Enhanced apoptosis and inhibition of gastric cancer cell invasion following treatment with LDH@Au loaded Doxorubicin

Background: The suppression of cancer cell growth and invasion has become a challenging clinical issue. In this study, we used nanotechnology to create a new drug delivery system to enhance the efficacy of existing drugs. We developed layered double hydroxide by combing Au nanosol (LDH@Au) and characterized the compound to prove its function as a drug delivery agent. The anti-cancer drug Doxorubicin was loaded into the new drug carrier to assess its quality. We used a combination of apoptosis assays, cell cycle assays, tissue distribution studies, cell endocytosis, transwell invasion assays, and immunoblotting to evaluate the characteristics of LDH@Au as a drug delivery system. Results: Our results show that the LDH@Au-Dox treatment significantly increased cancer cell apoptosis and inhibited cell invasion compared to the control Dox group. Additionally, our data indicate that LDH@Au-Dox has a better target efficiency at the tumor site and improved the following: cellular uptake, anti-angiogenesis action, changes in the cell cycle, and increased caspase pathway activation. Conclusions: Our findings suggest the nano drug is a promising anti-cancer agent and has potential clinical applications.

Angiogenesis and tumor progression inhibition of cyclooxygenase-2 selective inhibitor celecoxib associated with poly (lactic-co-glycolic acid) in tumor cell line resistant to chemotherapy / Inhibición de angiogénesis y progresión tumoral por inhibidor selectivo de ciclooxigenasa-2 celecoxib asociado con ácido (poli láctico co-glicólico) en línea de células tumorales resistentes a quimioterapia

Although, antineoplastic therapies have now been developed reduction of tumor progression,itis necessarytofind new therapeutic alternatives to suppress angiogenesis.Thus celecoxib (Cx) has been used for its antiangiogenic action in combination with certain polymeric compounds such as poly (lactic co-glycolic acid) (PLGA) acid, which help to improve the bioavailability and avoid effects of long drug administrations. For this purpose we used a murine tumor modelinduced by mammary adenocarcinoma cells resistant to chemotherapy (TA3-MTXR). CX/PLGA inhibits the microvascular density, VEGF expression and cell proliferationinaddition to increased apoptosis (P <0.0001). Cx reduces tumor progression in a concentration of 1000 ppm associated with PLGA, reducing cell proliferation, the presence of VEGF and promoting apoptosis of multiresistant TA3 tumor cells.

Si bien actualmente se han desarrollado terapias antineoplásicas que permiten reducir de cierta manera el avance tumoral, es necesario buscar nuevas alternativas terapéuticas que permitan suprimir la angiogénesis. Es así como el Celecoxib (Cx) ha sido utilizado por su acción antiangiogénica en combinación con algunos compuestos poliméricos, tal como el ácido poli (láctico co-glicólico) (PLGA), el cual ayudaría a mejorar la biodisponibilidad y evitaría efectos derivados de largas administraciones del fármaco. Para tal efecto se ha utilizado un modelo tumoral murino, inducido por células tumorales de adenocarcinoma mamario resistente a la quimioterapia (TA3-MTXR). Los resultados indican que CX/PLGA inhibe la microvascularización, expresión de VEGF y la proliferación celular además del aumento de la apoptosis (P<0,0001). El efecto antitumoral del Cx está bien reportado en la literatura; este sumado a la microencapsulación con PLGA, aportarían un sistema de administración útil, ya que nos otorga una administración sostenida en el tiempo, los cual podría ayudar a mantener los niveles de droga durante un período más prolongado, lo cual sería beneficioso en la terapia tumoral.

Propofol inhibits invasion and growth of ovarian cancer cells via regulating miR-9/NF-kappaB signal

Propofol is one of the most commonly used intravenous anesthetic agents during cancer resection surgery. A previous study has found that propofol can inhibit invasion and induce apoptosis of ovarian cancer cells. However, the underlying mechanisms are not known. miR-9 has been reported to be little expressed in ovarian cancer cells, which has been related to a poor prognosis in patients with ovarian cancer. Studies have also demonstrated that propofol could induce microRNAs expression and suppress NF-κB activation in some situations. In the present study, we assessed whether propofol inhibits invasion and induces apoptosis of ovarian cancer cells by miR-9/NF-κB signaling. Ovarian cancer ES-2 cells were transfected with anti-miR-9 or p65 cDNA or p65 siRNA for 24 h, after which the cells were treated with different concentrations of propofol (1, 5, and 10 μg/mL) for 24 h. Cell growth and apoptosis were detected using MTT assay and flow cytometry analysis. Cell migration and invasion were detected using Transwell and Wound-healing assay. Western blot and electrophoretic mobility shift assay were used to detect different protein expression and NF-κB activity. Propofol inhibited cell growth and invasion, and induced cell apoptosis in a dose-dependent manner, which was accompanied by miR-9 activation and NF-κB inactivation. Knockdown of miR-9 abrogated propofol-induced NF-κB activation and MMP-9 expression, reversed propofol-induced cell death and invasion of ES-2 cells. Knockdown of p65 inhibited NF-κB activation rescued the miR-9-induced down-regulation of MMP-9. In addition, overexpression of p65 by p65 cDNA transfection increased propofol-induced NF-κB activation and reversed propofol-induced down-regulation of MMP-9. Propofol upregulates miR-9 expression and inhibits NF-κB activation and its downstream MMP-9 expression, leading to the inhibition of cell growth and invasion of ES-2 cells.

Tolfenamic Acid Inhibits the Proliferation, Migration, and Invasion of Nasopharyngeal Carcinoma: Involvement of p38-Mediated Down-Regulation of Slug

PURPOSE: Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug, is known to exhibit antitumor effects in various cancers apart from nasopharyngeal cancer (NPC). NPC exhibits high invasiveness, as well as metastatic potential, and patients continue to suffer from residual, recurrent, or metastatic disease even after chemoradiation therapy. Therefore, new treatment strategies are needed for NPC. In this study, we investigated the efficacy and molecular mechanisms of TA in NPC treatment. MATERIALS AND METHODS: TA-induced cell death was detected by cell viability assay in the NPC cell lines, HNE1 and HONE1. Wound healing assay, invasion assay, and Western blot analysis were used to evaluate the antitumor effects of TA in NPC cell lines. RESULTS: Treatment with TA suppressed the migration and invasion of HNE1 and HONE1 cells. Hepatocyte growth factor enhanced the proliferation, migration, and invasion abilities of NPC cells. This enhancement was successfully inhibited by TA treatment. Treatment with TA increased phosphorylation of p38, and the inhibition of p38 with SB203580 reversed the cytotoxic, anti-invasive, and anti-migratory effects of TA treatment in NPC cell lines. Moreover, inhibition of p38 also reversed the decrease in expression of Slug that was induced by TA treatment. CONCLUSION: In conclusion, the activation of p38 plays a role in mediating TA-induced cytotoxicity and inhibition of invasion and migration via down-regulation of Slug.

Efecto antimetastásico de celecoxib/PLGA en un modelo murino de adenocarcinoma mamario TA3-MTX-R / Antimetastatic effect of celecoxib/PLGA in a TA3-MTX-R murine breast adenocarcinoma model

La metástasis es el proceso de propagación de un foco cancerígeno a un órgano distinto de aquel en que se inició; ocurriendo generalmente por vía sanguínea o linfática. La localización más frecuentes de las metástasis son los órganos más irrigados como el cerebro, pulmones, hígado, huesos y glándulas suprarrenales. El objetivo fue analizar el patrón de metástasis hepática de tumor TA3-MTX-R, luego de la aplicación del antiangiogénico Celecoxib microencapsulado en PLGA en ratones, así como la disminución de áreas metastásicas a nivel lobulillar. Se utilizó un modelo de tumor experimental, inducido por células TA3-MTX-R, en 18 ratones, separados en 3 grupos de 6 animales, los cuales fueron tratados con dos presentaciones de Celecoxib en administración intramuscular (Grupo 1, Control: TA3-MTX-R; Grupo 2: TA3-MTX-R+Cx y Grupo 3: TA3-MTX-R+Cx/PLGA). Los ratones fueron sacrificados y procesados histológicamente para ser teñidos con H&E y Tricrómico de Arteta. El estudio reveló que el higado muestra una marcada heterogeneidad, y un patrón de metástasis perivascular y neovascularización central y periférica. Además, Celecoxib redujo significativamente la invasión tumoral en el hígado (p<0,0001). Los resultados son similares a descripciones parciales realizadas previamente y son comparables a otras líneas tumorales. Creemos que la vía de administración del fármaco es crítica para la interpretación de los resultados. Los hallazgos son importantes para la discusión de otras investigaciones en donde Celecoxib es usado como un fármaco antiangiogénico.

Metastasis is the propagation process of a cancerous focus to an organ other than that in which it started; usually occurring through blood or lymphatic route. The most common sites of metastases are the organs most irrigated such as the brain, lungs, liver, bones and adrenal glands. The objective was to analyze the pattern of liver tumor metastasis TA3-MTX-R, after application of antiangiogenic Celecoxib microencapsulated in PLGA in mice and decreased metastatic to lobular level areas. An experimental model of tumor induced TA3-MTX-R cells was used, 18 mice divided into 3 groups of 6 animals, which were treated with two presentations Celecoxib intramuscular (Group 1, control was used -R; Group 1: TA3-MTX-R+Cx and Group 3: TA3-MTX-R+Cx/PLGA). The mice were sacrificed and processed histologically to be stained with H&E and Arteta trichrome. The study revealed that the liver shows a marked heterogeneity, and a pattern of perivascular metastasis and central and peripheral neovascularization. Furthermore, Celecoxib significantly reduced tumor invasion in the liver (p <0.0001). The results are similar to partial descriptions made previously and are comparable to other tumor lines. It is believed that the route of administration of the drug is critical for the interpretation of the results. These are important for the discussion of other investigations in which Celecoxib is used as an antiangiogenic drug.

Equol and daidzein decrease migration, invasion and matrix metalloproteinase (MMPs) gene expression in prostate cancer cell lines, DU-145 and PC-3 / Equol y daidzeina disminuyen la migración, invasión y la expresión génica de metaloproteinasa de la matriz(MMPs) en las líneas celulares prostáticas cancerosas DU-145 y PC-3

This search is focused on the study of diet compounds that may have any potential chemopreventive effect against cancer. Some compounds that fulfill this requirement are phytoestrogens. Among them we find genistein (1), the most studied, daidzein (2) and equol (3) (figure 1). To compare the sensitivities of different prostate cancer cells to phytoestrogen treatment, sulphorhodamine B dye assay was performed to determine cell viability. DU-145 and PC-3 prostate cancer cell lines treated with various doses of phytoestrogen (0-12.5-25-50 and 100 μM) for different times (24, 48 and 72h). For cell invasion or migration assay cells were seeded in a Transwell chamber with or without coating Matrigel respectively. DU-145 and PC-3 cells were treated previously with phytoestrogen (50 μM) for 24h. The study showed that equol, daidzein and genistein inhibited migration and invasion in prostate cancer cell lines. Moreover, we analyzed the effects of phytoestrogens in MMP-2 and MMP-9 mRNA expression by RT-PCR. The results indicated that equol, daidzein and genistein diminished the expression of MMP-2 and MMP-9 in a cell-dependent manner. Our data suggested that equol, daidzein and genistein inhibited migration and invasion in prostate cancer cell lines. Moreover, the results also suggest that down-regulation of MMP-2 and MMP- 9 might be involved in the inhibition of invasion of PC-3 and DU-145 cells after genistein, daidzein and equol treatment.

Este trabajo se centra en el estudio de los compuestos de dieta que pueden tener potencial efecto quimiopreventivo contra el cáncer. Algunos de estos compuestos son los fitoestrógenos. Entre ellos encontramos la genisteína (1), el más estudiado, la daidzeína (2) y el equol (3) (figura 1). Para comparar el efecto de estos fitoestrogenos sobre las líneas celulares de cáncer de próstata, DU-145 y PC-3, se utilizó el ensayo de sulforodamina B para determinar la viabilidad celular tras los tratamientos con diferentes concentraciones de fitoestrógenos (0-12.5-25-50-100 μM) durante diferentes tiempos (24, 48, 72 h). Para analizar el efecto sobre la migración celular, las células DU-145 y PC-3 fueron tratadas previamente con una concentración de fitoestrógrno (50 μM) durante 24 horas y sembradas en una cámara Transwell sin recubrir. El estudio mostró que el equol, daidzeína y genisteína inhibió en MMP-2 y MMP-9 expresiones de genes en líneas celulares de cáncer de próstata, la PC-3 y DU-145. Los resultados indicaron que la daidzeína disminuyó la expresión de MMP- 2 y MMP-9 en DU-145 células. Nuestros datos sugieren que equol, daidzeína y genisteína inhiben la migración y la invasión de líneas celulares de cáncer de próstata.

O corpo da nação: posicionamentos governamentais sobre a educação física no Brasil monárquico / The body of the nation: government positions on physical education during tHe Brazilian monarchy

Associadas a projetos de construção da ideia de nação, no Brasil monárquico foram encaminhadas, pelo governo imperial, algumas iniciativas no sentido de materializar propostas de educação física. O objetivo deste artigo é investigar os sentidos e significados atribuídos ao tema na legislação e nos relatórios anuais do Ministério dos Negócios do Império (1831-1889), com especial interesse pelo que se refere ao Rio de Janeiro. A abordagem do assunto nas fontes pesquisadas evidencia que as visões sobre a educação física se deram a partir de uma matriz que articulava concepções de moral, saúde e civilização, tendo que lidar com as condições concretas de um país recém-independente, periférico e com uma burocracia ainda em formação.

In association with its nation building projects, the imperial government in Brazil under monarchic rule took some concrete actions based on proposals for physical education. The aim of this article is to investigate the meanings and significations attributed to this subject in the legislation and the annual reports issued by the Ministry of Business of the Empire (1831-1889), giving special attention to Rio de Janeiro. The approach to the subject in the sources researched demonstrates that the views of physical education took shape through a web of ideas that associated moral, health and civilization conceptions, in a bid to deal with the concrete circumstances of a newly independent peripheral nation with a bureaucratic structure in the process of formation.

Evolución en la forma de sospecha y extensión de la cirugía del cáncer de mama en un centro de radio-oncología / Evolution in breast cancer suspicion and extent of surgery at a radio-oncology center

Introduction: Breast cancer diagnosis and treatment had evolved over the past quarter century. From self-examination to mammography as main suspicion tool and from radical to conservative surgery plus radiotherapy as prefered treatment. The aim of this review was to assess the evolution of presentation and local management of breast cancer at a Chilean radio-oncology center. Materials and Methods: We analyzed 1.204 breast cancer patients who received postoperative irradiation on two four-years periods. The first period included 223 patients and coincides with the introduction of mammography and conservative surgery. The second included 981 patients managed according to current guidelines. The variables analyzed were type of clinical suspicion, time between clinical suspicion and diagnosis confirmation, type of surgery, histology and tumor size. Data were obtained from medical records and analyzed using STATA 12. Results: In the second period mammographic suspicion reached 39.8 percent. Time between clinical suspicion and histological diagnosis was reduced to 50 percent, the proportion of tumors larger than 2 cm was reduced from 61 to 45 percent, the proportion of DCIS was tripled from 6 to 18 percent, use of conservative surgery has an absolute increase of 28 percent. All of these differences were statistically significant (p < 0.01). Conclusion: The introduction of mammography and conservative management allowed early diagnosis of breast cancer in the analyzed population.

Introducción: El enfrentamiento del cáncer de mama evolucionó en el último cuarto de siglo desde el autoexamen a la mamografía como herramienta de sospecha y desde el tratamiento con cirugía radical a la cirugía conservadora más radioterapia. El objetivo de esta revisión fue evaluar la evolución de la presentación y manejo local del cáncer de mama en un centro de radio-oncología. Materiales y Método: Se analizaron 1.204 pacientes con cáncer de mama que recibieron irradiación post-operatoria en dos períodos de cuatro años. El primer período incluyó 223 pacientes y coincide con la introducción de mamografía y cirugía conservadora. El segundo incluyó 981 pacientes manejadas según el estándar actual. Las variables analizadas fueron: forma de sospecha, tiempo entre sospecha y confirmación diagnóstica, tipo de cirugía, histología y tamaño tumoral. Los datos fueron obtenidos de fichas clínicas y analizados con STATA 12. Resultados: Al comparar el segundo período con el primero se evidenció un aumento absoluto del 39,8 por ciento de la sospecha por mamografía, disminución a la mitad del tiempo entre sospecha y diagnóstico histológico, reducción de la proporción de tumores mayores a 2 cm de 61 a 45 por ciento, triplicación en la proporción de carcinoma ductal in situ de 6 a 18 por ciento y aumento absoluto de 28 por ciento del uso de cirugía conservadora. Todas estas diferencias fueron estadísticamente significativas (p < 0,01). Conclusión: En el grupo analizado la introducción de mamografía y manejo conservador se asoció a un aumento de sospecha y diagnóstico precoz del cáncer de mama.

Role of the extracellular matrix in variations of invasive pathways in lung cancers

Among the most common features of highly invasive tumors, such as lung adenocarcinomas (AD) and squamous cell carcinomas (SqCC), is the massive degradation of the extracellular matrix. The remarkable qualitative and quantitative modifications of hyaluronidases (HAases), hyaluronan synthases (HAS), E-cadherin adhesion molecules, and the transforming growth factor β (TGF-β) may favor invasion, cellular motility, and proliferation. We examined HAase proteins (Hyal), HAS, E-cadherin, and TGF-β profiles in lung AD subtypes and SqCC obtained from smokers and non-smokers. Fifty-six patients, median age 64 years, who underwent lobectomy for AD (N = 31) and SqCC (N = 25) were included in the study. HAS-1, -2 and -3, and Hyal-1 and -3 were significantly more expressed by tumor cells than normal and stroma cells (P < 0.01). When stratified according to histologic types, HAS-3 and Hyal-1 immunoreactivity was significantly increased in tumor cells of AD (P = 0.01) and stroma of SqCC (P = 0.002), respectively. Tobacco history in patients with AD was significantly associated with increased HAS-3 immunoreactivity in tumor cells (P < 0.01). Stroma cells of SqCC from non-smokers presented a significant association with HAS-3 (P < 0.01). Hyal, HAS, E-cadherin, and TGF-β modulate a different tumor-induced invasive pathway in lung AD subgroups and SqCC. HAases in resected AD and SqCC were strongly related to the prognosis. Therefore, our findings suggest that strategies aimed at preventing high HAS-3 and Hyal-1 synthesis, or local responses to low TGF-β and E-cadherin, may have a greater impact in lung cancer prognosis.

Radioquimioterapia neoadyuvante en cáncer gástrico T4 localmente irresecable: resultados preliminares / Chemoradiotherapy in patients with non resectable gastric cancer: report of 10 patients

En el caso de pacientes con cáncer gástrico T4, puede estar indicada la quimiorradioterapia si no es posible la resección de las estructuras infiltradas. Analizamos 10 pacientes con cáncer gástrico irresecable (8 hombres, 2 mujeres) tratados por nosotros en el periodo 2003-2005. Después de la laparotomía exploradora, los pacientes con cáncer gástrico localmente avanzados e irresecables son tratados con RT-QT concomitante 2 semanas después de la laparotomía. El tratamiento consistió en radioterapia a dosis de 45 Gy en 25 fracciones de 1.8 Gy, 5 veces por semana por 5 semanas sobre estómago y linfáticosregionales, y 5 FU en 1ª y 5º semana (425mg/m2) o Capecitabina 825 mg/m2 diarios, en dos dosis, cada12 hrs. Un mes después se realiza la segunda laparotomía con resección del estómago y linfadenectomía en casos de remisión total o parcial de la enfermedad. Todos los carcinomas fueron proximales. Nueve pacientes se reintervinieron, un paciente tuvo progresión de la enfermedad. Un paciente fue nuevamente irresecable y ocho fueron sometidos a una gastrectomía total D2. Se logró respuesta patológica completa en tres casos (no había cáncer residual en el estómago ni en los ganglios) y parcial en cinco. Creemos que en cáncer gástrico T4 localmente irresecable la RT-QT seguida de cirugía es una buena alternativa terapéutica.

Estrategias efectivas para aumentar la cobertura del Papanicolaou en el programa de detección del cáncer cervicouterino / Effective strategies to increase the papanicolau coverage in the cervicouterine cancer detection program

El aumento de las coberturas del Papanicolaou depende de múltiples factores donde se destaca la motivación de los equipos de salud, en especial de la profesional matrona, así como de una red de apoyo interdisciplinario y comunitaria destinada a captar mujeres, y el concepto de auto-cuidado que tenga internalizado cada mujer. El objetivo de este trabajo es dar a conocer estrategias de salud pública que permitieron aumentar la cobertura del Papanicolaou (Pap) vigente en mujeres beneficiarias en un 12 y 8% en los Servicios de Salud Valdivia y Metropolitano Norte. Las estrategias de salud pública probadas en este estudio como efectivas fueron: a)fomento de la informática con: la instalación del cito-expert en la atención primaria, planilla de cálculo de coberturas y estadística mensual, planilla de contra-referencia de pacientes atendidas en la UPC y envío vía e-mail cada tres días; b) Captación de monitoras de Pap en la comunidad;c) Investigación operativa y capacitación permanente a matronas, médicos y monitoras de Pap.d) Implementación de un banco de proyectos de promoción. Esto traducido en el efecto en la salud de la mujer ha significado diagnosticar NIE III cuatro veces más que en 1993, detectar el cáncer invasor en etapas iniciales (etapas I y II), y descender consecuentemente la mortalidad por esta enfermedad, alcanzando actualmente a una tasa de 4,6 por 100.000 mujeres mayores de 15 años en el Servicio de Salud de Valdivia.

The increase in Papanicolau coverage depends on multiple factors, in which the motivation of health teams stands out, specially that of the professional midwife, aided by an interdisciplinaryand community support network destined to attract women, and the concept of self care that each woman has internalized. The objective of this work is that of making available public health strategies allowing to bring about an increase in Papanicolau (PAP) coverage in beneficiary women by a 12 percent and 8% in the Valdivia and North Metropolitan Health Services respectively. The public health strategies proved as effective in this study were: a) promotion of the informative aspect, with installation of the cito-expert in primary attention, statements of coverage calculations and monthly statistics, counter-reference statement of patients attended at the Cervical Pathology Unit (UPC) and e-mail dispatch every three days; b) winning over of Pap monitors in the community; c) operative research and permanent training of midwives, physicians and Pap monitors; d) implementation of a promotion projects bank. This, translated into the effect on women’s health, has implied diagnosing intraepithelial neoplasia III (NIE III) four times as much as in 1993 and invasive cancer in its initial stages (stages I and II) and, consequently, decreasing mortality from this disease which, at present, reaches a rate of 4.6 per 100.000 women over 15 years of age in the Valdivia Health Service.

Role of chemoradiation in advanced cervical cancer.

A prospective randomized study was conducted in our department of Radiotherapy, Regional Institute of Medical Sciences, Imphal to evaluating the role of chemoradiation in the management of advanced inoperable cervical cancer (stage IIB-IIIB) taking only radiation treatment as control spanning the period 1996-1999. Of the fifty patients accumulated in the study group, three patients did not complete treatment, one expired due to other causes and three were lost to follow up. Likewise, of the forty-six patients in the control group, one patient did not complete treatment and 4 were lost to follow up. Thus only 43 and 41 patients were available for the result analysis for the study and control groups respectively. The early treatment response as assessed after two months of treatment conclusion were 79.1%, 13.9%, 93.0% and 58.5%, 31.7%, 90.2% as complete response (CR), partial response (PR), and total response (TR) respectively for the study and control groups. Our patients included in this study had a median follow up of 35 months and 33 months for study and control groups respectively. For this follow up, the disease-free survival, survival with disease and overall survival were 67.4%, 7.0%, 74.4% and 43.9%, 12.2%, 56.1% for study and control groups respectively. There was an increase in early side-effects in the chemoradiation group but the difference was not significant. Because of the early side effects, treatment delays ensued in 7 patients (16.3%) and in 3 patients (7.3%) in the study and control groups respectively. There was no significant increase in the late treatment toxicities in both the groups.