AAZ2 induces mitochondrial-dependent apoptosis by targeting PDK1 in gastric cancer / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.

Cytotoxic effect of hydroalcoholic extract of Cota tinctoria (L) J. Gay on AGS and Hep-G2 cancer cell lines / Efecto citotóxico del extracto hidroalcohólico de Cota tinctoria (L) J. Gay sobre líneas celulares de cáncer AGS y Hep-G2

Cota tinctoria is a medicinal plant which has been used for management of cancer in folk medicine of various regions. The aim of present study is to investigate cytotoxic activity of different concentrations of hydroalcoholic extract of C. tinctoria flowers on gastric (AGS) and liver (Hep-G2) cancer cell lines as well as Human Natural GUM fibroblast (HUGU) cells. Cell mortality rates were examined after 24, 48 and 72 h incubations using the MTT assay. IC50of extract on AGS cells after 24, 48 and 72h was 1.46, 1.29 and 1.14 µg/mL respectively. The extract demonstrated IC50 of 5.15, 3.92 and 2.89 µg/mL on Hep-G2 cells after 24, 48 and 72 h respectively. No cytotoxic effect was detected on HUGU (Human Natural GUM fibroblast) cells. C. tinctoria seems to have a promising potential to be considered as a source for anticancer drug discovery. However, more experimental and clinical studies are required.

Cota tinctoria es una planta medicinal que se ha utilizado para el tratamiento del cáncer en la medicina popular de varias regiones. El objetivo del presente estudio es investigar la actividad citotóxica de diferentes concentraciones de extracto hidroalcohólico de flores de C. tinctoria en líneas celulares de cáncer gástrico (AGS) e hígado (Hep-G2), así como en células de fibroblasto GUM humano natural (HUGU). Se examinaron las tasas de mortalidad celular después de incubaciones de 24, 48 y 72 h utilizando el ensayo MTT. La CI50 del extracto en células AGS después de 24, 48 y 72 h fue de 1,46; 1,29 y 1,14 µg respectivamente. El extracto demostró una CI50 de 5,15, 3,92 y 2,89 µg/mL en células Hep-G2 después de 24, 48 y 72 h, respectivamente. No se detectó ningún efecto citotóxico en las células HUGU (fibroblasto GUM humano natural). C. tinctoria parece tener un potencial prometedor para ser considerada como una fuente de descubrimiento de fármacos contra el cáncer. Sin embargo, se requieren más estudios experimentales y clínicos.

Effect of hypoxia on HIF -1 α/MDR1/VEGF expression in gastric cancer cells treated with 5 -fluorouracil / 中南大学学报(医学版)

OBJECTIVES@#Fluorouracil chemotherapeutic drugs are the classic treatment drugs of gastric cancer. But the problem of drug resistance severely limits their clinical application. This study aims to investigate whether hypoxia microenvironment affects gastric cancer resistance to 5-fluorouracil (5-FU) and discuss the changes of gene and proteins directly related to drug resistance under hypoxia condition.@*METHODS@#Gastric cancer cells were treated with 5-FU in hypoxia/normoxic environment, and were divided into a Normoxic+5-FU group and a Hypoxia+5-FU group. The apoptosis assay was conducted by flow cytometry Annexin V/PI double staining. The real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to detect the expression level of hypoxia inducible factor-1α (HIF-1α), multidrug resistance (MDR1) gene, P-glycoprotein (P-gp), and vascular endothelial growth factor (VEGF) which were related to 5-FU drug-resistance. We analyzed the effect of hypoxia on the treatment of gastric cancer with 5-FU.@*RESULTS@#Compared with the Normoxic+5-FU group, the apoptosis of gastric cancer cells treated with 5-FU in the Hypoxia+5-FU group was significantly reduced (P<0.05), and the expression of apoptosis promoter protein caspase 8 was also decreased. Compared with the the Normoxic+5-FU group, HIF-1α mRNA expression in the Hypoxia+5-FU group was significantly increased (P<0.05), and the mRNA and protein expression levels of MDR1, P-gp and VEGF were also significantly increased (all P<0.05). The increased expression of MDR1, P-gp and VEGF had the same trend with the expression of HIF-1α.@*CONCLUSIONS@#Hypoxia is a direct influencing factor in gastric cancer resistance to 5-FU chemotherapy. Improvement of the local hypoxia microenvironment of gastric cancer may be a new idea for overcoming the resistance to 5-FU in gastric cancer.

Safety and short-term efficacy of apatinib combined with oxaliplatin and S-1 in the conversion treatment for gastric cancer with peritoneal metastasis / 中华胃肠外科杂志

Objective: To investigate the safety and short-term efficacy of apatinib combined with oxaliplatin and S-1 in the conversion treatment for gastric cancer with different types of peritoneal metastasis. Methods: A prospective study "one arm exploratory clinical study of conversion therapy of apatinib with S-1 and oxaliplatin in the treatment of advanced gastric cancer" (clinical registration ChiCTR-ONC-17010430) from medical record database was retrospectively analyzed. Patients aged 18-70 years with gastric cancer peritoneal metastasis confirmed by histology and laparoscopic exploration, and had not receive radiotherapy, chemotherapy, targeted therapy or immunotherapy before were enrolled. Before operation, the patients received 6 cycles of S-1 (80-120 mg/d, d1-d14) and oxaliplatin (130 mg/m(2), d1), and 5 cycles of apatinib (500 mg/d, d1-d21) conversion regimen. Three weeks after chemotherapy, whether the operation was performed or not depending on re-evaluation and patient preference. The main outcome were adverse reactions, and the secondary outcome were objective remission rate (ORR), disease control rate (DCR), and overall survival (OS) rate. The follow-up period was up to May 2020. Results: A total of 27 patients with gastric cancer peritoneal metastasis were enrolled in this study. There were 13 males and 14 females, with a median age of 58 (30-68) years old. There were 9 cases of P1a, 5 cases of P1b, and 13 cases of P1c. There were 14 cases with 1-5 scores of PCI (peritoneal cancer index), and 13 cases with 6 scores or above. The incidence of adverse reactions was 100%. The most common adverse reactions were hematological events including leucopenia (70.4%, 19/27) and granulocytopenia (74.1%, 20/27). Non-hematological adverse events included fatigue (51.9%, 14/27) and oral mucositis (37.0%, 10/27). One patient was withdrawn due to grade 4 thrombocytopenia. Among 26 patients with feasible efficacy evaluation, 18 (69.2%) achieved partial remission, 3 (11.5%) achieved stable disease, and 5 (19.2%) disease progression. The objective remission rate was 69.2% (18/26) and the disease control rate was 80.8% (21/26). Fourteen patients underwent surgery, including 6 patients undergoing R0 resection with the R0 resection rate of 42.9% (6/14). The postoperative pathological response rate was 64.3% (9/14). The follow-up time was 12-40 months, and the follow-up rate was 100%. The 1-year OS rate was 65.2% and the survival time was (14.0±1.7) months. The 1-year OS rates of P1a/P1b group and P1c group were 81.8% and 42.0% respectively, whose difference was statistically significant (P=0.041). The 1-year OS rates of PCI 1-5 group and PCI ≥6 group were 67.3% and 38.5% respectively, whose difference was statistically significant (P=0.022). Conclusion: In the conversion treatment of gastric cancer peritoneal metastasis, the safety of apatinib combined with oxaliplatin and S-1 is acceptable, and this regimen shows a good short-term survival efficacy in patients with P1a/P1b and PCI of 1-5.

Endoscopic characteristics of patients with complete pathological response after neoadjuvant chemotherapy for gastric and esophagogastric junction adenocarcinomas / Características endoscópicas de pacientes com resposta patológica completa após quimioterapia neoadjuvante para adenocarcinomas gástricos e de junção esofagogástrica

ABSTRACT Background: Gastric and esophagogastric junction adenocarcinoma are responsible for approximately 13.5% of cancer-related deaths. Given the fact that these tumors are not typically detected until they are already in the advanced stages, neoadjuvancy plays a fundamental role in improving long-term survival. Identification of those with complete pathological response (pCR) after neoadjuvant chemotherapy (NAC) is a major challenge, with effects on organ preservation, extent of resection, and additional surgery. There is little or no information in the literature about which endoscopic signs should be evaluated after NAC, or even when such re-evaluation should occur. Aim: To describe the endoscopic aspects of patients with gastric and esophagogastric junction adenocarcinomas who underwent NAC and achieved pCR, and to determine the accuracy of esophagogastroduodenoscopy (EGD) in predicting the pCR. Methods: A survey was conducted of the medical records of patients with these tumors who were submitted to gastrectomy after NAC, with anatomopathological result of pCR. Results: Twenty-nine patients were identified who achieved pCR after NAC within the study period. Endoscopic responses were used to classify patients into two groups: G1-endoscopic findings consistent with pCR and G2-endoscopic findings not consistent with pCR. Endoscopic evaluation in G1 was present in an equal percentage (47.4%; p=0.28) in Borrmann classification II and III. In this group, the predominance was in the gastric body (57.9%; p=0.14), intestinal subtype with 42.1% (p=0.75), undifferentiated degree, 62.5% (p=0.78), Herb+ in 73.3% (p=0.68). The most significant finding, however, was that the time interval between NAC and EGD was longer for G1 than G2 (24.4 vs. 10.2 days, p=0.008). Conclusion: EGD after NAC seems to be a useful tool for predicting pCR, and it may be possible to use it to create a reliable response classification. In addition, the time interval between NAC and EGD appears to significantly influence the predictive power of endoscopy for pCR.

RESUMO Racional: O adenocarcinoma gástrico e da junção esofagogástrica é responsável por aproximadamente 13,5% das mortes relacionadas ao câncer. Dado que esses tumores não são normalmente detectados até que já estejam em estágios avançados, a neoadjuvância desempenha um papel fundamental na melhoria da sobrevida em longo prazo. A identificação daqueles com resposta patológica completa (pCR) após a quimioterapia neoadjuvante (NAC) é um grande desafio, com efeitos na preservação do órgão, extensão da ressecção e cirurgia adicional. Há pouca ou nenhuma informação na literatura sobre quais sinais endoscópicos devem ser avaliados após a NAC, ou mesmo quando essa reavaliação deve ocorrer. Objetivo: Descrever os aspectos endoscópicos de pacientes com adenocarcinoma gástrico e da junção esofagogástrica que foram submetidos à quimioterapia neoadjuvante e alcançaram pCR, e determinar a acurácia da esofagogastroduodenoscopia (EGD) em predizer a pCR. Métodos: Foram revisados os prontuários de pacientes submetidos à gastrectomia subtotal e total após NAC, com resultado anatomopatológico de pCR. Resultados: Vinte e nove pacientes que alcançaram pCR após NAC foram identificados no período estudado. As respostas endoscópicas foram usadas para classificar os pacientes em dois grupos: G1- achados endoscópicos consistentes com pCR, G2 - achados endoscópicos não consistentes com pCR. A avaliação endoscópica no G1 esteve presente em igual percentual (47,4%; p=0,28) na classificação de Borrmann II e III. Nesse grupo, a predominância foi no corpo gástrico (57,9%; p=0,14), subtipo intestinal com 42,1% (p=0,75), grau indiferenciado, 62,5% (p=0,78), Herb+ em 73,3% (p=0,68). O achado mais significativo, no entanto, foi que o intervalo de tempo entre NAC e EGD foi maior para G1 do que G2 (24,4 vs. 10,2 dias, p=0,008). Conclusão: A EGD após NAC, nessa pesquisa, sugeriu ser método útil para prever pCR, mediante uma classificação de resposta confiável. Além disso, o intervalo de tempo entre NAC e EGD parece influenciar significativamente a sua capacidade preditiva de diagnosticar a pCR.

Research progress in establishment of N-methyl-N'-nitro-N-nitroso-guanidine-induced rat model of Precancerous lesion of gastric cancer / 中国中药杂志

Gastric cancer(GC), one of the most common malignancies worldwide, seriously threatens human health due to its high morbidity and mortality. Precancerous lesion of gastric cancer(PLGC) is a critical stage for preventing the occurrence of gastric cancer, and PLGC therapy has frequently been investigated in clinical research. Exploring the proper animal modeling methods is necessary since animal experiment acts as the main avenue of the research on GC treatment. At present, N-methyl-N'-nitro-N-nitroso-guanidine(MNNG) serves as a common chemical inducer for the rat model of GC and PLGC. In this study, MNNG-based methods for modeling PLGC rats in related papers were summarized, and the applications and effects of these methods were demonstrated by examples. Additionally, the advantages, disadvantages, and precautions of various modeling methods were briefly reviewed, and the experience of this research group in exploring modeling methods was shared. This study is expected to provide a reference for the establishment of MNNG-induced PLGC animal model, and a model support for the following studies on PLGC.

Extract from Zanthoxylum piperitum Induces Apoptosis of AGS Gastric Cancer Cells Through Akt/MDM2/p53 Signaling Pathway / 中国结合医学杂志

OBJECTIVE@#To determine the effect of Zanthoxylum piperitum extracet (ZPE) on apoptosis and analyze anticancer substances in ZPE, changes in proteins related to apoptosis, and pathological changes in tumors in mouse.@*METHODS@#Fifteen 4-week-old female BALB/c nu/nu mice were divided into 3 groups depending on ZPE dose, with 5 in each group. AGS gastric carcinoma cells (1 × 10@*RESULTS@#High performance liquid chromatography (HPLC) analysis showed that ZPE contained organic sulfur compounds such as alliin and S-allylcysteine. MTT assay results revealed that ZPE (10-85 µ g/mL) could effectively inhibit the growth of AGS gastric cancer cells at higher concentrations (P<0.05, P<0.01). The annexin V & dead cell staining assay and cell cycle arrest assay confirmed a dose-dependent increase in the apoptosis rate and G@*CONCLUSION@#ZPE decreases AGS cell proliferation and induces apoptosis by inhibiting Akt and MDM2 expression.

Identification of active components of Dendrobium inhibit growth of gastric cancer cells based on component-activity relationship / 中国中药杂志

Three cancer cell lines including gastric cancer SGC-7901, HGC-27, and MGC-803 cells were employed to evaluate the bioactivity of seven Dendrobium species. Simultaneously, these Dendrobium species were assessed with UPLC-Q-TOF-MS, and 504 common peaks were found. Based on the hypothesis that biological effects varied with differences in components, multivariate relevance analysis for chemical component-activity relationship of Dendrobium, including grey relation(GRA) and partial least squares(PLS) analysis were performed to evaluate the contribution of each identified component. The target peaks were identified by standards toge-ther with databases of Dendrobium, Nature Chemistry, MassBank, etc. Finally, four active components, including 3,5,9-trihydroxy-23-methylergosta-7,22-dien-6-one, diacylglycerol(14∶1/22∶6/0∶0), pipercitine, and 22-tricosenoic acid, might have negative effect on the growth of gastric cancer cells.

Biomarcadores suPAR y citocinas en la detección temprana de cáncer gástrico / suPAR and cytokines as biomarkers in early detection of gastric cancer

El cáncer gástrico (CG) es un problema prevalente a nivel mundial, presentándose aproximadamente 18 millones de casos nuevos en el año 2018, representa el 5.7% del total de cánceres, siendo la quinta neoplasia maligna más común en el mundo. En Guatemala se sitúa entre los primeros cinco cánceres respecto a morbilidad y mor-talidad. El CG se ha asociado de manera contundente a infección por Helicobacter pylori el cual desencadena un proceso inflamatorio crónico; adicionalmente algunas cepas de H. pylori producen toxinas bacterianas capaces de inducir cambios celulares que conllevan al desarrollo del proceso neoplásico. La alta mortalidad por CG en parte, se relaciona con la etapa tardía en la que se diagnostica ya que se requiere el uso de métodos invasivos, lo que dificulta su detección temprana. El objetivo de la presente revisión, fue realizar una narrativa de los estudios y las evidencias científicas, respecto de la identificación de biomarcadores séricos en la detección temprana del cáncer gástrico. Se revisaron dos tipos de biomarcadores, la proteína soluble uPAR (suPAR) que es el receptor del activador del plasminógeno (uroquinasa) y promotora de angiogénesis y por otro lado, la detección sérica de las citocinas IL-1ß, IL-6, TNFα, IL-10, IFNγ, IL-4 e IL-17 en el CG así como su potencial utilidad en su detección temprana. Estos biomarcadores fueron seleccionados por la ventaja que tendrían de ser métodos no invasivos que podrían mejorar la detección, tratamiento y pronóstico de esta enfermedad.

Gastric cancer (GC) is a prevalent problem worldwide, presenting approximately 18 million new cases in 2018, representing 5.7% of all cancers, being the fifth most common malignancy in the world. In Guatemala it is among the first five cancers in terms of morbidity and mortality. CG has been strongly associated with Helicobacter pylori infection, which triggers a chronic inflammatory process; additionally, some strains of H. pylori produce bacterial toxins capable of inducing cellular changes that lead to the development of cancer. The high mortality due to GC in part is related to the late stage in which it is diagnosed since the use of invasive methods is required, making it difficult to detect it early. The objective of this review was to make a narrative of the studies carried out and the scientific evidence regarding the identification of serum biomarkers in the early detection of gastric cancer. Two types of biomarkers were reviewed, the soluble protein uPAR (suPAR) which is the receptor for plasminogen activator (urokinase) and promoter of angiogenesis and, on the other hand, serum detection of cytokines IL-1ß, IL-6, TNFα, IL-10, IFNγ, IL-4 and IL-17 in the CG as well as its potential usefulness in its early detection. These biomarkers were selected for the advantage they would have of being non-invasive methods that could improve the detection, treatment and prognosis of this disease.

Mieloptisis y cáncer gástrico: Una asociación infrecuente / Myelophthisis and gastric cancer. An unusual association

Se denomina mieloptisis a la infiltración de la médula ósea por células no hematopoyéticas. En pacientes con cáncer gástrico esta invasión es extremadamente infrecuente y la supervivencia suele ser menor a tres meses. Presentamos el caso de un hombre de 35 años con compromiso de la médula ósea secundario a un carcinoma gástrico difuso de células en anillo de sello.

The infiltration of the bone marrow y non-hematopoietic cells is called myelophthisis. In patients with gastric cancer, this invasion is extremely infrequent and the survival is usually less than three months. We present the case of a 35-year-old man with bone marrow involvement secondary to diffuse gastric carcinoma of signet ring cells.

Effect of ethyl acetate extract of usnea longissima on esophagogastric adenocarcinoma in rats

Abstract Purpose: To investigate the effects of the EtOAc extract of U. longissima which is uninvestigated previously on esophagogastric cancer induced in rats with N-methyl-N-nitro-N-nitrosoguanidin (MNNG). Methods: The anticancer activity of EtOAc extract of U. longissima was examined in the esophagogastric adenocarcinoma models induced in rats with MNNG. EtOAc extract of U. longissima, 50 and 100 mg/kg oral doses were administered once daily for six months. MNNG induced differentiated and undifferentiated type adenocarcinomas in the esophageal and gastric tissues of rats. Results: EtOAc extract of U. longissima obtained from U. longissima prevented gastric and esophageal cancerogenesis induced in rats with MNNG. EtOAc extract of U. longissima did not have a lethal effect at doses of 500, 1000 and 2000 mg/kg. The prominent anticarcinogenic activity of EtOAc extract of U. longissima 50 and 100 mg/kg suggests that it is not toxic and it is selective to the cancer tissue. Conclusion: This information may shed light on clinical implementation of EtOAc extract of U. longissima in future.

Modificación del abordaje quirúrgico en tumores estromales gástricos posterior a neoadyuvancia con Imatinib / Change of surgical approach in gastrointestinal stromal tumors after neoadyuvant therapy with Imatinib

Resumen Introducción: El tratamiento de los tumores estromales gastrointestinales (GIST) de alto riesgo es quirúrgico. Su resultado podría variar al usarse neoadyuvancia. Objetivo: Evaluar si el uso de la terapia neoadyuvante con imatinib puede cambiar el abordaje quirúrgico en los tumores estromales gastrointestinales de alto riesgo. Materiales y Métodos: Se realizó un análisis retrospectivo en el Hospital Clínic de Barcelona entre enero de 2002 y mayo de 2016. Resultados: Se obtuvo un total de 8 pacientes. La edad media fue 66,1 ± 13,3 años. La ubicación del tumor fue de 37,5% (3) en el tercio superior, el 50% (4) en el tercio medio y el 12,5% (1) en el tercio inferior. Debido a la clasificación de riesgo alto, la ubicación y/o la necesidad de resecciones multiviscerales, se indicó, previa evaluación comité oncológico, realizar terapia neoadyuvante. La mediana de tiempo de neoadyuvancia fue de 30 semanas. En el 100% (8) de los casos se logró un cambio de enfoque quirúrgico después de la utilización de imatinib. En todos los casos se realizó un resección local (7 laparoscópica y 1 endolaparoscópica) con márgenes negativos La biopsia posoperatoria mostró un promedio de 51,2% de reducción del tamaño tumoral inicial, lo que resultó en una diferencia estadística (p < 0,01) con el tamaño inicial de las lesiones. Durante el seguimiento, tanto la sobrevida relacionada al tumor como la global, fue de un 100%. Conclusión: La terapia neoadyuvante podría cambiar el abordaje quirúrgico de los pacientes con GIST gástrico de riesgo intermedio o alto mediante la reducción del tamaño tumoral, permitiendo realizar cirugías más económicas y logrando resultados oncológicos adecuados.

Introduction: The treatment of high-risk gastrointestinal stromal tumors (GIST) is surgical. Results may change when using neoadjuvant. Objetive: To evaluated if the use of neoadjuvant therapy with imatinib can change the surgical approach in high risk gastrointestinal stromal tumors (GIST). Materials and Methods: A retrospective analysis was performed from a prospective collected database in Hospital Clinic of Barcelona between January 2002 and May 2016. Results: A total of 8 patients were analyzed with a mean age of 66.1 ± 13.3 years. The tumor location was upper third 37.5% (3) cases, 50% (4) in the middle third and 12.5% (1) in lower third. Because of high risk classification, location and the need of multivisceral resections, neoadjuvant therapy was indicated. The median time of neoadjuvant therapy was 30 weeks. In 87.5% (7) cases a change of surgical approach was achieved after the use of imatinib. In 100% of our series laparoscopic wedge resection was performed achieving negative margins of resection. The postoperative biopsy showed 51.2% of reduction of initial tumor size, resulting in statistical difference (p < 0.01). All patients are alive and 100% of tumor related survival was achieved. Conclusion: Neoadjuvant therapy maybe can change the surgical approach of patients with high-intermediate risk gastric GIST by reducing tumor size. This response also eventually can achieve optimal oncological outcome.

Huge recurrent gastric neuroendocrine tumor: a second-line chemotherapeutic dilemma

Chemotherapy is considered "state of the art" for the treatment of poorly differentiated neuroendocrine neoplasms. Unfortunately, there is no standard effective post-first-line treatment for relapsing high-grade gastroenteropancreatic neuroendocrine neoplasms. We report the case of a patient with a gastric neuroendocrine carcinoma stage IV, with massive gastrointestinal bleeding at diagnosis. After the first line of platin-based chemotherapy a major tumoral response was documented, but the patient relapsed after 4 months. A second line of chemotherapy treatment was given, with the FOLFOX regimen, and the patient has been free of progression for almost 2 years. There is no second-line standard treatment accepted for this type of carcinoma, but 5-fluorouracil combined with oxaliplatin showed interesting antitumor activity.

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.

Papel das vesículas extracelulares secretadas por adenocarcinomas gástricos na resposta ao tratamento quimioterápico / Role of extracellular vesicles secreted by gastric adenocarcinomas in response to chemotherapy

O adenocarcinoma gástrico (AdG) é a terceira causa mais comum de morte por câncer no mundo e um dos tumores com maior índice de mortalidade no Brasil. Estes tumores aparecem em terceiro lugar na incidência entre homens e em quinto nas mulheres. A quimioterapia neoadjuvante (QT) com 5-fluorouracil (5-FU) pode melhorar a ressecabilidade e a sobrevida dos pacientes com AdG, porém sua eficácia está limitada pela resistência à droga. Apenas pacientes que respondem a esta terapia com toxicidade tolerável são potencialmente beneficiados, entretanto não é possível identificar e separar clinicamente estes indivíduos. Assim, identificar marcadores preditivos de resposta para selecionar os pacientes que se beneficiariam deste tratamento é relevante. Vesículas extracelulares (VEs) são componentes secretados pelas células incluindo células tumorais, cujo conteúdo é regulado e composto por moléculas que podem ter uma miríade de funções locais e a distância. Muitas destas moléculas podem ser também usadas como biomarcadores séricos por conterem informações importantes sobre o tumor. Desta forma, este trabalho tem como objetivo identificar marcadores de resistência a 5-FU em VEs secretadas por linhagens celulares humanas de câncer gástrico e avaliar o papel das VEs na quimioresistência. Para tanto, foram geradas células de AdG derivadas da linhagem AGS, resistentes a 5-FU (rAGS_FU) de onde foram isoladas, quantificadas e caracterizadas VEs. Células rAGS-FU secretam cerca de 2 vezes mais VEs que as células parentais (AGS), entretanto a distribuição destas por tamanho é semelhante. As células rAGS_FU apresentaram maior proliferação, capacidade de formação de colônias e invasão que as células AGS. Interessantemente, as VEs provenientes de células resistentes a 5-FU, rAGS_FU, são capazes de transferir à células AGS os fenótipos de resistência ao quimioterápico bem como um aumento na capacidade de formação de colônias e invasão. As células AGS que se tornam resistentes ao tratamento não têm este fenótipo revertido pela remoção das VEs da células resistentes nem pelo tratamento com VEs de células AGS parental, indicando que o fenótipo de resistência adquirido após o tratamento é irreversível, pelo menos pelo período estudado. O conteúdo proteico das VEs das células AGS e rAGS_FU e suas respectivas VEs foi comparado por proteômica. Nessa abordagem foram identificadas 1.915 proteínas nas células e 1.638 proteínas em VEs das quais 309 proteínas eram diferencialmente expressas em células e 66 em VEs. Entre as proteínas com expressão diferencial entre as duas células e também nas suas respectivas VEs, selecionamos e validamos por western blotting a proteina fascina. Esta parece ser um potencial candidato a biomarcador de resistência a 5-FU uma vez que sua expressão é indetectável na célula AGC e suas VEs e altamente expressa nas células rAGS_FU e suas vesículas. A fascina é uma proteína do citoesqueleto com um papel chave nas interações célula-célula, adesão e motilidade celulares e é associada a agressividade tumoral. Estes dados apontam o papel das VEs nos mecanismos relacionados à resistência a 5-FU em células de AdG e sugerem que fascina possa estar associada ao mecanismo de resistência a este quimioterápico e que também seja um potencial biomarcador deste fenótipo

Gastric adenocarcinoma (GAd) is the third most common cause of cancer related death worldwide, and one of the tumors with the highest mortality rates in Brazil. In men, this cancer ranks the third most common cancer, while in women, it ranks fifth. 5-fluorouracil (5-FU) based neoadjuvant chemotherapy can improve tumor resectability and patient's survival rates. Its effectiveness however, is limited by drug resistance. Thus, an effort to identify predictive markers of response to neoadjuvant therapy and select patients who could benefit from this treatment is relevant. One such approach could be to use contents of extracellular vesicles (EVs). EVs are components secreted by cells including tumor cells, whose contents are composed of molecules that can have a myriad of local and distance functions and many of these molecules can also be used as serum biomarkers since they contain important information about the tumor. This work aims to identify 5-FU resistance markers in EVs secreted by human gastric cancer cell line and to evaluate the role of EVs in chemoresistance. GAd cells resistant to 5-FU (rAGS_FU) were generated from the AGS cell line and EVs secreted by rAGS_FU cells and parental AGS cells were isolated, quantified and characterized. Our results showed that AGS_FU cells secrete about 2 times more EVs than parental AGS cells, however their size distribution is similar. The resistant rAGS_FU cells showed higher proliferation rates, capacity of colony formation and invasion properties. Interestingly, EVs from 5-FU resistant cells, rAGS_FU, are able to transfer to the AGS cells the phenotypes of resistance to chemotherapy as well as an increase in the capacity of colony formation and invasion. AGS cells that become resistant to treatment do not have this phenotype reversed by removal of the EVs from the resistant cells or by treatment with EVs from parental AGS cells, indicating that the resistance phenotype acquired after treatment is irreversible, at least for the period studied. The protein content of the AGS and rAGS_FU cells and their respective EVs was compared by proteomics. In this approach, 1,915 proteins were identified in cells and 1,638 proteins in EVs of which 309 proteins were differentially expressed in cells and 66 in EVs. Among the proteins with differential expression between the two cells and also in their respective EVs, we selected and validated by western blotting the protein fascin. Fascin protein appears to be a potential candidate for biomarker of 5-FU resistance since its expression is undetectable in AGS cells and their EVs and highly expressed in rAGS_FU cells and their vesicles. Fascin is a cytoskeletal protein with a key role in cellcell interactions, cell adhesion and motility and is associated with tumor aggressiveness. These data point to the role of EVs in the mechanisms related to 5-FU resistance in GAd cells and suggest that fascin may be associated with the mechanism of resistance to this chemotherapeutic agent and that it is also a potential biomarker of this phenotype

CMPD1 inhibited human gastric cancer cell proliferation by inducing apoptosis and G2/M cell cycle arrest

BACKGROUND: Gastric cancer occupies the fourth highest morbidity rate of cancers worldwide. Clinical therapies of gastric cancer remain limited because of uncertainty of mechanisms and shortness of effective medicine. Thus, new drug candidates for gastric cancer treatment is urgently needed. RESULTS: In this study, CMPD1 as a wildly used MK2 phosphorylation inhibitor was employed to find its impact on gastric cancer cell proliferation, apoptosis and cell cycle using colony formation assay and flow cytometry analysis. Along with its anti-proliferation effect on gastric cancer cell line MKN-45 and SGC7901, CMPD1 also induced massive apoptosis and significant G2/M phase arrest in a time-dependent and dose-dependent manner in MKN-45 cells respectively. Furthermore, Western blot confirmed that the expression of anti-apoptotic proteins Bcl-2 was decreased while BAX, cytochrome c release and cleaved PARP were increased. In addition, oncogene c-Myc was downregulated in response to CMPD1 treatment. CONCLUSIONS: Our results demonstrated that CMPD1 has anti-tumor effect on human gastric cancer cell line MKN- 45 possibly via downregulating oncogene c-Myc expression and CMPD1 could be applied as a potential candidate for treating gastric malignancy. To the best of our knowledge, it is the first report of anti-tumor effect of CMPD-1 on human gastric cancer cells.

Oridonin induces growth inhibition and apoptosis in human gastric carcinoma cells by enhancement of p53 expression and function

The tumor suppressive role of oridonin, an active compound extracted from Rabdosia rubescens, has been proven in several gastric cancer (GC) cell lines. The present study aimed to evaluate the effect of oridonin on another GC cell line, SNU-216, and explore the potential mechanisms. The viable cell numbers, cell migration, survival fraction, and cell viability were, respectively, evaluated by trypan blue exclusion assay, wound healing assay, clonogenic assay, and CCK-8 assay. Cell apoptosis was determined by flow cytometry assay and western blot. The expression of p53 was inhibited by transient transfection, and the efficiency was verified by western blot. qRT-PCR was performed to measure the mRNA expression of p53. Western blot was used to evaluate the protein expression of apoptosis, DNA damage and p53 function related factors. We found that oridonin significantly inhibited cell proliferation, migration, and survivability, and enhanced cell apoptosis in SNU-216 cells. However, it had no influence on HEK293 cell viability. Oridonin also remarkably enhanced the anti-tumor effect of cisplatin on SNU-216 cells, as it significantly increased apoptotic cells and decreased cell viability. Moreover, the mRNA and protein expression of p53 was significantly up-regulated in oridonin-treated cells, while Mdm2 expression was down-regulated. Furthermore, oridonin enhanced p53 function and induced DNA damage. Knockdown of p53 or employing the caspase inhibitor, Boc-D-FMK, reversed the effect of oridonin on cell viability and apoptosis-related protein expression. The present study demonstrated that oridonin exhibited an anti-tumor effect on GC SNU-216 cells through regulating p53 expression and function.

Histiocitoma fibroso maligno metastásico en estómago / Metastatic malignant fibrous histiocytoma in the stomach

El histiocitoma fibroso maligno es el sarcoma de partes blandas más frecuente de la adultez tardía. Se desarrolla habitualmente en los miembros inferiores y en el retroperitoneo. Su pronóstico es malo, la recidiva local y las metástasis a distancia. Se presenta el caso de un paciente con metástasis en el estómago de un histiocitoma fibroso maligno. El objetivo de esta publicación es la presentación de una forma poco común de diseminación metastásica del histiocitoma fibroso maligno(AU)

Malignant fibrous histiocytoma is the most common soft tissue sarcoma of late adult life. It usually develops in the lower extremities and in the retroperitonium. Prognosis is fairly poor; local relapse and distant metastasis are the common natural history. The is presented of a patient with stomach metastasis of malignant fibrous histiocytoma. This paper is aimed at presenting a rare way of metastatic dissemination of the malignant fibrous histiocytoma(AU)

Respuesta histológica completa a la neoadyuvancia en carcinoma gástrico avanzado: A propósito de un caso y revisión de la literatura / Histological complete response to neoadjuvant therapy in advanced gastric carcinoma: A case report and review of literature

La presente comunicación, describe el primer caso en el Instituto Regional de Enfermedades Neoplásicas "Luis Pinillos Ganoza" IREN Norte en la que una paciente con carcinoma gástrico avanzado ha mostrado respuesta histopatológica completa a neoadyuvancia. Se presenta una paciente mujer de 70 años con diagnóstico histopatológico de adenocarcinoma gástrico tubular moderadamente diferenciado, localmente avanzado con imágenes de adenopatías perigástricas asociadas y pérdida de la interfase entre tumoración gástrica, hilio hepático y vesícula biliar. Luego de 6 cursos de quimioterapia neoadyuvante con esquema FOLFOX - 4 al 80%, se obtiene una respuesta casi completa desde el punto de vista tomográfico; por ello a la paciente se le realiza gastrectomía subtotal distal más linfadenectomía D2 más gastroyeyunoanastomosis Billroth II término lateral tipo Hofmeister Finsterer, verificándose, al examen microscópico de la pieza operatoria, sólo gastritis crónica y aguda con áreas mucosas y cambios reactivos. No se observa neoplasia maligna viable. Ganglios linfáticos: 0/33. Paciente evoluciona favorablemente. A propósito del caso se hace una revisión de la literatura médica relevante actualizada

This communication describes the first case in the Regional Institute of Neoplastic Diseases "Luis Pinillos Ganoza" IREN North in which a patient with advanced gastric carcinoma showed complete response to neoadjuvant histopathologic. We describe the case of a patient woman of 70 years old with histopathologic diagnosis of moderately differentiated tubular gastric adenocarcinoma, locally advanced associated with images of perigastric lymphadenopathy and loss of the interface between gastric tumor, hepatic hilum and gallbladder. After 6 courses of neoadjuvant chemotherapy with FOLFOX scheme - 4 to 80%, an almost complete response from the point of tomographic view is obtained, so the patient is underwent to distal subtotal gastrectomy lymphadenectomy D2 more gastrojejunoanastomosis Billroth II termino lateral type Hofmeister Finsterer verifying on microscopic examination of surgical specimen only acute and chronic gastritis with mucous areas and reactive changes. No feasible malignancy is observed. Lymph nodes: 0/33. Commenting on the case, a review of recent relevant literature is realized