• Biomedical Science Letters
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• v.12 no.3
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• pp.161-170
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• 2006

A new piperazine derivative, 8J-8029, is a synthetic anti-cancer agent which exhibits both microtubule and topoisomerase II inhibiting activities. In this study, we investigated the ability of 8J-8029 for anti-angiogenesis and apoptosis. 8J-8029 decreased the bFGF-induced angiogenesis in the CAM and the mouse Matrigel implants, in vivo. 8J-8029 inhibited the proliferation, migration, invasion, tube fonnation, and expression of MMP-2 in BAECs. In addition, 8J-8029 reduced the cell viability in HepG2 cells, caused the production of fragmented DNA and the morphological changes corresponding to apoptosis. 8J-8029 also elicited the release of cytochrome c and the activation of caspase-3. Taken together, these results suggest 8J-8029 may be a candidate for anti-cancer agent with the ability to inhibit the angiogenesis of endothelial cells and to induce the apoptosis of tumor cells.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3239-3245
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• 2012

Gliomas are a group of heterogeneous primary central nervous system tumors. Hyperthermia has proven to be a potential therapeutic tool for cancers in the clinic. However, the molecular mechanisms of hyperthermia remain unclear. The objective of this study was to investigate the effects of hyperthermia on the invasiveness in C6 glioma cells and related molecular pathways. Here our data show hyperthermia stimulated the release of tumor necrosis factor-alpha (TNF-${\alpha}$) and decreased C6 glioma cell migration and invasive capability at 30, 60, 120 and 180 min; with increased spontaneous apoptosis in C6 glioma cells at 120 min. We also found mitogen-activated protein kinase (P38 MAPK) protein expression to be increased and nuclear factor-kappa B (NF-${\kappa}B$) protein expression decreased. Based on the results, we conclude that hyperthermia alone reduced invasion of C6 glioma cells through stimulating TNF-${\alpha}$ signaling to activate apoptosis, enhancing P38 MAPK expression and inhibiting the NF-${\kappa}B$ pathway, a first report in C6 rat glioma cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.8539-8548
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• 2014

Mitogen-activated protein kinase (MAPK) is an important signaling pathway in living beings in response to extracellular stimuli. There are 5 main subgroups manipulating by a set of sequential actions: ERK(ERK1/ERK2), c-Jun N(JNK/SAPK), p38 MAPK($p38{\alpha}$, $p38{\beta}$, $p38{\gamma}$ and $p38{\delta}$), and ERK3/ERK4/ERK5. When stimulated, factors of upstream or downstream change, and by interacting with each other, these groups have long been recognized to be related to multiple biologic processes such as cell proliferation, differentiation, death, migration, invasion and inflammation. However, once abnormally activated, cancer may occur. Several components of the MAPK network have already been proposed as targets in cancer therapy, such as p38, JNK, ERK, MEK, RAF, RAS, and DUSP1. Among them, alteration of the RAS-RAF-MEK-ERK-MAPK(RAS-MAPK) pathway has frequently been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations in genes. The reported roles of MAPK signaling in apoptotic cell death are controversial, so that further in-depth investigations are needed to address these controversies. Based on an extensive analysis of published data, the goal of this review is to provide an overview on recent studies about the mechanism of MAP kinases, and how it generates certain tumors, as well as related treatments.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.8
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• pp.3573-3577
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• 2015

Background: Sirtuin7 (SIRT7) is a type of nicotinamide adenine dinucleotide oxidized form (NAD+)-dependent deacetylase and the least understood member of the sirtuins family; it is implicated in various processes, such as aging, DNA damage repair and cell signaling transduction. There is some evidence that SIRT7 may function as a tumor trigger for human malignancy. Here, we aimed to explore the biological function of SIRT7 in ovarian carcinoma cells and its potential mechanism. Materials and Methods: Expression of SIRT7 in ovarian cancer cell lines was detected by western blotting. Transduced cell lines with SIRT7 knockdown or overexpression were constructed. Cell viability, cologenic, apoptosis-associated and motility assays were performed to elucidate the biological function of SIRT7 in ovarian cancer cells. Results: SIRT7 demonstrated a higher level in ovarian cancer cell lines compared with normal cells. On the one hand, down-regulation of SIRT7 significantly reduced ovarian cancer cell growth, repressed colony formation and increased cancer cell apoptosis; on the other hand, up-regulation promoted the migration of cancer cells. Additionally, repression of SIRT7 also induced change in apoptosis-related molecules and subunits of the NF-${\kappa}B$ family. Conclusions: In the present study, our data indicated that SIRT7 might play a role of oncogene in ovarian malignancy and be a potential therapeutic target.

• Nutrition Research and Practice
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• v.6 no.5
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• pp.396-404
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• 2012

The aim of the study was to investigate the inhibitory effects of calcium against intestinal cancer in vitro and in vivo. We first investigated the effects of calcium treatment in HCT116 and HT29 human colon cancer cells. At the concentration range of 0.8-2.4 mM, calcium significantly inhibited cell growth (by 9-29%), attachment (by 12-26%), invasion (by 15-31%), and migration (by 19-61%). An immunofluorescence microscope analysis showed that the treatment with calcium (1.6 mM) for 24 h increased plasma membrane ${\beta}$-catenin but decreased nuclear ${\beta}$-catenin levels in HT29 cells. We then investigated the effect of dietary calcium on intestinal tumorigenesis in $Apc^{Min/+}$ mice. Mice received dietary treatment starting at 6 weeks of age for the consecutive 8 weeks. The basal control diet contained high-fat (20% mixed lipids by weight) and low-calcium (1.4 mg/g diet) to mimic the average Western diet, while the treatment diet contained an enriched level of calcium (5.2 mg calcium/g diet). The dietary calcium treatment decreased the total number of small intestinal tumors (by 31.4%; P < 0.05). The largest decrease was in tumors which were ${\geq}$ 2 mm in diameter, showing a 75.6% inhibition in the small intestinal tumor multiplicity (P < 0.001). Immunohistochemical analysis showed significantly reduced nuclear staining of ${\beta}$-catenin (expressed as nuclear positivity), but increased plasma membrane staining of ${\beta}$-catenin, in the adenomas from the calcium-treated groups in comparison to those from the control group (P < 0.001). These results demonstrate intestinal cancer inhibitory effects of calcium both in human colon cancer cells and $Apc^{Min/+}$ mice. The decreased ${\beta}$-catenin nuclear localization caused by the calcium treatment may contribute to the inhibitory action.

• Biomolecules & Therapeutics
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• v.21 no.1
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• pp.60-65
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• 2013

3,4,5-Trihydroxycinnamic acid (THC) is a derivative of hydroxycinnamic acids, which have been reported to possess a variety of biological properties such as anti-inflammatory, anti-tumor, and neuroprotective activities. However, biological activity of THC has not been extensively examined. Recently, we reported that THC possesses anti-inflammatory activity in LPS-stimulated BV2 microglial cells. However, its precise mechanism by which THC exerts anti-inflammatory action has not been clearly identified. Therefore, the present study was carried out to understand the anti-inflammatory mechanism of THC in BV2 microglial cells. THC effectively suppressed the LPS-induced induction of pro-inflammatory mediators such as NO, TNF-${\alpha}$, and IL-$1{\beta}$. THC also suppressed expression of MCP-1, which plays a key role in the migration of activated microglia. To understand the underlying mechanism by which THC exerts these anti-inflammatory properties, involvement of Nrf2, which is a cytoprotective transcription factor, was examined. THC resulted in increased phosphorylation of Nrf2 with consequent expression of HO-1 in a concentration-dependent manner. THC-induced phosphorylation of Nrf2 was blocked with SB203580, a p38 MAPK inhibitor, indicating that p38 MAPK is the responsible kinase for the phosphorylation of Nrf2. Taken together, the present study for the first time demonstrates that THC exerts anti-inflammatory properties through the activation of Nrf2 in BV2 microglial cells, suggesting that THC might be a valuable therapeutic adjuvant for the treatment of inflammation-related disorders in the CNS.

• Biomolecules & Therapeutics
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• v.28 no.4
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• pp.370-379
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• 2020

Econazole, a potent broad-spectrum antifungal agent and a Ca²⁺ channel antagonist, induces cytotoxicity in leukemia cells and is used for the treatment of skin infections. However, little is known about its cytotoxic effects on solid tumor cells. Here, we investigated the molecular mechanism underlying econazole-induced toxicity in vitro and evaluated its regulatory effect on the metastasis of gastric cancer cells. Using the gastric cancer cell lines AGS and SNU1 expressing wild-type p53 we demonstrated that econazole could significantly reduce cell viability and colony-forming (tumorigenesis) ability. Econazole induced G0/G1 phase arrest, promoted apoptosis, and effectively blocked proliferation- and survival-related signal transduction pathways in gastric cancer cells. In addition, econazole inhibited the secretion of matrix metalloproteinase- 2 (MMP-2) and MMP-9, which degrade the extracellular matrix and basement membrane. Econazole also effectively inhibited the metastasis of gastric cancer cells, as confirmed from cell invasion and wound healing assays. The protein level of p53 was significantly elevated after econazole treatment of AGS and SNU1 cells. However, apoptosis was blocked in econazole-treated cells exposed to a p53-specific small-interfering RNA to eliminate p53 expression. These results provide evidence that econazole could be repurposed to induce gastric cancer cell death and inhibit cancer invasion.

• Korean Journal of Food Science and Technology
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• v.50 no.2
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• pp.209-215
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• 2018

To evaluate the radical scavenging activity of phenolic-rich fractions of Gardenia jasminoides, we first measured the levels of total polyphenols in hexane, ethyl acetate, and butanol fractions from the extract of G. jasminoides. The ethyl acetate fraction of G. jasminoides extract (GJ-EA) showed high level of phenolics, potent reducing power, and 2,2-diphenyl-1-picrylhydrazyl/2,2'-azino-bis 3-ethylbenzothiazoline-6-sulfonic acid radical scavenging effect. In addition, GJ-EA inhibited the overproduction of nitric oxide in lipopolysaccharide-activated BV-2 microglia. Furthermore, we found that GJ-EA suppressed $H_2O_2$-induced PANC-1 pancreatic cancer cell proliferation in a concentration-dependent manner and also reduced their migratory ability. These results suggest that GJ-EA may be a good source for functional foods with antioxidant and chemo-preventive activities.

• Toxicological Research
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• v.31 no.2
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• pp.151-156
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• 2015

5-Fluorouracil (5-FU) is commonly used for the therapy of colon cancer; however, acquired resistance to 5-FU is a critical barrier to successful treatment and the primary cause of chemotherapy failure. Epithelial-mesenchymal transition (EMT) is a process whereby cells undergo alterations in morphology and molecular characteristics promoting tumor progression and metastasis. Accumulating evidence shows that transition from epithelial to mesenchymal phenotype in cancer cells is associated with their resistance to chemotherapy. However, it is still poorly understood whether EMT is involved in acquired resistance to 5-FU. In this study, we developed an in vitro cell model, 5-FU-resistant HT-29 colon cancer cells, and characterized the differences in cellular morphology and molecular alterations between parental and resistant cells. In accord with mesenchymal-like morphology of 5-FU-resistant HT-29 cells, the expression of the mesenchymal marker fibronectin was significantly increased in these cells in comparision with that in the parental cells. Of interest, we also found a marked increase in the expression of EMT-inducing transcription factors Twist, Zeb1, and Zeb2. Finally, 5-FU-resistant cells showed enhanced migration in comparison with parental HT-29. Taken together, these results indicate that EMT could be associated with 5-FU resistance acquired by HT-29 cells. A specific role of each transcription factor found in this study will require further investigation.

• Journal of Gastric Cancer
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• v.17 no.3
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• pp.212-219
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• 2017

Purpose: The aims of this study were to compare the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging manuals on tumor, node, and metastasis (TNM) staging systems and to evaluate whether the 8th edition represents a better refinement of the 7th staging system, when applied for the classification of gastric cancers. Materials and Methods: A total of 5,507 gastric cancer patients, who underwent treatment from January 1989 to December 2013 at a single institute, were included. We compared patient survival rates across the disease groups classified according to the 7th and 8th editions of the AJCC TNM staging systems. Results: Stage migration was observed in 6.4% (n=355) of the patients. Of these, 3.5% (n=192) and 2.9% (n=158) of patients showed a higher stage and lower stage, respectively. According to the 8th edition of the AJCC TNM staging criteria, the 5-year overall survival rates of the patients with stage IIIB and IIIC showed a significant difference (40.8% vs. 20.2%, P<0.001) whereas no significant differences in the 5-year overall survival rates were observed according to the 7th edition criteria (37.6% vs. 33.2%, P=0.381). Conclusions: Restaging stage III cancers according to the 8th edition of the AJCC TNM classification criteria improved survival rate discrimination, particularly, in institutes where the stage III patients were not distinctly categorized.