epiglucan and Lung-Neoplasms

The potential of natural substances with immunotherapeutic properties has long been studied. β-glucans, a cell wall component of certain bacteria and fungi, potentiate the immune system against microbes and toxic substances. Moreover, β-glucans are known to exhibit direct anticancer effects and can suppress cancer proliferation through immunomodulatory pathways. Mortality of lung cancer has been alarmingly increasingly worldwide; therefore, treatment of lung cancer is an urgent necessity. Numerous researchers are now dedicated to using β-glucans as a therapy for lung cancer. In the present attempt, we have reviewed the studies addressing therapeutic effects of β-glucans in primary and metastatic lung cancer published in the time period of 1991-2016.

Topics: Animals; beta-Glucans; Humans; Lung Neoplasms

Maitake mushroom (Grifola frondosa) MD-fraction containing beta-1,6 glucan with beta-1,3 branched chains has previously exhibited strong anticancer activity by increasing immune-competent cell activity.1,2 In this non-random case series, a combination of MD-fraction and whole maitake powder was investigated to determine its effectiveness for 22- to 57-year-old cancer patients in stages II-IV. Cancer regression or significant symptom improvement was observed in 58.3 percent of liver cancer patients, 68.8 percent of breast cancer patients, and 62.5 percent of lung cancer patients. The trial found a less than 10-20 percent improvement for leukemia, stomach cancer, and brain cancer patients. Furthermore, when maitake was taken in addition to chemotherapy, immune-competent cell activities were enhanced 1.2-1.4 times, compared with chemotherapy alone. Animal studies have supported the use of maitake MD-fraction for cancer.

Topics: Adult; Agaricales; Animals; Antibiotics, Antineoplastic; beta-Glucans; Breast Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Female; Glucans; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasms

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that promote tumor progression. In this study, we demonstrated that activation of a C-type lectin receptor, dectin-1, in MDSC differentially modulates the function of different MDSC subsets. Yeast-derived whole β-glucan particles (WGP; a ligand to engage and activate dectin-1, oral treatment in vivo) significantly decreased tumor weight and splenomegaly in tumor-bearing mice with reduced accumulation of polymorphonuclear MDSC but not monocytic MDSC (M-MDSC), and decreased polymorphonuclear MDSC suppression in vitro through the induction of respiratory burst and apoptosis. On a different axis, WGP-treated M-MDSC differentiated into F4/80(+)CD11c(+) cells in vitro that served as potent APC to induce Ag-specific CD4(+) and CD8(+) T cell responses in a dectin-1-dependent manner. Additionally, Erk1/2 phosphorylation was required for the acquisition of APC properties in M-MDSC. Moreover, WGP-treated M-MDSC differentiated into CD11c(+) cells in vivo with high MHC class II expression and induced decreased tumor burden when inoculated s.c. with Lewis lung carcinoma cells. This effect was dependent on the dectin-1 receptor. Strikingly, patients with non-small cell lung carcinoma that had received WGP treatment for 10-14 d prior to any other treatment had a decreased frequency of CD14(-)HLA-DR(-)CD11b(+)CD33(+) MDSC in the peripheral blood. Overall, these data indicate that WGP may be a potent immune modulator of MDSC suppressive function and differentiation in cancer.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antigen-Presenting Cells; Apoptosis; beta-Glucans; Blotting, Western; Carcinoma, Lewis Lung; Carcinoma, Non-Small-Cell Lung; Cell Differentiation; Cell Separation; Disease Models, Animal; Female; Flow Cytometry; Humans; Lectins, C-Type; Lung Neoplasms; Lymphocyte Culture Test, Mixed; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Monocytes; Myeloid Cells; Neutrophils; Real-Time Polymerase Chain Reaction; Yeasts

Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.

Topics: Animals; beta-Glucans; Humans; Lung Neoplasms; Lysophospholipids; Macrophages; Mice; Monocytes; Trained Immunity; Tumor Microenvironment

The current study evaluated the diagnostic performance of serum (1,3)-beta-D Glucan (BDG) in differentiating PJP from P. jirovecii-colonization in HIV-uninfected patients with P. jirovecii PCR-positive results.. This was a single-center retrospective study between 2019 and 2021. The diagnosis of PJP was based on the following criteria: detection of P. jirovecii in sputum or BAL specimen by qPCR or microscopy; Meet at least two of the three criteria: (1) have respiratory symptoms of cough and/or dyspnea, hypoxia; (2) typical radiological picture findings; (3) receiving a complete PJP treatment. After exclusion, the participants were divided into derivation and validation cohorts. The derivation cohort defined the cut-off value of serum BDG. Then, it was verified using the validation cohort.. Two hundred and thirteen HIV-uninfected patients were enrolled, with 159 PJP and 54 P. jirovecii-colonized patients. BDG had outstanding specificity, LR, and PPV for PJP in both the derivation (90.00%, 8.900, and 96.43%) and the validation (91.67%, 9.176, and 96.30%) cohorts at ≥ 117.7 pg/mL. However, it had lower sensitivity and NPV in the derivation cohort (89.01% and 72.97%), which was even lower in the validation cohort (76.47% and 57.89%). Of note, BDG ≥ 117.7 pg/mL has insufficient diagnostic efficacy for PJP in patients with lung cancer, interstitial lung disease (ILD) and nephrotic syndrome. And although lymphocytes, B cells, and CD4. Serum BDG ≥ 117.7 pg/mL could effectively distinguish P. jirovecii-colonization from infection in qPCR-positive HIV-uninfected patients with infectious diseases, solid tumors (excluding lung cancer), autoimmune or inflammatory disorders, and hematological malignancies. Of note, for patients with lung cancer, ILD, and nephrotic diseases, PJP should be cautiously excluded at BDG < 117.7 pg/mL.

Topics: beta-Glucans; Glucans; HIV Infections; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Pneumocystis carinii; Pneumonia, Pneumocystis; Retrospective Studies

Etoposide is regarded as one of the main standard cytotoxic drugs for lung cancer. However, mutations in Kelch-like ECH-associated protein 1 (

Topics: A549 Cells; beta-Glucans; Cullin Proteins; Etoposide; Humans; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; NF-E2-Related Factor 2; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Saccharomyces cerevisiae

β-glucan, glucopyranosyl polymers of fungi cell wall, represent an immune stimulating effects with potential anti-cancer activity. Mesenchymal stem cells (MSC) have immunomodulating properties in cancer microenvironment. The aim of this study was to investigate the anti-cancer effect of Candida albicans (C. albicans) beta-glucan on MSCs supernatant for apoptosis assay of lung cancer cells in vitro.. Beta-glucan was extracted from cell wall of C.albicans. MSC isolated from adipose tissue of patients and confirmed using specific surface markers expression which examined by flow cytometry. MSCs treated with various concentrations of β-glucans for 48 hours. Cytotoxic effect of β-glucans was evaluated using MTT assay. MSC and lung cancer line cocultured and treated with β-glucans and apoptosis assay was done by flow cytometry.. Cytotoxicity findings showed a significant decrease in MSC viability during 48h, however it was dose-dependent (P<0.05). According to the obtained findings, supernatant of mesenchymal stem cells treated with β-glucans increased cancer cells apoptosis (P<0.05).. Beta glucan may highlight a potential and novel promising candidate in future strategies to cause apoptosis of cancer cells and consider as therapeutic  agent against tumor growth as well. Definitely, more in vitro and in vivo studies are required to understand its functions.

Topics: beta-Glucans; Candida albicans; Cell Survival; Cells, Cultured; Humans; Lung Neoplasms; Mesenchymal Stem Cells

β-glucan from Lentinus edodes (LNT) is a plant-derived medicinal fungus possessing significant bioactivities on anti-tumor. Both hypoxia-induced factor-1α (HIF)-1α and Nur77 have been shown to be involved in the development of breast cancer. However, there is yet no proof of Nur77/HIF-1α involvement in the process of LNT-mediated tumor-inhibition effect.. Immunohistochemistry, immunofluorescence and Hematoxylin-Eosin staining were used to investigate tumor growth and metastasis in MMTV-PyMT transgenic mice. Proliferation and metastasis-associated molecules were determined by Western blotting and reverse transcription-quantitative PCR. Hypoxic cellular model was established under the exposure of CoCl2. Small interference RNA was transfected using Lipofectamine reagent. The ubiquitin proteasome pathway was blunted by adding the proteasome inhibitor MG132.. LNT inhibited the growth of breast tumors and the development of lung metastases from breast cancer, accompanied by a decreased expression of HIF-1α in the tumor tissues. In in vitro experiments, hypoxia induced the expression of HIF-1α and Nur77 in breast cancer cells, while LNT addition down-regulated HIF-1α expression in an oxygen-free environment, and this process was in a manner of Nur77 dependent. Mechanistically, LNT evoked the down-regulation of HIF-1α involved the Nur77-mediated ubiquitin proteasome pathway. A strong positive correlation between Nur77 and HIF-1α expression in human breast cancer specimens was also confirmed.. Therefore, LNT appears to inhibit the progression of breast cancer partly through the Nur77/HIF-1α signaling axis. The findings of the present study may provide a theoretical basis for targeting HIFs in the treatment of breast cancer.

Topics: Adult; Aged; Animals; Antineoplastic Agents; beta-Glucans; Breast Neoplasms; Disease Progression; Female; Fungal Polysaccharides; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; MCF-7 Cells; Mice, Transgenic; Middle Aged; Nuclear Receptor Subfamily 4, Group A, Member 1; Proteasome Endopeptidase Complex; Shiitake Mushrooms; Signal Transduction; Tumor Burden; Ubiquitination

Beta-glucans are widely used in treatment, cosmetics, and the food industry. Glucans play a significant role in activation of the immune and antioxidant system and inhibiting tumor proliferation. In the current study the antitumor activities of new high and low molecular weight beta-glucan derived from oats were investigated in two human lung cancer cell line (A549, H69AR) and normal keratinocytes (HaCaT). The effect of high and low molecular weight beta-glucan from oat was evaluated by cellular viability assessment, lipid peroxidation and manganese superoxide dismutase evaluation and cytoskeleton visualisation. Additionally the level of red blood cells hemolysis was performed. Our results indicate strong anti-tumor properties of new beta-glucan from oat and at the same time no toxicity for normal cells.

Topics: Antineoplastic Agents; Antioxidants; Avena; beta-Glucans; Cell Survival; Hemolysis; Humans; Lipid Peroxidation; Lung Neoplasms; Male; Middle Aged; Molecular Weight; Neoplasms, Glandular and Epithelial; Tumor Cells, Cultured

Gemcitabine (GEM) is widely used in clinical practice in the treatment of cancer and several other solid tumors. Nevertheless, the antitumor effect of GEM is partially prevented by some limitations including short half life, and lack of tumor localizing. Carboxymethyl glucan (CMG), a carboxymethylated derivative of β-(1-3)-glucan, shows biocompatibility and biodegradability as well as a potential anticarcinogenic effect. To enhance the antiproliferative activity of GEM, four water soluble conjugates of GEM bound to CMG via diverse amino acid linkers were designed and synthesized.

Topics: Antineoplastic Agents; beta-Glucans; Caco-2 Cells; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Gemcitabine; HeLa Cells; Humans; Lung Neoplasms; Molecular Structure; Structure-Activity Relationship

β-Glucan is a naturally occurring glucose polysaccharide with immunostimulatory activity in both infection and malignancy. β-Glucan's antitumor effects have been attributed to the enhancement of complement receptor 3-dependent cellular cytotoxicity, as well as modulation of suppressive and stimulatory myeloid subsets, which in turn enhances antitumor T cell immunity. In the present study, we demonstrate antitumor efficacy of yeast-derived β-glucan particles (YGP) in a model of metastatic-like melanoma in the lung, through a mechanism that is independent of previously reported β-glucan-mediated antitumor pathways. Notably, efficacy is independent of adaptive immunity, but requires inflammatory monocytes. YGP-activated monocytes mediated direct cytotoxicity against tumor cells in vitro, and systemic YGP treatment upregulated inflammatory mediators, including TNFα, M-CSF, and CCL2, in the lungs. Collectively, these studies identify a novel role for inflammatory monocytes in β-glucan-mediated antitumor efficacy, and expand the understanding of how this immunomodulator can be used to generate beneficial immune responses against metastatic disease.

Topics: Adaptive Immunity; Adjuvants, Immunologic; Animals; beta-Glucans; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation Mediators; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Receptors, CCR2; T-Lymphocytes; Tumor Cells, Cultured

Tumor-elicited immunosuppression is one of the essential mechanisms for tumor evasion of immune surveillance. It is widely thought to be one of the main reasons for the failure of tumor immunotherapy. Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of cells that play an important role in tumor-induced immunosuppression. These cells expand in tumor-bearing individuals and suppress T cell responses via various mechanisms. Curdlan, the linear (1 → 3)-β-glucan from Agrobacterium, has been applied in the food industry and other sectors. The anti-tumor property of curdlan has been recognized for a long time although the underlying mechanism still needs to be explored. In this study, we investigated the effect of curdlan on MDSCs and found that curdlan could promote MDSCs to differentiate into a more mature state and then significantly reduce the suppressive function of MDSCs, decrease the MDSCs in vivo and down-regulate the suppression in tumor-bearing mice, thus leading to enhanced anti-tumor immune responses. We, therefore, increase the understanding of further mechanisms by which curdlan achieves anti-tumor effects.

Topics: Agrobacterium; Animals; Antineoplastic Agents; beta-Glucans; Carcinoma, Lewis Lung; Cell Differentiation; Immunity; Immunosuppression Therapy; Immunotherapy; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Myeloid-Derived Suppressor Cells; Neoplasms, Experimental; T-Lymphocytes; Tumor Burden; Tumor Escape

β-Glucan is a natural immunomodulator consisting of glucose molecules. It is a well-established modifier with significant beneficial properties in infectious diseases and cancer therapy. Glucan effects on melanoma are relatively less studied, despite the increasing incidence of this type of cancer. In the current study, we focused on possible effects of insoluble yeast-derived β-glucan on the growth of melanoma cells. We found that glucan supplementation had a strong-positive effect in both reducing tumor weight, lung colonies and overall survival rate of tested animals. In addition, glucan inhibited the damage to blood cells and potentiated the effects of regular chemotherapy. By using depletion of natural killer (NK) cells, we showed that these effects are, at least partly, mediated by direct action of glucan on NK cells.

Topics: Administration, Oral; Animals; Antineoplastic Agents; beta-Glucans; Cell Line, Tumor; Female; Immunomodulation; Killer Cells, Natural; Lung Neoplasms; Lymphocyte Activation; Melanoma, Experimental; Mice; Skin Neoplasms; Survival Analysis; Xenograft Model Antitumor Assays

Common genetic alteration in cancer genomes is implicated for embracing an aberrant cancer gene participated in tumor progression. In this study, we identified a somatic mutated LIM and cysteine-rich domains-1 (LMCD1) as a putative metastatic oncogene in human hepatocellular carcinoma (HCC) using integrated genomic approaches. In addition to revealing genomic amplification and gene upregulation, we identified recurrent E135K (3/48 cases) mutations in HCC tissues and K237R mutation in the PLC/PRF/5 HCC cell line. Expression of mutant LMCD1 E135K or K237R reduced the stress fiber assembly, increased cortical actin accumulation and induced lamellipodial extension. Consistently, these mutations enhanced cell migration and showed activation of the Rac1-signaling pathway. Inhibition of the LMCD1/Rac1 pathway by an LMCD1 short-hairpin RNA (shLMCD1) or the Rac1 inhibitor NSC23766 suppressed the mutation-mediated lamellipodial protrusion and cell migration. In PLC/PRF/5 cells with endogenous K237R mutation, cell migration was enhanced by estrogen-induced LMCD1 expression but reversed by shLMCD1 treatment. Moreover, overexpression of LMCD1 E135K mutation significantly promoted systemic lung metastasis in a murine tail vein injection model. Together, our results suggest that LMCD1 mutations are potential oncogenic events in HCC metastasis to promote cell migration through the Rac1-signaling pathway.

Topics: Animals; beta-Glucans; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Co-Repressor Proteins; Gene Amplification; Gene Knockdown Techniques; Humans; LIM Domain Proteins; Liver Neoplasms; Lung Neoplasms; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Point Mutation; Pseudopodia; rac1 GTP-Binding Protein; Signal Transduction; Up-Regulation

Sparassis crispa (SC), Hanabiratake in Japanese, is an edible mushroom with medicinal properties, that contains more than 40% beta-D-glucan. It was concluded from results of the methylation study that beta-D-glucan from SC (SBG) was composed of a backbone of beta-(1-->3)-linked D-glucopyranosyl residues, and had beta-D-glucopyranosyl groups joined through O-6 and O-2 of D-glucose of the backbone. We purified SBG and investigated its anti-angiogenic functions and anti-metastatic effects on neoplasm using different animal models. The oral administration of the purified SBG suppressed B16-F10 cell-induced angiogenesis in the dorsal air sac assay using female ICR mice as well as vascular endothelial growth factor induced neovascularization in the Matrigel plug assay using female C57BL/6J mice. Furthermore, it suppressed the growth and numbers of the metastatic tumor foci in lung, along with the primary tumor growth in the spontaneous metastatic model using female C57BL/6J mice. From these results, it is apparent that the oral administration of SBG results in suppressive effect on tumor growth and metastasis in lung through the inhibition of tumor induced-angiogenesis. These effects are not a result of direct action on the endothelial cells because cell growth, migration and capillary-like tube formation were not affected in the human umbilical vein endothelial cells by SBG application. This is the first report showing that the oral administration of SBG is capable of suppressing angiogenesis and metastasis.

Topics: Agaricales; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; beta-Glucans; Capillaries; Cell Line; Cell Movement; Cell Proliferation; Female; Humans; Lung Neoplasms; Melanoma, Experimental; Methylation; Mice; Mice, Inbred ICR; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; Proteoglycans; Structure-Activity Relationship; Vascular Endothelial Growth Factor A

Cisplatin is broadly used clinically as an anticancer drug. Despite its significant anticancer activity, cisplatin-induced nephrotoxicity and myelosuppression limit its use. MD-Fraction is glucan purified from maitake (Grifola frondosa), which has beta-1, 6-main chain with beta-1, 3-branches, has been reported to exhibit antitumor and antimetastatic activities by enhancing the immune system. In this study, we demonstrate that MD-Fraction in combination with cisplatin significantly enhanced antitumor and antimetastatic activity compared to cisplatin alone. MD-Fraction reduced decreases in body weight, spleen weight and the number of immunocompetent cells such as macrophages, DCs and NK cells in cisplatin-treated mice. MD-Fraction also induced IL-12p70 production by splenocytes, resulting in increased NK cell activity in cisplatin-treated mice. MD-Fraction significantly increased the mRNA expression of GM-CSF, G-CSF, M-CSF, IFN-gamma, IL-12 p40 in splenocytes and reduced the decrease in the number of CFU-GM colonies in cisplatin-treated bone marrow. These facts suggest that MD-Fraction can reduce cisplatin-induced myelosuppression. Moreover, treatment with MD-Fraction significantly reduced cisplatin-induced nephrotoxicity accompanied by increases in serum creatinine level, necrosis and apoptosis of renal tubular cells. These results suggest that MD-Fraction in combination with cisplatin cannot only enhance antitumor and antimentastatic acitivity, but also reduce cisplatin-induced myelotoxicity and nephrotoxicity.

Topics: Animals; Antigens, Fungal; Antineoplastic Agents; Apoptosis; beta-Glucans; Bone Marrow; Cell Line, Tumor; Cisplatin; Colony-Forming Units Assay; Colorectal Neoplasms; Creatinine; Drug Synergism; Female; Grifola; Interferon-gamma; Interleukin-12; Kidney; Killer Cells, Natural; Lung Neoplasms; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Organ Size; Phytotherapy

Human lung cancer is the leading cause of cancer death worldwide. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with chemotherapy showed significant therapeutic efficacy in human lung cancer patients. However, increased adverse effects limit its clinical utilization. Previous studies demonstrated that polysaccharide beta-glucan significantly augments antitumor monoclonal antibody-mediated efficacy via stimulation of the innate effector neutrophil complement receptor 3. Here, we explored combined beta-glucan with bevacizumab therapy for human lung cancer using murine xenograft models. To that end, human lung adenocarcinomas were screened for membrane-bound VEGF expression. Both subcutaneous and orthotopic lung cancer xenograft models were used to evaluate the combination therapy. We found that PC14PE6 adenocarcinoma cells express membrane-bound VEGF both in vitro and in vivo. Bevacizumab bound to surface VEGF on PC14PE6 cells and activated complement. In the subcutaneous PC14PE6 tumor model, beta-glucan plus bevacizumab showed augmented efficacy in terms of tumor progression and long-term survival compared with bevacizumab-treated alone. These effects were accompanied with massive complement deposition and neutrophil infiltration within tumors. However, this effect was not observed in surface-bound VEGF-negative human lung tumors. Therapeutic efficacy of beta-glucan with bevacizumab was further demonstrated in an orthotopic lung cancer model. Thus, our data suggest that beta-glucan enhances bevacizumab-mediated efficacy and may provide therapeutic benefits for lung cancers with membrane-bound VEGF expression.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Complement Activation; Humans; Lung Neoplasms; Mice; Mice, SCID; Neutrophil Infiltration; Treatment Outcome; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays; Yeasts

The beta-glucans isolated from Saccharomyces cerevisiae (S. cerevisiae) enhance the innate immune system, but there is little evidence for its antitumor activity. To examine the antitumor and immunostimulating activities of beta-glucan (IS-2) purified from mutated S. cerevisiae, we made an experiment on innate immune response against metastasis of cancer cells by comparing with the beta-glucan from wild-type S. cerevisiae. In experimental lung metastasis of colon 26-M3.1 carcinoma or B16-BL6 melanoma cells, prophylactic administration of beta-glucan purified from mutated S. cerevisiae significantly inhibited lung metastasis in a dose-dependent manner. Furthermore, therapeutic administration of IS-2 also significantly inhibited the colon 26-M3.1 cell growth in mice. In an assay of liver and spleen metastasis produced by i.v. inoculation of L5178Y-ML25 lymphoma cells, IS-2 also significantly inhibited metastasis in CDF1 mice. Furthermore, pretreatment with IS-2 two days before tumor inoculation significantly prolonged the survival time of tumor-bearing mice. In an in vitro cytotoxicity analysis, IS-2 (up to 100 microg/ml) did not affect the growth of colon 26-M3.1 cells. In contrast, IS-2 enhanced splenocyte proliferating activity in a dose-dependent manner. Peritoneal macrophages stimulated with IS-2 produced various cytokines, such as IL-1beta, IFN-gamma, and IL-12. In addition, treatment with IS-2 (20 microg/mouse) induced tumoricidal activity of peritoneal macrophages against colon 26-M3.1 cells. In an assay for natural killer (NK) cell activity, IS-2 (20 microg/mouse, i.v.) significantly augmented NK cytotoxicity against Yac-1 tumor cells at 2 days after IS-2 treatment. The depletion of NK cells by injection of rabbit anti-asialo GM1 serum abolished the inhibitory effect of IS-2 on lung metastasis of colon 26-M3.1 cells. These data suggest that IS-2 inhibits tumor metastasis via activation of macrophages and NK cells.

Topics: Animals; beta-Glucans; Cell Line, Tumor; Coculture Techniques; Female; Leukemia L5178; Lung Neoplasms; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mutagenesis; Rabbits; Saccharomyces cerevisiae

Administration of a combination of yeast-derived beta-glucan with antitumor monoclonal antibodies (mAb) has significant therapeutic efficacy in a variety of syngeneic murine tumor models. We have now tested this strategy using human carcinomas implanted in immunocompromised severe combined immunodeficient mice. Combined immunotherapy was therapeutically effective in vivo against NCI-H23 human non-small-cell lung carcinomas, but this modality was surprisingly ineffective against SKOV-3 human ovarian carcinomas. Whereas NCI-H23 tumors responded to this combination therapy with increased intratumoral neutrophil infiltration and C5a production, these responses were lacking in treated SKOV-3 tumors. Further results suggested that SKOV-3 tumors were protected by up-regulation of the membrane complement regulatory protein CD55 (decay-accelerating factor). Blockade of CD55 in vitro led to enhanced deposition of C activation product C3b and increased cytotoxicity mediated by beta-glucan-primed neutrophils. In vivo, administration of anti-CD55 mAb along with beta-glucan and anti-Her-2/neu mAb caused tumor regression and greatly improved long-term survival in animals bearing the previously resistant SKOV-3 tumors. This was accompanied by increased intratumoral neutrophil accumulation and C5a production. We conclude that CD55 suppresses tumor killing by antitumor mAb plus beta-glucan therapy (and, perhaps, in other circumstances). These results suggest a critical role for CD55 to regulate iC3b and C5a release and in turn to influence the recruitment of beta-glucan-primed neutrophils eliciting killing activity.

Topics: Animals; Antibodies, Monoclonal; beta-Glucans; Carcinoma, Non-Small-Cell Lung; CD55 Antigens; Cell Line, Tumor; Chemotaxis, Leukocyte; Complement C3a; Complement C5a; Drug Therapy, Combination; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred ICR; Mice, SCID; Neutrophil Infiltration; Ovarian Neoplasms; Saccharomyces cerevisiae; Tumor Cells, Cultured

Both moderate exercise and the soluble fiber beta-glucan can have beneficial effects on the initiation and growth of tumors, but the data are limited, and there is no information on their combined effects. This study tested the independent and combined effects of short-term moderate-exercise training and the soluble oat fiber beta-glucan (ObetaG) on the metatastic spread of injected tumor cells and macrophage antitumor cytotoxicity. Male C57BL/6 mice were assigned to one of four groups: exercise (Ex)-H2O, Ex-ObetaG, control (Con)-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 days before tumor administration and death. Exercise consisted of treadmill running (1 h/day) for 6 days. After rest or exercise on the last day of training, syngeneic B16 melanoma cells (2 x 10(5)) were administered via intravenous injection (n = 8-11 per group). Lungs were removed 14 days later, and tumor foci were counted. Additional mice (n = 8 per group) were killed, and peritoneal macrophages were assayed for cytotoxicity against the same mouse tumor cell line at various effector-to-target ratios. Both moderate exercise and ObetaG decreased lung tumor foci and increased macrophage cytotoxicity. However, there were no differences in lung tumor foci and macrophage cytotoxicity between Ex-ObetaG and either Ex-H2O or Con-ObetaG. These data suggest that, although not additive in their effects, both short-term moderate-exercise training and consumption of the soluble ObetaG can decrease the metatastic spread of injected B16 melanoma cells, and these effects may be mediated in part by an increase in macrophage cytotoxicity to B16 melanoma.

Topics: Administration, Oral; Animals; beta-Glucans; Combined Modality Therapy; Cytotoxicity, Immunologic; Dietary Supplements; Exercise Therapy; Lung Neoplasms; Macrophage Activation; Male; Melanoma; Mice; Mice, Inbred C57BL; Physical Conditioning, Animal; Treatment Outcome

The efficiency of chemotherapy of Lewis lung carcinoma with cyclophosphamide was affected by administration of the water-soluble yeast polysaccharide derivative--carboxymethylated (1 --> 3)-beta-D-glucan (CMG)-a well-known macrophage stimulator. It was found that while cyclophosphamide showed 57% growth inhibition of the intramuscular tumor implants in comparison with the control group, its combined administration with CMG led to 75-90% inhibition. Similarly, increased inhibition of occurrence of lung metastases (up to 92-94%) was observed using the combined application of the two compounds. The stimulatory effect of CMG is not associated with the changed cellularity of peripheral blood, but is rather due to the obviously increased concentration of the intracellular inhibitor of cysteine proteases-stefin A and cystatin C in tumor tissue.

Topics: Animals; beta-Glucans; Carcinoma, Lewis Lung; Cyclophosphamide; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Drug Therapy, Combination; Glucans; Leukocytes; Lung Neoplasms; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Saccharomyces cerevisiae; Xenograft Model Antitumor Assays

We studied the effect of macrophage stimulator water-soluble beta-(1-->3)-D-carboxymethylglucan on the efficiency of cyclophosphamide chemotherapy in Lewis lung carcinoma. Cyclophosphamide inhibited the growth of primary tumor nodes by 57%. The preparation possessed pronounced antimetastatic activity: metastases were found in 40.9% animals. Combination therapy with cyclophosphamide and (1-->3)-beta;-D-glucan inhibited the growth of intramuscular tumors by 75-89% and reduced the incidence of metastases into the lungs by 92-94%. The therapeutic effect was most pronounced after simultaneous administration of these preparations: tumor growth was suppressed by 89.3% and metastases were found in only 7.5% animals (vs. 100% in the control). The potentiating effect of beta-(1-->3)-D-carboxymethylglucan is related to accumulation of cysteine proteinase inhibitors in the tumor tissue and plasma, but not to changes in blood cell composition.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; beta-Glucans; Body Weight; Carcinoma, Lewis Lung; Cathepsin B; Cathepsin L; Cathepsins; Cyclophosphamide; Cystatin A; Cystatin C; Cystatins; Cysteine Endopeptidases; Drug Synergism; Glucans; Injections, Intraperitoneal; Lung Neoplasms; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Neoplasm Transplantation

In this study, we examined the effect of systemic administration of SSG, a soluble highly branched (1-->3)-beta-D-glucan obtained from a fungus Sclerotinia sclerotiorum IFO 9395, on pulmonary immune responses in mice. SSG (10 mg/kg) administered intravenously (i.v.) rapidly leaked into the alveolar space and enhanced several functions of alveolar macrophages (AMs), such as phagocytic activity, lysosomal enzyme activity, active oxygen secretion and cytokine production, on day 1 post-administration. However, kinetic changes of influx of SSG into alveoli and AM activation after SSG treatment were different. The enhanced AM functions decreased to control value on day 2 when SSG still existed at the alveolar space. Additionally, a high dose (500 micrograms/ml) of SSG was needed to activate AMs in vitro. These data imply that the stimulation by SSG alone is not effective on AM activation. SSG administered i.v. also augmented interferon gamma (IFN gamma) mRNA expression in the lung tissue, and the kinetic change of the expression was similar to that of AM activation. Additionally, a synergistic effect of SSG and IFN gamma was observed on AM activation in vitro. It may be possible that IFN gamma produced by pulmonary T cells is one of the important factors for AM activation in vivo by SSG injection. Furthermore, SSG administered i.v. enhanced candidacidal activity and cytolytic activity against pulmonary metastatic Lewis lung carcinoma (3LL) cells of AMs, and inhibited significantly the experimental pulmonary metastasis of 3LL cells. These observations are very useful for the clinical application of SSG as a biological response modifier (BRM).

Topics: Animals; Ascomycota; Base Sequence; beta-Glucans; DNA Primers; Glucans; Immunologic Factors; In Vitro Techniques; Interferon-gamma; Lung; Lung Neoplasms; Macrophage Activation; Macrophages, Alveolar; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Molecular Sequence Data; RNA, Messenger; Solubility