RESUMEN
Natural polysaccharides have attracted considerable interests due to diverse biological activities. Succinoglycan is an extracellular polysaccharide produced by most Agrobacterium strains. Here, we confirmed riclin was a typical succinoglycan by NMR and methylation analysis, and investigated the antitumor effects of riclin in sarcoma 180 tumor-bearing mice. The results showed that riclin inhibited the tumor growth significantly as well as cyclophosphamide (CTX). While CTX caused serious damage to spleen structure, riclin increased the spleen index and promoted lymphocytes proliferation in peripheral blood, spleen and lymph nodes. Riclin decreased splenocytes apoptosis as evidenced by alterations of B-cell lymphoma-2 family proteins and Cleaved Caspase-3 protein. Moreover, 1H nuclear magnetic resonance (NMR)-based metabolomics analysis revealed that riclin partially altered the metabolic profiles of splenocytes. In conclusion, riclin is a succinoglycan that performed strong immunogenicity and suppressed sarcoma growth in mice. Succinoglycan riclin could be a potential antitumor agent for functional food and pharmaceutical purpose.
Asunto(s)
Antineoplásicos/farmacología , Regulación Neoplásica de la Expresión Génica , Factores Inmunológicos/farmacología , Linfocitos/efectos de los fármacos , Polisacáridos Bacterianos/farmacología , Sarcoma 180/tratamiento farmacológico , Agrobacterium/química , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Apoptosis/genética , Secuencia de Carbohidratos , Caspasa 3/genética , Caspasa 3/inmunología , Proliferación Celular/efectos de los fármacos , Ciclofosfamida/farmacología , Factores Inmunológicos/química , Factores Inmunológicos/aislamiento & purificación , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Linfocitos/inmunología , Linfocitos/patología , Masculino , Metaboloma/inmunología , Metilación , Ratones , Ratones Endogámicos C57BL , Polisacáridos Bacterianos/química , Polisacáridos Bacterianos/aislamiento & purificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Sarcoma 180/genética , Sarcoma 180/inmunología , Sarcoma 180/patología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Carga Tumoral/efectos de los fármacosRESUMEN
BACKGROUND: Very little is known about the role inflammation and mechanism(s) that enables the tumor to evade host's anti-tumor immune function during very initial days of tumor establishment. Our study focuses on the immune response and local inflammation specially the pro-inflammatory and immune modifier components that are responsible for tumor-induced immune-suppression, tumor-associated macrophages (TAM) at tumor microenvironment in mouse model from very early to late phase of tumor progression. METHODS: 1 × 105 Ascites tumor, EAC in Swiss albino or Sarcoma-180 (S-180) in Balb c mice strain were inoculated intra-peritonially and grouped into Control (0 day or no tumor), initial phase (3 day tumor), early (7 Day), Late (14 day) and terminal (21 day tumor) sets. T cell activity, tumor niche macrophage, inflammatory signatures were studied using Confocal microscopy, flowcytometry, ELISA, q-RT PCR and Western blot. RESULTS: We observed increased T cell infiltration at a very early stage of tumorigenesis in the tumor site with elevated percentage of activated/memory T cells. But increased cellular death and functional suppression of tumor site T cells during final stages. We observed increased infiltration of TAMs with skewed M2 phenotype. Increased chemokine receptor expression could be noted on these TAMs. Using HIF-1α inhibitor and prostaglandin receptor antagonists we demonstrated crucial role of these factor in functional alteration in TAMs. HIF-1α inhibition and also by prostaglandin receptor inhibition reduced signature pro-inflammatory gene expression, migration of macrophages and T cell suppression capacity of TAMs. We also demonstrated that PGE2 can induce HIF-1α activation in relatively less hypoxic microenvironment during early stages of tumor. CONCLUSION: Altogether, these findings strongly suggest link between prostaglandin mediated early HIF-1α activation and subsequent hypoxia induced HIF-1α activation that further enhances prostaglandin synthesis driving the recruitment and functional alteration of tumor site macrophages.
Asunto(s)
Carcinoma de Ehrlich/patología , Dinoprostona/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/patología , Sarcoma 180/patología , Animales , Carcinoma de Ehrlich/inmunología , Movimiento Celular , Progresión de la Enfermedad , Inflamación/inmunología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Fenotipo , Sarcoma 180/inmunología , Linfocitos T/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: In Brazil, latex of Himatanthus drasticus is used to treat inflammation, wound healing and cancer. The present study evaluated the antitumoral potential of H. drasticus latex (HdCL) in Sarcoma 180-bearing mice (S180). MATERIALS AND METHODS: HdCL was obtained in Crato-CE, Brazil. Qualitative phytochemicals assays, nuclear magnetic resonance (NMR) and microbiological analyzes were performed. Swiss mice were divided into six groups, according to tumor forms: 1) ascitic model, GI (Control; 0.9% saline), GII (S180asc) and GIII (S180asc/HdCL/14 days); 2) solid model, GIV (Control; 0.9% saline), GV (S180sol) and GVI (S180sol/HdCL/10 days). HdCL and 0.9% saline were administered at 0.2â¯mL, SID, by gavage, for 10 or 14 days. For ascitic model, 0.5â¯mL of S180 suspension (4×106 cells/mL) was inoculated intraperitoneally and for solid model, cells were inoculated subcutaneously (25⯵L) on the right hind paw of mice. Blood samples were collected for hematological and oxidative stress evaluation. Thickness, volume and weight of paws were measured in solid model. After euthanasia, spleen, liver and kidney were collected in order to assess the relative organ weight. Tissue fragments of paws and popliteal lymph nodes (PLN) were analyzed by H&E and CD4+, CD8+, HSP-60+ and Foxp3+ immunohistochemistry. RESULTS: HdCL presented milky aspect and pinkish supernatant. Phenols, flavonols, flavanones, free steroids and cinnamoyl derivatives of lupeol, α-amyrin and ß-amyrin were detected at the phytochemistry analysis. HdCL did not alter the relative weight of organs, hematological parameters and volume of ascitic fluid recovered. In solid model, HdCL reduced (Pâ¯<â¯0.05) paw volume, but did not altered thickness, paw weight and histological parameters. S180sol induced necrosis, metastasis and destruction of bone, cartilage and muscles. Bleeding, vessel congestion and oncocytes were observed in PLN. In paw, HdCL did not alter FoxP3+ and HSP-60+ expressions but reduced the CD4+ and CD8+ expressions, while at PLN, HdCL reduced the expressions of all markers. HdCL decreased (Pâ¯<â¯0.05) serum levels of malondialdehyde in ascitic model. CONCLUSIONS: Treatment with HdCL reduced oxidative damage and modulated the expressions of CD4+, CD8+, FoxP3+and HSP-60+ in S180 solid tumor model, which can be associated to the presence of triterpenes, such as α-amyrin, ß-amyrin and lupeol cinnamate. Present data emphasizes the importance of immune system in cancer and highlights the evaluation of the pharmacological properties of plants used by population as phytoterapics.
Asunto(s)
Apocynaceae/química , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/farmacología , Sarcoma 180/tratamiento farmacológico , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Brasil , Antígenos CD4/genética , Antígenos CD8/genética , Chaperonina 60/genética , Femenino , Factores de Transcripción Forkhead/genética , Malondialdehído/sangre , Ratones , Proteínas Mitocondriales/genética , Sarcoma 180/inmunología , Sarcoma 180/patologíaRESUMEN
Degeneration of immune organs like thymus and spleen has been discovered in tumor-bearing mice; which increases the difficulties on oncotherapy. More effective drugs which target the protection of immune organs are expected to be researched. In this study; we aim to analyze the antitumor and immunoregulatory activities of seleno-ß-lactoglobulin (Se-ß-lg) on S180 tumor-bearing mice. Results indicated that Se-ß-lg exhibited a remarkable inhibitory effect on S180 solid tumors with the inhibition rate of 48.38%; and protected the thymuses and spleens of S180-bearing mice. In addition, Se-ß-lg could also balance the proportions of CD4⺠and CD8⺠T cells in spleens; thymuses and peripheral bloods; and improve Levels of IL-2; IFN-γ; TNF-α in mice serums. ß-lg showed weaker bioactivities while SeO2 showed stronger toxicity on mice. Therefore our results demonstrated that Se-ß-lg possessed stronger antitumor and immunoregulatory activities with lower side effects and had the potential to be a novel immunopotentiator and antitumor agent.
Asunto(s)
Antineoplásicos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Lactoglobulinas/uso terapéutico , Compuestos de Organoselenio/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Animales , Línea Celular Tumoral , Femenino , Humanos , Interleucina-2/metabolismo , Ratones , Sarcoma 180/inmunología , Sarcoma 180/metabolismo , Bazo/metabolismo , Linfocitos T/metabolismo , Timo/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Enterococcus faecalis 2001 is a probiotic lactic acid bacterium and has been used as a biological response modifier (BRM). From physiological limitation of bacterial preservation in storage and safety, the live E. faecalis 2001 has been heat-treated and the BRM components containing high level of ß-glucan, named EF-2001, were prepared. METHOD: The heat-treated EF-2001 has been examined for the antioxidative potential for radical scavenging and anti-tumor activities as well as immune-enhancing response in mice. Lymphocyte versus polymorphonuclear leukocyte ratio was increased in mice upon treatment with EF-2001. The number of lymphocytes was increased in the EF-2001-treated group. In the mice bearing two different Ehrlich solid and Sarcoma-180 carcinomas, the treatment with EF-2001 resulted in anti-tumor action. Tumor-suppressive capacity upon treatment with EF-2001 was significantly increased compared to normal controls. RESULTS: During the time interval administration of 5 weeks between the priming and secondary administration of EF-2001, the expression and production levels of TNF-α were also observed in the EF- 2001-administered mice. Additionally, anti-tumor activity examined with the intravenous administration of EF 2001 with a 34 times interval was also observed, as the growth of Sarcoma180 cells was clearly inhibited by the EF-2001. CONCLUSION: From the results, it was suggested that the immune response is enhanced due to antioxidative activity caused by the EF-2001 and anti-tumor activity by NK cells and TNF-α.
Asunto(s)
Antineoplásicos/farmacología , Enterococcus faecalis , Factores Inmunológicos/farmacología , Linfocitos/efectos de los fármacos , Macrófagos/efectos de los fármacos , beta-Glucanos/farmacología , Animales , Antineoplásicos/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Antioxidantes/farmacología , Carcinoma de Ehrlich/tratamiento farmacológico , Carcinoma de Ehrlich/inmunología , Factores Inmunológicos/aislamiento & purificación , Células Asesinas Naturales/efectos de los fármacos , Linfocitos/inmunología , Macrófagos/inmunología , Masculino , Ratones Endogámicos ICR , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Probióticos , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/inmunología , Factor de Necrosis Tumoral alfa/análisis , beta-Glucanos/aislamiento & purificaciónRESUMEN
Novel tumor antigens are necessary for the development of efficient tumor vaccines for overcoming the immunotolerance and immunosuppression induced by tumors. Here, we developed a novel strategy to create tumor antigens by construction of random tumor transcriptome expression library (RTTEL). The complementary DNA (cDNA) from S180 sarcoma was used as template for arbitrarily amplifying gene fragments with random primers by PCR, then ligated to the C-terminal of HSP65 in a plasmid pET28a-HSP for constructing RTTEL in Escherichia coli. A novel antigen of A5 was selected from RTTEL with the strongest immunotherapeutic effects on S180 sarcoma. Adoptive immunotherapy with anti-A5 sera also inhibited tumor growth, further confirming the key antitumor roles of A5-specific antibodies in mice. A5 contains a sequence similar to protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1). The antisera of A5 were verified to cross-react with PCMT1 by Western blotting assay and vice versa. Both anti-A5 sera and anti-PCMT1 sera could induce antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity toward S180 cells by in vitro assay. Further assay with fluorescent staining showed that PCMT1 is detectable on the surface of S180 cells. Summary, the strategy to construct RTTEL is potential for creating and screening novel tumor antigens to develop efficient tumor vaccines. By RTTEL, we successfully created a protein antigen of A5 with significant immunotherapeutic effects on S180 sarcoma by induction of antibodies targeting for PCMT1.
Asunto(s)
Antígenos de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica/genética , Biblioteca de Genes , Sarcoma 180/genética , Transcriptoma/genética , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Antígenos de Neoplasias/inmunología , Western Blotting , Línea Celular Tumoral , Proteínas del Sistema Complemento/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Citotoxicidad Inmunológica/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Sueros Inmunes/inmunología , Sueros Inmunes/farmacología , Inmunización/métodos , Masculino , Ratones Endogámicos BALB C , Microscopía Confocal , Proteína D-Aspartato-L-Isoaspartato Metiltransferasa/genética , Proteína D-Aspartato-L-Isoaspartato Metiltransferasa/inmunología , Sarcoma 180/inmunología , Sarcoma 180/terapia , Transcriptoma/inmunologíaRESUMEN
Polyoxometalates (POMs) have attracted a considerable attention due to their unique structural characteristics, physicochemical properties and biological activities. In this study, iron hepta-tungsten phosphate oxygen clusters complex Na12H[Fe(HPW7O28)2]·44H2O (IHTPO) was synthesized and evaluated for in vitro cytotoxic activities on human hepatoma HepG2, leukemia K562, lung carcinoma A549, and large cell lung cancer NCI-H460 cells, therapeutic efficacies on mice transplantable tumor, and immunomodulatory potentials on the immune response in tumor-bearing mice. IHTPO exhibited lower in vitro cytotoxic activities against four human tumor cell lines, with the IC50 values being higher than 62.5µM (ca. 300µg/ml). IHTPO, however, significantly inhibited the growth of S180 sarcoma transplanted in mice. It was further showed that IHTPO could not only significantly promote splenocytes proliferation, NK cell and CTL activity from splenocytes, but remarkably enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. IHTPO also significantly promoted Th1 cytokines IFN-γ and IL-2 production, and up-regulated the mRNA expression levels of IFN-γ, IL-2 and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. These results suggested that IHTPO significantly inhibited the growth of mice transplantable tumor, and that its in vivo antitumor activity might be achieved by improving Th1 protective cell-mediated immunity. IHTPO could act as antitumor agent with immunomodulatory activity.
Asunto(s)
Antineoplásicos/farmacología , Factores Inmunológicos/farmacología , Compuestos de Hierro/farmacología , Hierro/farmacología , Oxígeno/farmacología , Compuestos de Tungsteno/farmacología , Tungsteno/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Humanos , Inmunoglobulina G/biosíntesis , Células Asesinas Naturales/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Trasplante de Neoplasias , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Sarcoma 180/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Linfocitos T Citotóxicos/efectos de los fármacosRESUMEN
The pro-inflammatory and immunomodulatory properties of Helicobacter pylori neutrophil activating protein (Hp-NAP) not only make it to play an important role in disease pathogenesis but also make it to be a potential candidate for therapeutic applications, including vaccine and drug development. Our previous work demonstrated that the recombinant Hp-NAP fused with the maltose binding protein of Escherichia coli (rMBP-NAP) play an important role in regulating the differentiation of Th1 cells. In this study, we investigated the ability of rMBP-NAP to induce antitumor immunity using two murine models of hepatoma H22 and sarcoma S180. Subcutaneous administration of mice with rMBP-NAP resulted in an about 40%-50% decrease of tumor growth compared with that of the control mice. Splenocytes from the tumor-bearing mice treated with rMBP-NAP showed a significant accumulation of CD4(+) IFN-γ-secreting cells, which is a cytokine profile of Th1 cells. Furthermore, intravenous injection of T2.5, toll like receptor (TLR) 2 blocking antibody, significantly recede the antitumor effect of rMBP-NAP and the production of IFN-γ induced by rMBP-NAP. Our findings indicate that potentiality of rMBP-NAP to be a candidate for the development of immunomodulatory antitumoral drugs.
Asunto(s)
Proteínas Bacterianas/farmacología , Vacunas contra el Cáncer/farmacología , Factores Inmunológicos/farmacología , Inmunoterapia/métodos , Neoplasias Experimentales/tratamiento farmacológico , Receptor Toll-Like 2/efectos de los fármacos , Animales , Proteínas Bacterianas/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Escherichia coli/metabolismo , Femenino , Factores Inmunológicos/uso terapéutico , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/inmunología , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/patología , Proteínas Recombinantes de Fusión/farmacología , Proteínas Recombinantes de Fusión/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Células TH1/efectos de los fármacosRESUMEN
In this study, a water-soluble polysaccharide (CSP) was successfully purified from Chaenomeles speciosa by DEAE-Sepharose and Sephadex G-100 column chromatography. CSP had a weight-average molecular weight of about 6.3 × 10(4)Da and was composed of glucose (Glc), galactose (Gal), rhamnose (Rha) and arabinose (Ara) with a relative molar ratio of 4.6:1.3:0.8:0.5. CSP could not only inhibit the growth of S180 tumor transplanted in mice, but also increase the relative spleen index and body weight of tumor bearing mice. Moreover, concanavalin A (ConA) and lipopolysaccharide (LPS) induced splenocyte proliferation and peritoneal macrophage phagocytosis were also enhanced after CSP administration. Furthermore, CSP treatment could improve delayed type hypersensitivity (DTH) and promote the secretion of IL-2, TNF-α and IFN-γ in serum. The overall findings suggest that the antitumor effect of CSP is might be associated with its potent immunostimulatory activity.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/uso terapéutico , Factores Inmunológicos/química , Factores Inmunológicos/uso terapéutico , Polisacáridos/química , Polisacáridos/uso terapéutico , Rosaceae/química , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Línea Celular Tumoral , Factores Inmunológicos/aislamiento & purificación , Interferón gamma/sangre , Interferón gamma/inmunología , Interleucina-2/sangre , Interleucina-2/inmunología , Masculino , Ratones , Fagocitosis/efectos de los fármacos , Polisacáridos/aislamiento & purificación , Sarcoma 180/sangre , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/inmunología , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
UNLABELLED: Abstract Context: Most of the present studies on the antitumor efficiency of Cymbopogon citratus (DC.) Stapf (Gramineae) are limited to its low-mass compounds, and little information about the antitumor activity of polysaccharides from this plant is available. OBJECTIVES: This study focused on the potential antitumor and immunomodulatory activities of polysaccharides (CCPS) from C. citratus. MATERIALS AND METHODS: CCPS was isolated using the water extraction-ethanol precipitation method. The sarcoma 180 (S180) cells-inoculated mice were intraperitoneally administrated with CCPS (30-200 mg/kg/d) for seven consecutive days. The effects of CCPS on tumor growth, thymus and spleen weights, splenocyte proliferation, and cytokine secretion in the tumor-bearing mice were measured. The cytotoxicity of CCPS (50-800 µg/mL) towards S180 cells was also studied. RESULTS: CCPS significantly inhibited the growth of the transplanted S180 tumors, with the inhibition rates ranging from 14.8 to 37.8%. Simultaneously, CCPS dose-dependently improved the immunity of the tumor-bearing mice. With the highest dose of 200 mg/kg/d, the thymus and spleen indices were increased by 21.9 and 91.9%, respectively; ConA- and LSP-induced splenocyte proliferations were increased by 32.7 and 35.3%, respectively. The secretions of interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 2 (IL-12), and tumor necrosis factor-α (TNF-α) were increased by 103.2, 40.2, 23.6, and 26.3%, respectively. Nevertheless, almost no toxicity of CCPS towards S180 cells was observed, with the maximal inhibition rate less than 15% at the CCPS concentration of 800 µg/mL. CONCLUSION: CCPS exhibited antitumor activity in vivo, and this activity might be achieved by immunoenhancement rather than direct cytotoxicity.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Cymbopogon/química , Factores Inmunológicos/farmacología , Polisacáridos/farmacología , Animales , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Factores Inmunológicos/aislamiento & purificación , Factores Inmunológicos/uso terapéutico , Masculino , Ratones Endogámicos , Trasplante de Neoplasias , Tamaño de los Órganos/efectos de los fármacos , Componentes Aéreos de las Plantas/química , Polisacáridos/aislamiento & purificación , Polisacáridos/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/inmunología , Sarcoma 180/patología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Timo/efectos de los fármacos , Timo/inmunología , Timo/patologíaRESUMEN
Water-soluble polysaccharides extracted from mushrooms have been found to have some physiological effects. In this study, exopolysaccharides (EPSs) were extracted by alcohol precipitation from cultivated broth of the mushroom Clitocybe maxima. EPSs with molecular weights of 10(4) and 10(5) Da were obtained by ultrafiltration; they are referred to as EPA and EPB, respectively. The major components of these EPSs were glucose, galactose, mannose, rhamnose, and arabinose. ICR mice with artificially induced metastatic pulmonary tumors were fed a daily diet containing EPA or EPB at doses of 8, 20, or 50 mg/kg. Results showed that the proliferation of pulmonary sarcoma lesions was lower in the groups fed EPS. In addition, the numbers of total T cells, CD4+ cells, CD8+ cells, and macrophages significantly increased in EPS-fed mice compared with the negative control group. The antitumor and immunomodulating effects observed in the EPB-fed groups were higher than those of EPA-fed groups. These results demonstrate the ability of EPSs of C. maxima to inhibit tumor cells while enhancing immune response.
Asunto(s)
Antineoplásicos/uso terapéutico , Basidiomycota/química , Productos Biológicos/uso terapéutico , Factores Inmunológicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Polisacáridos/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Productos Biológicos/farmacología , Linfocitos T CD4-Positivos/metabolismo , Factores Inmunológicos/farmacología , Inmunomodulación , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos ICR , Peso Molecular , Polisacáridos/farmacología , Sarcoma 180/inmunologíaRESUMEN
AIM: To induce cancer resistance in wild-type mice and detect if the resistance could be inherited to the progeny of the induced resistant mice. Furthermore to investigate the spectrum and immunology of this inherited cancer resistance. MATERIALS AND METHODS: Resistance to with live S180 cancer cells in BALB/c mice was induced by immunization with inactivated S180 cancer cells. The immunization was performed by either frozen/thawed or irradiated cancer cells or cell-free ascitic fluid (CFAF). RESULTS: In all instances the induced resistance was demonstrated to be inheritable. The phenotype was named HICR (heritable induced cancer resistance) and was defined as primary resistant progeny from mice immunized with frozen/thawed or irradiated S180 cells or CFAF obtained from mice with S180 induced ascites. Notably, this resistance was transferred from both male and female mice to the offspring of the immunized mice for at least two generations. Although inheritable, the frequency of cancer-resistant pups was lost over a few generations. Cells from the J774A.1 and RAW cancer cell lines did not induce inheritable cancer resistance, and C57BL/6 mice could not pass on cancer resistance fluorescence-activated cell sorting (FACS) analyses of the peritoneal cells revealed an increased fraction of macrophages. In necropsies of resistant mice no histological signs of cancer or other disease was found. CONCLUSION: Only materials derived from S180 cells could give rise to HICR mice. The molecular basis of the resistance is unknown but may involve epigenetic mechanisms. Other examples of inheritability of acquired phenotypic changes exist but, to our knowledge, this is the first demonstration of acquired, inherited cancer resistance.
Asunto(s)
Líquido Ascítico/patología , Predisposición Genética a la Enfermedad , Inmunidad Innata , Sarcoma 180/inmunología , Sarcoma 180/prevención & control , Animales , Líquido Ascítico/inmunología , Femenino , Citometría de Flujo , Humanos , Inmunización , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Fenotipo , Sarcoma 180/genética , Sarcoma 180/mortalidad , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
We evaluated the antitumor activity of crude extract and ascophyllan prepared from Ascophyllum nodosum in sarcoma-180 solid tumor-bearing mice with continuous intraperitoneal (i.p.) administration at a dose of 50 mg/kg body weight/day or oral administration at a dose of 500 mg/kg body weight/day. Ascophyllan and crude extract administered via the oral route showed greater antitumor effects than via i.p. route, and the tumor sizes in mice treated with ascopyllan and crude extract were reduced by a mean of 68.7±6.8% and 42.4±24.8% by the oral route, and 41.4±16.1% and 13.6±20.6% by i.p. route compared to control mice. Splenic natural killer cell activity in the mice treated with ascophyllan and crude extract by i.p. route was significantly enhanced, while only a slight increase of this activity was observed in orally-treated mice. Furthermore, increase in spleen weight of tumor-bearing mice was slightly suppressed by oral administration of ascophyllan, whereas i.p. administration resulted in further enlargement. Analysis of serum cytokines revealed that oral treatment with ascophyllan resulted in significant increase of tumor necrosis factor-α and interleukin-12 levels. Since ascophyllan showed no direct cytotoxic effect on sarcoma-180 cells, orally-administered ascophyllan is suggested to exhibit its antitumor activity through the activation of the host immune system.
Asunto(s)
Antineoplásicos/farmacología , Ascophyllum/química , Polisacáridos/farmacología , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Peso Corporal , Línea Celular Tumoral , Citocinas/sangre , Citocinas/metabolismo , Inyecciones Intraperitoneales , Células Asesinas Naturales/efectos de los fármacos , Masculino , Ratones , Peso Molecular , Tamaño de los Órganos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacología , Polisacáridos/administración & dosificación , Polisacáridos/química , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/inmunología , Sarcoma 180/patología , Bazo/citología , Bazo/efectos de los fármacos , Carga Tumoral/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The larvae of Musca domestica (Diptera: Muscidae) have been used traditionally for malnutritional stagnation, decubital necrosis, osteomyelitis, ecthyma and lip scald and also to treat coma and gastric cancer in the traditional Chinese medicine. Its in vitro antitumor activity and immunomodulatory effect in naïve mice in relation to the traditional uses were also reported. However, the in vivo antitumor effect of this insect and its mechanism of action have not yet been well studied. The objectives of this study were to evaluate the in vivo antitumor potential of the peptide fraction from Musca domestica larvae (MDPF) and to elucidate its immunological mechanisms. MATERIALS AND METHODS: The mice inoculated with sarcoma S180 cells were orally administered with MDPF at three doses for 10 days. The effects of MDPF on the growth of mouse S180 sarcoma, splenocyte proliferation, the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), production and mRNA expression of cytokines from splenocytes, and serum antigen-specific antibody levels in tumor-bearing mice were measured. RESULTS: MDPF could significantly not only inhibit the growth of mouse transplanted S180 sarcoma, but also promote splenocytes proliferation, NK cell and CTL activity from splenocytes, and enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. MDPF also significantly promoted the production of IFN-γ and up-regulated the mRNA expression levels of IFN-γ and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. However, Th2 cytokine IL-10 and transcription factors GATA-3 and STAT-6 were not significantly changed both at transcriptional and protein levels following MDPF treatment. CONCLUSIONS: MDPF significantly inhibit the growth of transplantable tumor in mice and its in vivo antitumor activity might be achieved by switching-on of Th1-based protective cell-mediated immunity. MDPF could act as antitumor agent with immunomodulatory activity.
Asunto(s)
Antineoplásicos , Productos Biológicos , Moscas Domésticas , Factores Inmunológicos , Péptidos , Sarcoma 180/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Línea Celular Tumoral , Femenino , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Factores Inmunológicos/farmacología , Factores Inmunológicos/uso terapéutico , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/genética , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Larva/química , Masculino , Ratones Endogámicos ICR , Péptidos/farmacología , Péptidos/uso terapéutico , ARN Mensajero/metabolismo , Sarcoma 180/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Factores de Transcripción/genéticaRESUMEN
The aim of this study was to investigate the immunological mechanisms by which synthetic methionine enkephalin (MENK) exerts therapeutic effects on tumor growth. Our findings in vivo or in vitro show that MENK treatment either in vivo or in vitro could up-regulate the percentages of CD8+T cells, induce markers of activated T cells, increased cytotoxic activity against mouse S180 tumor cells and increase secretion of IFNγ. In addition, the adoptively transferred CD8+T cells, after either in vitro or in vivo treatment with MENK, result in significantly increased survival of S180 tumor-bearing mice and significant shrinkage in tumor growth. Opioid receptors are detected on normal CD8+T cells and exposure to MENK leads to increased expression of opioid receptors. Interaction between MENK and the opioid receptors on CD8+T cells appears to be essential for the activation of CTL, since the addition of naltrexone (NTX), an opioid receptor antagonist, significantly inhibits all of the effects of MENK. The evidence obtained indicates that the MENK-induced T cell signaling is associated with a significant up-regulation of Ca2+ influx into the cytoplasm and the translocation of NFAT2 into nucleus, and these signaling effects are also inhibited by naltrexone.
Asunto(s)
Encefalina Metionina/farmacología , Inmunoterapia Adoptiva/métodos , Sarcoma 180/inmunología , Sarcoma 180/terapia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Calcio/metabolismo , Núcleo Celular/inmunología , Núcleo Celular/metabolismo , Encefalina Metionina/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Distribución Aleatoria , Receptores Opioides delta/biosíntesis , Receptores Opioides delta/inmunología , Receptores Opioides mu/biosíntesis , Receptores Opioides mu/inmunología , Sarcoma 180/tratamiento farmacológicoRESUMEN
The SR/CR mouse phenotype, first described in 1999 in BALB/c and later bred into C57BL/6 mice, is resistant to cancer formation following high doses of cancer cells administered intraperitoneally. The tumor cell targeting and destruction mechanisms have not been identified. By fluorescence-activated cell sorting analysis, the immune response of SR/CR mice after intraperitoneal injection of cancer cells was investigated and compared with parent strain mice. A massive influx of leukocytes into the peritoneal cavity was found. A large fraction of these leukocytes were polymorphonuclear granulocytes, macrophages and natural killer cells. A relative decrease in influx of B-cells compared with controls was demonstrated. Increased proportions of leukocytes belonging to the innate immune system were also demonstrated in splenocytes of SR/CR mice. Cytospins of peritoneal fluid from SR/CR mice after cancer cell injection showed formations of immune cells morphologically resembling polymorphonuclear granulocytes and macrophages adjoining the cancer cells. The results point to the potential involvement of innate immune cells in cancer immunology. Our data support migration of polymorphonuclear granulocytes, macrophages and NK cells into the peritoneum of the SR/CR mouse in response to intraperitoneal injection of S180 cancer cells. The cell composition of spleens of SR/CR mice reflected the differential regulation of the innate immune cells in peritoneal exudates. Both peritoneal exudates and the spleens of SR/CR mice contained decreased proportions of B-cells compared with BALB/c and C57BL/6 mice. We reproduce important aspects of previous published data and further extend them by showing differentially regulated populations of splenocytes including B-lymphocytes in SR/CR mice compared with parent strain controls. Importantly, this differentially regulated immune response of SR/CR mice could not be found in response to challenge with the lymphoma cell line EL-4.
Asunto(s)
Granulocitos/inmunología , Inmunidad Innata , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Sarcoma 180/inmunología , Animales , Líquido Ascítico/citología , Linfocitos B/inmunología , Línea Celular Tumoral , Predisposición Genética a la Enfermedad , Interleucina-10/análisis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Cavidad Peritoneal , Sarcoma 180/patología , Bazo/inmunologíaRESUMEN
BACKGROUND: Abnormal Savda Munziq (ASMq), a traditional uyghur medicine, has shown anti-tumour properties in vitro. This study attempts to confirm these effects in vivo and measure effects on the immune system. METHODS: Kunming mice transplanted with Sarcoma 180 cells were treated with ASMq (2-8 g/kg/day) by intra-gastric administration compared to model and cyclophosphamide (20 mg/kg/day). After the 14th day post tumour implant, thymus, liver, spleen and tumours were removed, weighed, and processed for histopathological analysis. Blood samples were also taken for haematological and biochemical analyses including TNF-α , IL-1 ß and IL-2. Splenic lymphocyte function was measured with MTT; lymphocyte subpopulations were measured by flow cytometry. RESULTS: ASMq treated animals had reduced tumour volume compared to model and increased concentrations of TNF-α, IL-1ß and IL-2 compared to untreated and to cyclophosphamide-treated animals. No histopathological alterations were observed. The absence of viable S180 cells and the presence of necrotic cells and granulation tissue were observed in tumour tissue of treated animals. The effect on T lymphocytes was unclear. CONCLUSIONS: ASMq confirmed in vivo anti-tumour effects observed in vitro, which may be at least in part mediated by increased immune activity.
Asunto(s)
Antineoplásicos/administración & dosificación , Medicamentos Herbarios Chinos/administración & dosificación , Factores Inmunológicos/administración & dosificación , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/inmunología , Animales , Citocinas/inmunología , Femenino , Humanos , Sistema Inmunológico/efectos de los fármacos , Masculino , Medicina Tradicional China , RatonesRESUMEN
Solasodine rhamnosyl glycosides (SRGs) induce apoptosis in a wide variety of cancer cells and are more effective than many well-established anticancer agents. Combination therapy of SRGs with cisplatin treats cisplatin-resistant cells such as lung cancer and breast cancer cells. Anticancer therapies with SRGs have been used intravenously, intraperitoneally, intralesionally, orally, and topically. Data is now presented that in addition to apoptosis and, perhaps as a consequence thereof, SRGs also have an effect of stimulating lasting immunity against cancer as shown with a mouse model and the terminal cancer Sarcoma 180. Mice were inoculated i. p. with Sarcoma 180. Groups of animals were administered SRGs half an hour after Sarcoma 180 inoculation. Mice treated with Sarcoma 180 but not with SRGs all died within 20 days. Four doses of SRGs caused total remission of Sarcoma 180 activity. Mice that went into remission were then reinoculated 20 days later with the cancer. Ten of twelve SRGs cured-animals were resistant to reinduction of terminal doses of the cancer. In comparison, twelve of twelve mice treated with SRGs without initial Sarcoma 180 activity but which were inoculated with Sarcoma 180 cells 20 days later, all died. In addition to apoptosis, SRGs stimulate lasting immunity against cancer. SRGs could play an important role in clinical management of diseases such a malignancy and also be used as a preventative therapy.
Asunto(s)
Apoptosis/efectos de los fármacos , Glicósidos/farmacología , Sarcoma 180/tratamiento farmacológico , Sarcoma 180/inmunología , Alcaloides Solanáceos/farmacología , Animales , Antineoplásicos/farmacología , Cisplatino/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Frutas/química , Ratones , Extractos Vegetales/farmacología , Sarcoma 180/patología , Solanum/químicaRESUMEN
The purpose of this study was to assess the anti-tumor and immunomodulatory effects of PIE on tumor cells Sarcoma 180 and Hepatoma 22 in implanted mice. The monosaccharide composition of PIE was analyzed by GC. The results demonstrated that PIE monosaccharide composition was n(Xyl): n(Man): n(Fuc): n(Glc): n(Gal)=2.3: 1: 6.4: 22.1: 19.83. The oral administration of PIE characteristically inhibited the growth of S180 and H22 cells and increased the life span. The concentrations of serum IL-2 and IL-18 were significantly increased in the S180 implanted mice fed with PIE in the doses of 500 mg/kg and 250 mg/kg compared with those in control (p<0.01). The concentrations of serum IL-2 were significantly increased in H22 implanted mice in the doses of 500 mg/kg and 250 mg/kg compared with those in control (p<0.01).
Asunto(s)
Antineoplásicos/uso terapéutico , Basidiomycota/química , Inmunidad Celular/efectos de los fármacos , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Polisacáridos/uso terapéutico , Sarcoma 180/tratamiento farmacológico , Animales , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Citocinas/inmunología , Femenino , Neoplasias Hepáticas Experimentales/inmunología , Ratones , Ratones Endogámicos ICR , Micelio/química , Polisacáridos/aislamiento & purificación , Sarcoma 180/inmunologíaRESUMEN
Solanum lyratum Thunb (Solanaceae) has been widely used for cancer as a folk remedy in Chinese traditional medicine. In this study, the main active fraction n-butanol extract from S. lyratum (BESL) was evaluated for the therapeutic efficacies on mice transplantable tumor and immunomodulatory potentials on the immune response in tumor-bearing mice. The effects of BESL on the growth of mouse transplantable S180 sarcoma, splenocyte proliferation, the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), production of cytokines from splenocytes, and serum antigen-specific antibody levels in S180-bearing mice were measured. BESL could not only significantly inhibit the growth of S180 sarcoma transplanted in mice, but also remarkably promote splenocytes proliferation, NK cell and CTL activity, interleukin-2 and interferon-γ production from splenocytes, and serum antigen-specific antibody levels in tumor-bearing mice (P < 0.05, P < 0.01, or P <0.001). The results suggested that BESL might exhibit antitumor activity by improving immune response, and it could act as antitumor agent with immunomodulatory activity. This study provided evidence to understand the therapeutic effects of S. lyratum for treatment of cancer and a natural product to further researches to be developed as a cancer chemopreventive agent.