread of distal colorectal cancer.