• Asian Pacific Journal of Cancer Prevention
• /
• 제15권13호
• /
• pp.5181-5186
• /
• 2014

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-${\beta}$(TGF-${\beta}$) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-${\beta}$ produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-${\beta}$ in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-${\beta}$ using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and $CD4^+Foxp3^+$ Treg cells, and consequently enhanced IFN-${\gamma}$ production by CTLs. Knockdown of tumor-derived TGF-${\beta}$ also significantly reduced the conversion of na$\ddot{i}$ve $CD4^+$ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-${\beta}$ suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-${\beta}$ is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-${\beta}$ may serve as a potential therapeutic approach for cancer.

• Biomolecules & Therapeutics
• /
• 제13권3호
• /
• pp.143-149
• /
• 2005

We have demonstrated previously on a replication incompetent recombinant adenoviral vector, AdLPCD, in which the expression of cytosine deaminase (CD) gene is driven by the tumor-specific L-plastin promoter. The object of this study was to evaluate the efficacy of AdLPCD together with 5-fluorocytosine (5-FC) in suppression of the growth of established human tumor cells of ovary, Consistent with the knowledge that infection of OVCAR-3 cells with AdLPCD resulted in expression of a functional intracellular CD enzyme capable of converting 5-FC to 5-fluorouracil (5-FU) (Chung and Deisseroth, 2004), statistically significant differences in cytotoxicity were observed when AdLPCD infected cells were also exposed to 5-FC for 6 days (p=0.05), 9 days (p<0.0005) and 12 days (p<0.005), compared to 5-FC exposure alone, These results indicate that the CD gene delivered by adenoviral vector could efficiently sensitize OVCAR-3, otherwise non-toxic 5-FC. On the other hand, SKOV-3 cells, an ovarian carcinoma cell line, were more resistant to the CD/5-FC strategy compared with OVCAR-3 cells under the same condition. The results of present study suggest that the replacement of 5-FU with CD/5-FC in combination chemotherapy would be less toxic and much greater cytotoxicity than the conventional combination chemotherapy in some patients.

• Genomics & Informatics
• /
• 제11권4호
• /
• pp.164-173
• /
• 2013

Genomic instability, which occurs through both genetic mechanisms (underlying inheritable phenotypic variations caused by DNA sequence-dependent alterations, such as mutation, deletion, insertion, inversion, translocation, and chromosomal aneuploidy) and epigenomic aberrations (underlying inheritable phenotypic variations caused by DNA sequence-independent alterations caused by a change of chromatin structure, such as DNA methylation and histone modifications), is known to promote tumorigenesis and tumor progression. Mechanisms involve both genomic instability and epigenomic aberrations that lose or gain the function of genes that impinge on tumor suppression/prevention or oncogenesis. Growing evidence points to an epigenome-wide disruption that involves large-scale DNA hypomethylation but specific hyper-methylation of tumor suppressor genes, large blocks of aberrant histone modifications, and abnormal miRNA expression profile. Emerging molecular details regarding the modulation of these epigenetic events in cancer are used to illustrate the alterations of epigenetic molecules, and their consequent malfunctions could contribute to cancer biology. More recently, intriguing evidence supporting that genetic and epigenetic mechanisms are not separate events in cancer has been emerging; they intertwine and take advantage of each other during tumorigenesis. In addition, we discuss the collusion between epigenetics and genetics mediated by heterochromatin protein 1, a major component of heterochromatin, in order to maintain genome integrity.

• Biomolecules & Therapeutics
• /
• 제19권4호
• /
• pp.411-418
• /
• 2011

Ginsenoside Rp1 (G-Rp1) is a novel ginseng saponin derivative with anti-tumor activity. However, the biochemical and molecular mechanisms of G-Rp1 on anti-tumor activity are not fully understood. In the present study, we report that G-Rp1 inhibits lung cancer cell proliferation, migration and adhesion in p53 wild-type A549 and p53-defi cient H1299 cells. Anti-proliferative activity of G-Rp1 in lung cancer cells is mediated by enhanced nuclear localization of cyclin-dependent kinase inhibitors including $p27^{Kip1}$ and $p21^{WAF1/Cip1}$, and subsequent inhibition of pRb phosphorylation. We also show that these anti-tumor activities of G-Rp1 in both A549 and H1299 cells appear to be mediated by suppression of mitogenic signaling pathways such as ERK, Akt and $p70^{S6K}$. Taken together, these findings suggest further development and evaluation of G-Rp1 for the treatment of lung cancers with mutated p53 as well as wild-type p53.

• Biomolecules & Therapeutics
• /
• 제28권1호
• /
• pp.1-17
• /
• 2020

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that exert suppressive function on the immune response. MDSCs expand in tumor-bearing hosts or in the tumor microenvironment and suppress T cell responses via various mechanisms, whereas a reduction in their activities has been observed in autoimmune diseases or infections. It has been reported that the symptoms of various diseases, including malignant tumors, can be alleviated by targeting MDSCs. Moreover, MDSCs can contribute to patient resistance to therapy using immune checkpoint inhibitors. In line with these therapeutic approaches, diverse oligonucleotide-based molecules and small molecules have been evaluated for their therapeutic efficacy in several disease models via the modulation of MDSC activity. In the current review, MDSC-targeting oligonucleotides and small molecules are briefly summarized, and we highlight the immunomodulatory effects on MDSCs in a variety of disease models and the application of MDSC-targeting molecules for immuno-oncologic therapy.

• 생명과학회지
• /
• 제22권9호
• /
• pp.1224-1230
• /
• 2012

항암화학요법제는 의약품 시장 중 가장 큰 시장의 하나이며, 세계적으로 수많은 연구와 신약의 개발이 진행되고 있다. 그러나 암 세포 뿐만 아니라 정상세포와 조직에 대한 독성과 내성으로 인해 심각한 부작용이 지속되어, 최근 신혈관형성 억제와 천연물 유래의 암 치료제 개발이 많은 관심을 얻고 있다. 본 연구에서는 오미자의 활성성분 중 하나인 Gomisin A의 종양성장 및 전이억제 효과와 이들의 작용기전에 대해 확인하고자 하였다. Gomisin A의 종양성장 억제활성은 B16BL6 cell line을 C57/BL6 mice의 피하에 주입하여 유도된 종양모델을 활용 하였으며, Gomisin A 10 ${\mu}g/ml$, 100 ${\mu}g/ml$에서 양성 대조군에 비해 각각 $80.5{\pm}8.1%$, $96.2{\pm}2%$의 유의한 억제활성을 나타내었다. Gomisin A의 암세포에 대한 직접적인 독성은 MTT assay를 통해 확인하였고, 정상세포(HUVECs)와 종양세포주(A549, B16BL6, Du145, Huh7)에 대한 유의한 독성은 관찰되지 않았다. 종양조직에 의해 유도되는 신혈관형성 억제능은 C57/BL6 mice에 배양된 B16BL6 cell line을 피하주사하여 종양조직을 형성하고, 이들이 유도하는 신생혈관에 대한 Gomsin A의 억제활성을 확인하였다. Gomisin A를 10 ${\mu}g$/head와 100 ${\mu}g$/head에서 신혈관형성 억제활성은 양성 대조군에 비해 각각 $151{\pm}16.9%$, $98.5{\pm}29.5%$의 유의한 감소활성을 나타내었다. 종양전이 억제활성은 B16BL6 cell line을 C57/BL6 mice 미정맥에 주입하여 in vivo 폐전이 모델을 만들고 폐에 전이된 종양의 colony를 측정하여 확인하였다. Gomisin A의 농도 10 ${\mu}g$/head, 100 ${\mu}g$/head에서 각각 양성 대조군에 비해 $13.5{\pm}8.56%$, $58.3{\pm}9.12%$의 전이 억제활성을 나타내었다. 또한 Gomisin A는 B16BL6 cell line이 세포외기질에 대한 부착능을 유의하게 감소시킴을 확인하였다. 이러한 결과는 Gomisin A의 종양성장 억제활성이 암세포에 대한 직접적인 독성에 의한 것이 아닌 신혈관형성 억제에 의한 것이며, 또한 종양 전이 억제 활성을 나타냄으로서 향후, 암 예방 및 치료제 개발의 선도물질을 제공할 수 있음을 확인하였다. 본 연구는 오미자의 주요 생리활성 물질인 Gomisin A의 종양성장 억제 활성과 전이억제 활성을 규명하고자 하였다. Gomisin A가 종양성장 억제활성이 있음을 확인하였고, 이러한 효과는 종양세포에 대한 직접적인 독성에 의한 것이 아니라, 종양조직에 의해 유도되는 신혈관형성 저해 활성에 의해 나타나는 것을 규명하였다. 이러한 결과는 대부분의 항암화학요법제가 가지는 독성작용을 극복하고, 선택적인 종양성장 억제제로서의 개발 가능성을 시사하여 주고 있다. 또한 Gomisin A는 종양세포의 세포외기질 부착억제활성을 통해 암 전이 억제활성을 나타냄을 확인하였다. 지금까지의 결과는, Gomisin A를 활용한 부작용이 적으며 효과적인 암 치료제 개발의 선도 물질로서 활용 가능성을 나타내 주고 있으며, 또한 고 기능성 식품 및 화장품의 개발에 활용이 가능할 것이다. 그러나, 향후 종양 면역활성, 암세포 자살 유도능과 같은 다양한 부분의 연구가 수반되어야 할 것이다.

• BMB Reports
• /
• 제45권11호
• /
• pp.659-664
• /
• 2012

Extracellular superoxide dismutase (EC-SOD) overexpression modulates cellular responses such as tumor cell suppression and is induced by $IFN{\gamma}$. Therefore, we examined the role of EC-SOD in $IFN{\gamma}$-mediated tumor cell suppression. We observed that the dominant-negative protein kinase C delta ($PKC{\delta}$) suppresses $IFN{\gamma}$-induced EC-SOD expression in both keratinocytes and melanoma cells. Our results also showed that $PKC{\delta}$-induced EC-SOD expression was reduced by pretreatment with a PKC-specific inhibitor or a siRNA against $PKC{\delta}$. $PKC{\delta}$-induced EC-SOD expression suppressed cell proliferations by the up-regulation of p21 and Rb, and the downregulation of cyclin A and D. Finally, we demonstrated that increased expression of EC-SOD drastically suppressed lung melanoma proliferation in an EC-SOD transgenic mouse via p21 expression. In summary, our findings suggest that $IFN{\gamma}$-induced EC-SOD expression occurs via activation of $PKC{\delta}$. Therefore, the upregulation of EC-SOD may be effective for prevention of various cancers, including melanoma, via cell cycle arrest.

• 대한한방내과학회지
• /
• 제26권2호
• /
• pp.310-319
• /
• 2005

Objectives: The aim is to identify any anti-tumor effects of Duchesnea indica(Andr.) Focke on colon cancer cells. Materials & Methods: Colo201 human adenocarcinoma cells were obtained from American Type Culture Collection. The boiled extract of Duchesnea indica(Andr.) Focke was added (10 and 20 microliters) to cultures and observed at 0, 6, and 12 hours, and at 12-hour intervals thereafter. Morphological changes in colon cancer cells were observed through an inverted microscope, Destruction of colon cancer cells was measured through Trypan blue exclusion testing. Suppression of the viability of colon cancer cells were measured via MTT assay. Anti-cancer mechanisms in the cell cycle of colon cancer cells were analysed via flow cytometry. Results: After introduction of Duchesnea indica(Andr.) Focke to cultures several changes were seen. Significant atrophy of the nucleus and cytoplasm of colon cancer cells was observed, indicating cell injury. Destruction of colon cancer cells was observed in direct proportion to dosage and duration. Suppression of viability of colon cancer cells for each test group was greater than that of the control group increasingly over time(36h, 48h, 60h, 72h), which was statistical significant (p<0.05). Cell numbers of the mitosis phase of the colon cancer cell cycle reduced. Conclusions: Statistcally significant anti-tumor effects of Duchesnea indica(Andr.) Focke were observed in this in vitro experiment. Results support a role for Duchesnea indica(Andr.) Focke in treatment of colon cancer. though it will required progressive research to develop a practical treatment.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권1호
• /
• pp.239-244
• /
• 2014

Several recent studies have showed that the n-myc downstream regulated gene 2 (NDRG2) is a new tumor suppressor gene, and that it plays an important role in tumor suppression in several cancers or cancer cell lines. However, few studies focused on its function in neuroblastoma cells. In the present investigation, we demonstrated that NDRG2 overexpression inhibited their proliferation. Using a cDNA microarray, we found that overexpression of NDRG2 inhibited the expression of cysteine-rich protein 61 (CYR61), a proliferation related gene. From our research, CYR61 may partially hinder NDRG2-mediated inhibition of cell proliferation. Overexpression of NDRG2 resulted in accumulation of cells in the G1 phase, which was accompanied by upregulation of p21 and p27 and downregulation of CDK4 and cyclin D1. Taken together, these data indicate that NDRG2 inhibits the proliferation of neuroblastoma cells partially through suppression of CYR61. Our findings offer novel insights into the physiological roles of NDRG2 in neuroblastoma cell proliferation, and NDRG2 may prove to be effective candidate for the treatment of children with neuroblastoma.

• 대한한의학회지
• /
• 제30권6호
• /
• pp.35-43
• /
• 2009

Objectives: Hwangryunhaedok-tang (HRHDT), a prescription composed of four herbs, has been wi dely used in Oriental Medicine for the treatment of cerebral infarction. However, the mechanisms by which the herbal formula affects on the production of pro- and anti-inflammatory cytokines in cerebral infarction patients remain unknown yet. Methods: The levels of pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6, IL-10, and TGF-${\beta}1$ were determined in peripheral blood mononuclear cells (PBMCs) from cerebral infarction patients under our experimental conditions. Results: The secretory levels of pro- and anti-inflammatory cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6, and IL-10 were significantly increased in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from cerebral infarction patients. However, pretreatment with HRHDT significantly inhibited the secretion of pro- and anti-inflammatory in PBMCs. Also, HRHDT induced a significant increase of transforming growth factor (TGF)-b1 in PBMCs. Conclusions: These data indicate that HRHDT may be beneficial in the suppression of inflammatory processes of cerebral infarct through suppression of TNF-$\alpha$, IL-$1{\beta}$, IL-6, and IL-10 and induction of TGF-${\beta}1$.