• Title, Summary, Keyword: tumor cells

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Dealcoholized Korean Rice Wine (Makgeolli) Exerts Potent Anti-Tumor Effect in AGS Human Gastric Adenocarcinoma Cells and Tumor Xenograft Mice

  • Shin, Eun Ju;Kim, Sung Hee;Kim, Jae Ho;Ha, Jaeho;Hwang, Jin-Taek
    • Journal of Microbiology and Biotechnology
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    • v.25 no.9
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    • pp.1485-1492
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    • 2015
  • Makgeolli is a traditional wine in Korea and has been traditionally believed to exhibit health benefits. However, the inhibitory effect of dealcoholized makgeolli (MK) on cancer has never been investigated scientifically. In this study, MK exhibited an anti-angiogenic effect by inhibiting tube formation in human umbilical vein endothelial cells, without cytotoxicity. Treatment with MK reduced the proliferation of AGS human gastric adenocarcinoma cells in a dose-dependent manner and increased the sub-G1 population. Next, we evaluated whether MK could induce apoptosis in AGS cells by using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay or Annexin V method. Treatment with MK at 500 and 1,000 μg/ml increased the number of TUNEL-positive AGS cells. Under the same conditions, MK-treated (500 and 1,000 μg/ml) cells showed significant induction of early or late apoptosis, compared with untreated cells (no induction). In addition, MK also induced phosphatase and tensin homolog (PTEN) expression in AGS cells. However, p53 expression in AGS cells was not changed by MK treatment. Furthermore, MK at 500 mg/kg·d reduced the tumor size and volume in AGS tumor xenografts. Taken together, MK may be useful for the prevention of cancer cell growth.

Selenium Inhibits Metastasis of Murine Melanoma Cells through the Induction of Cell Cycle Arrest and Cell Death

  • Song, Hyun-Keun;Hur, In-Do;Park, Hyun-Jin;Nam, Joo-Hyung;Park, Ga-Bin;Kong, Kyoung-Hye;Hwang, Young-Mi;Kim, Yeong-Seok;Cho, Dae-Ho;Lee, Wang-Jae;Hur, Dae-Young
    • IMMUNE NETWORK
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    • v.9 no.6
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    • pp.236-242
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    • 2009
  • Background: Melanoma is the most fatal form of skin cancer due to its rapid metastasis. Recently, several studies reported that selenium can induce apoptosis in melanoma cells. However, the precise mechanism remains to be elucidated. In this study, we investigated the effect of selenium on cell proliferation in murine melanoma and on tumor growth and metastasis in C57BL/6 mice. Methods: Cell proliferation was measured by MTT assay in selenium-treated melanoma cells. Cell cycle distribution was analysized by staining DNA with propidum iodide (PI). mRNA and protein expression related to cell cycle arrest was measured by reverse transcription PCR and western blot. Tumor growth and metastasis was measured by in vivo model. Results: Selenium was suppressed the proliferation of melanoma cells in a dose dependent manner. The growth inhibition of melanoma by selenium was associated with an arrest of cell cycle distribution at G0/G1 stage. The mRNA and protein level of CDK2/CDK4 was suppressed by treatment with selenium in a time-dependent manner. In vivo, tumor growth was not suppressed by selenium; however tumor metastasis was suppressed by selenium in mouse model. Conclusion: These results suggest that selenium might be a potent agent to inhibit proliferative activity of melanoma cells.

Exosomes from Murine-derived GL26 Cells Promote Glioblastoma Tumor Growth by Reducing Number and Function of CD8+T Cells

  • Liu, Zhi-Ming;Wang, Yu-Bin;Yuan, Xian-Hou
    • Asian Pacific Journal of Cancer Prevention
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    • v.14 no.1
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    • pp.309-314
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    • 2013
  • Aim: Brain tumors almost universally have fatal outcomes; new therapeutics are desperately needed and will only come from improved understandins of glioma biology. Methods: Exosomes are endosomally derived 30~100 nm membranous vesicles released from many cell types. Examples from GL26 cells were here purified using density gradient ultracentrifugation and monitored for effects on GL26 tumor growth in C57BL/6j mice (H-2b). Lactate dehydrogenase release assays were used to detect the cytotoxic activity of CD8+T and NK cells. Percentages of immune cells producing intracellular cytokines were analyzed by FACS. Results: In this study, exosomes from murine-derived GL26 cells significantly promoted in vivo tumor growth in GL26-bearing B6 mice. Then we further analyzed the effects of the GL26 cells-derived exosomes on immune cells including CD8+T, CD4+T and NK cells. Inhibition of CD8+T cell cytotoxic activity was demonstrated by CD8+T cell depletion assays in vivo and LDH release assays in vitro. The treatment of mice with exosomes also led to a reduction in the percentages of CD8+T cells in splenocytes as determined by FACS analysis. Key features of CD8+T cell activity were inhibited, including release of IFN-gamma and granzyme B. There were no effects of exosomes on CD4+T cells and NK cells. Conclusion: Based on our data, for the first time we demonstrated that exosomes from murine derived GL26 cells promote the tumor growth by inhibition of CD8+T cells in vivo and thus may be a potential therapeutic target.

Antitumor Activity of the Korean Mistletoe Lectin is Attributed to Activation of Macrophages and NK Cells

  • Yoon, Tae-Joon;Yoo, Yung-Choon;Kang, Tae-Bong;Song, Seong-Kyu;Lee, Kyung-Bok;Her, Erk;Song, Kyung-Sik;Kim, Jong-Bae
    • Archives of Pharmacal Research
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    • v.26 no.10
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    • pp.861-867
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    • 2003
  • Inhibitory effect of the lectins (KML-C) isolated from Korean mistletoe (KM; Viscum album coloratum) on tumor metastases produced by murine tumor cells (B16-BL6 melanoma, colon 26M3.1 carcinoma and L5178Y-ML25 lymphoma cells) was investigated in syngeneic mice. An intravenous (i.v.) administration of KML-C (20-50 ng/mouse) 2 days before tumor inoculation significantly inhibited lung metastases of both B16-BL6 and colon 26-M3.1 cells. The prophylactic effect of 50 ng/mouse of KML-C on lung metastasis was almost the same with that of 100 $\mu$ g/mouse of KM. Treatment with KML-C 1 day after tumor inoculation induced a significant inhibition of not only the experimental lung metastasis induced by B16-BL6 and colon 26M3.1 cells but also the liver and spleen metastasis of L5178Y-ML25 cells. Furthermore, multiple administration of KML-C given at 3 day-intervals after tumor inoculation led to a significant reduction of lung metastasis and suppression of the growth of B16-BL6 melanoma cells in a spontaneous metastasis model. In an assay for natural killer (NK) cell activity. i.v. administration of KML-C (50 ng/mouse) significantly augmented NK cytotoxicity against Yac-1 tumor cells 2 days after KML-C treatment. In addition, treatment with KML-C (50 ng/mouse) induced tumoricidal activity of peritoneal macrophages against B16-BL6 and 3LL cells. These results suggest that KML-C has an immunomodulating activity to enhance the host defense system against tumors, and that its prophylactic and therapeutic effect on tumor metastasis is associated with the activation of NK cells and macrophages.

Combination Doxorubicin and Interferon-α Therapy Stimulates Immunogenicity of Murine Pancreatic Cancer Panc02 Cells via Up-regulation of NKG2D ligands and MHC Class I

  • Wang, Wen-Jia;Qin, Si-Hao;Zhang, Ji-Wei;Jiang, Yue-Yao;Zhang, Jin-Nan;Zhao, Lei
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.22
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    • pp.9667-9672
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    • 2014
  • Background: Pancreatic adenocarcinoma is a malignant gastrointestinal cancer with significant morbidity and mortality. Despite severe side effects of chemotherapy, the use of immunotherapy combined with chemotherapy has emerged as a common clinical treatment. In this study, we investigated the efficacy of the combined doxorubicin and interferon-${\alpha}$ (IFN-${\alpha}$) therapy on murine pancreatic cancer Panc02 cells in vitro and in vivo and underlying mechanisms. Materials and Methods: A Panc02-bearing mouse model was established to determine whether doxorubicin and interferon-${\alpha}$ (IFN-${\alpha}$) could effectively inhibit tumor growth in vivo. Cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) was evaluated using a standard LDH release assay. To evaluate the relevance of NK cells and CD8 T cells to the combination therapy-mediated anti-tumor effects, they were depleted in tumor-bearing mice by injecting anti-asialo-GM-1 antibodies or anti-CD8 antibodies, respectively. Finally, the influence of doxorubicin+interferon-${\alpha}$ (IFN-${\alpha}$) on the ligands of NK and T cells was assessed by flow cytometry. Results: The combination therapy group demonstrated a significant inhibition of growth of Panc02 in vivo, resulting from activated cytotoxicity of NK cells and CTLs. Depleting CD8 T cells or NK cells reduced the anticancer effects mediated by immunochemotherapy. Furthermore, the doxorubicin+IFN-a treatment increased the expression of major histocompatibility complex class I (MHC I) and NKG2D ligands on Panc02 cells, suggesting that the combined therapy may be a potential strategy for enhancing immunogenicity of tumors. All these data indicate that the combination therapy using doxorubicin and interferon-${\alpha}$ (IFN-${\alpha}$) may be a potential strategy for treating pancreatic adenocarcinoma.

Gecko Proteins Exert Anti-Tumor Effect against Cervical Cancer Cells Via PI3-Kinase/Akt Pathway

  • Jeong, Ae-Jin;Chung, Chung-Nam;Kim, Hye-Jin;Bae, Kil-Soo;Choi, Song;Jun, Woo-Jin;Shim, Sang-In;Kang, Tae-Hong;Leem, Sun-Hee;Chung, Jin-Woong
    • The Korean Journal of Physiology and Pharmacology
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    • v.16 no.5
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    • pp.361-365
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    • 2012
  • Anti-tumor activity of the proteins from Gecko (GP) on cervical cancer cells, and its signaling mechanisms were assessed by viable cell counting, propidium iodide (PI) staining, and Western blot analysis. GP induced the cell death of HeLa cells in a dose-dependent manner while it did not affect the viability of normal cells. Western blot analysis showed that GP decreased the activation of Akt, and co-administration of GP and Akt inhibitors synergistically exerted anti-tumor activities on HeLa cells, suggesting the involvement of PI3-kinase/Akt pathway in GP-induced cell death of the cancer cells. Indeed, the cytotoxic effect of GP against HeLa cells was inhibited by overexpression of constituvely active form of Akt in HeLa cells. The candidates of the functional proteins in GP were analyzed by Mass-spectrum. Taken together, our results suggest that GP elicits anti-tumor activity against HeLa cells by inhibition of PI3-kinase/Akt pathway.

Analysis of the Expression and Regulation of PD-1 Protein on the Surface of Myeloid-Derived Suppressor Cells (MDSCs)

  • Nam, Sorim;Lee, Aram;Lim, Jihyun;Lim, Jong-Seok
    • Biomolecules & Therapeutics
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    • v.27 no.1
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    • pp.63-70
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    • 2019
  • Myeloid-derived suppressor cells (MDSCs) that are able to suppress T cell function are a heterogeneous cell population frequently observed in cancer, infection, and autoimmune disease. Immune checkpoint molecules, such as programmed death 1 (PD-1) expressed on T cells and its ligand (PD-L1) expressed on tumor cells or antigen-presenting cells, have received extensive attention in the past decade due to the dramatic effects of their inhibitors in patients with various types of cancer. In the present study, we investigated the expression of PD-1 on MDSCs in bone marrow, spleen, and tumor tissue derived from breast tumor-bearing mice. Our studies demonstrate that PD-1 expression is markedly increased in tumor-infiltrating MDSCs compared to expression in bone marrow and spleens and that it can be induced by LPS that is able to mediate $NF-{\kappa}B$ signaling. Moreover, expression of PD-L1 and CD80 on $PD-1^+$ MDSCs was higher than on $PD-1^-$ MDSCs and proliferation of MDSCs in a tumor microenvironment was more strongly induced in $PD-1^+$ MDSCs than in $PD-1^-$ MDSCs. Although we could not characterize the inducer of PD-1 expression derived from cancer cells, our findings indicate that the study on the mechanism of PD-1 induction in MDSCs is important and necessary for the control of MDSC activity; our results suggest that $PD-1^+$ MDSCs in a tumor microenvironment may induce tumor development and relapse through the modulation of their proliferation and suppressive molecules.

THE EXPRESSION OF MMP-2, MMP-3, MMP-10, MMP-13 IN SQUAMOUS CELL CARCINOMA OF THE TONGUE (혀의 편평상피세포암에서 MMP-2, MMP-3, MMP-10, MMP-13의 발현 양상)

  • Yun, Kyoung-In;Pyo, Sung-Woon;Kim, Young-Sill;Lee, Cheol-Won
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.28 no.3
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    • pp.182-187
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    • 2002
  • Matrix metalloproteinase(MMP) is the proteolytic enzyme of the extracellular matrix. MMPs play a role in the invasion and metastasis of malignant tumor, but it is not known whether the expression of MMPs in squamous cell carcinoma of the tongue is related to the prognostic factors of this tumor. In this study, 32 paraffin-embedded tumor specimens were examined immunohistochemically using monoclonal antibodies of MMP-2, MMP-3, MMP-10 and MMP-13. The possible relationships between the expressions of the MMPs and TNM staging, the differentiation of tumor cells, size of tumor mass and lymph node metastasis were anlaysed statistically. The results were as follows. 1. The expression of MMP-2 increased according to TNM staging (P<0.05) and lymph node metastasis (P<0.05) and the expression of MMP-2 was not affected by the differentiation of tumor cells or tumor size. 2. The expression of MMP-3 increased with increasing tumor size (P<0.05). However it was not related to TNM staging, the differentiation of tumor cells or lymph node metastasis. 3. The expression of MMP-10 was unrelated to TNM staging, differentiation of tumor cells, lymph node metastasis or tumor size. 4. The expression of MMP-13 increased as tumor size increased (P<0.05). However it was not related to TNM staging, the differentiation of tumor cells or lymph node metastasis. We concluded that the expression patterns of MMP-2, MMP-3, and MMP-13 may play a role in the diagnosis, treatment plan and prognostic evaluation of malignant tumors of the tongue.

5-Fluorouracil and Interleukin-2 Immunochemotherapy Enhances Immunogenicity of Non-Small Cell Lung Cancer A549 Cells through Upregulation of NKG2D Ligands

  • Zhao, Lei;Wang, Wen-Jia;Zhang, Jin-Nan;Zhang, Xing-Yi
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.9
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    • pp.4039-4044
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    • 2014
  • Background: The aim of this study was to investigate the anti-cancer effects and mechanisms of immunochemotherapy of 5-fluorouracil (5-FU) and interleukin-2 (IL-2) on non-small cell lung cancer (NSCLC) A549 cells. Materials and Methods: In order to detect whether 5-FU+IL-2 could effectively inhibit tumor growth in vivo, we established an A549-bearing nude mouse model. The cytotoxicity of natural killer (NK) cells was evaluated using a standard chromium release assay. To evaluate the relevance of NK cells in 5-FU+IL-2-mediated tumor inhibitory effects, we depleted NK cells in A549-bearing mice by injecting anti-asialo-GM-1 antibodies. Effects of 5-FU+IL-2 on the expression and promoter activity of NKG2D ligands (MICA/MICB) in A549 cells in vitro were also assessed. Results: In A549-bearing nude mice, combination therapy significantly inhibited tumor growth in comparison with monotherapy with 5-FU or IL-2 and enhanced the recognition and lysis of tumor cells by NK cells. Further study of mechanisms showed that NK cells played a vital role in the anticancer immune response of 5-FU+IL-2 immunochemotherapy. In addition, the combination therapy synergistically stimulated the expression and promoter activity of MICA/MICB. Conclusions: 5-FU and IL-2 immunochemotherapy significantly inhibited tumor growth and activated NK cytotoxicity in vivo, and these effects were partly impaired after depleting NK cells in tumor-bearing mice. Combination treatment of 5-FU and IL-2 upregulated the expression and the promoter activity of MICA/MICB in A549 cells, which enhanced the recognition of A549 cells by NK cells. All of the data indicated that immunochemotherapy of 5-FU and IL-2 may provide a new treatment option for patients with lung cancer.

NDRG2 Expression Decreases Tumor-Induced Osteoclast Differentiation by Down-regulating ICAM1 in Breast Cancer Cells

  • Kim, Bomi;Nam, Sorim;Lim, Ji Hyun;Lim, Jong-Seok
    • Biomolecules & Therapeutics
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    • v.24 no.1
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    • pp.9-18
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    • 2016
  • Bone matrix is properly maintained by osteoclasts and osteoblasts. In the tumor microenvironment, osteoclasts are increasingly differentiated by the various ligands and cytokines secreted from the metastasized cancer cells at the bone metastasis niche. The activated osteoclasts generate osteolytic lesions. For this reason, studies focusing on the differentiation of osteoclasts are important to reduce bone destruction by tumor metastasis. The N-myc downstream-regulated gene 2 (NDRG2) has been known to contribute to the suppression of tumor growth and metastasis, but the precise role of NDRG2 in osteoclast differentiation induced by cancer cells has not been elucidated. In this study, we demonstrate that NDRG2 expression in breast cancer cells has an inhibitory effect on osteoclast differentiation. RAW 264.7 cells, which are monocytic preosteoclast cells, treated with the conditioned media (CM) of murine breast cancer cells (4T1) expressing NDRG2 are less differentiated into the multinucleated osteoclast-like cells than those treated with the CM of 4T1-WT or 4T1-mock cells. Interestingly, 4T1 cells stably expressing NDRG2 showed a decreased mRNA and protein level of intercellular adhesion molecule 1 (ICAM1), which is known to enhance osteoclast maturation. Osteoclast differentiation was also reduced by ICAM1 knockdown in 4T1 cells. In addition, blocking the interaction between soluble ICAM1 and ICAM1 receptors significantly decreased osteoclastogenesis of RAW 264.7 cells in the tumor environment. Collectively, these results suggest that the reduction of ICAM1 expression by NDRG2 in breast cancer cells decreases osteoclast differentiation, and demonstrate that excessive bone resorption could be inhibited via ICAM1 down-regulation by NDRG2 expression.