• Molecules and Cells
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• v.42 no.11
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• pp.755-762
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• 2019

Despite decades of research into colorectal cancer (CRC), there is an ongoing need for treatments that are more effective and safer than those currently available. Lactic acid bacteria (LAB) show beneficial effects in the context of several diseases, including CRC, and are generally regarded as safe. Here, we isolated a Lactobacillus rhamnosus (LR)-derived therapeutic protein, p8, which suppressed CRC proliferation. We found that p8 translocated specifically to the cytosol of DLD-1 cells. Moreover, p8 down-regulated expression of Cyclin B1 and Cdk1, both of which are required for cell cycle progression. We confirmed that p8 exerted strong anti-proliferative activity in a mouse CRC xenograft model. Intraperitoneal injection of recombinant p8 (r-p8) led to a significant reduction (up to 59%) in tumor mass when compared with controls. In recent years, bacterial drug delivery systems (DDSs) have proven to be effective therapeutic agents for acute colitis. Therefore, we aimed to use such systems, particularly LAB, to generate the valuable therapeutic proteins to treat CRC. To this end, we developed a gene expression cassette capable of inducing secretion of large amounts of p8 protein from Pediococcus pentosaceus SL4 (PP). We then confirmed that this protein (PP-p8) exerted anti-proliferative activity in a mouse CRC xenograft model. Oral administration of PP-p8 DDS led to a marked reduction in tumor mass (up to 64%) compared with controls. The PP-p8 DDS using LAB described herein has advantages over other therapeutics; these advantages include improved safety (the protein is a probiotic), cost-free purification, and specific targeting of CRC cells.

• Environmental Mutagens and Carcinogens
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• v.19 no.1
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• pp.46-55
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• 1999

To develop a chemopreventive strategy based on the different stages of premalignant lesions, we hypothesized that the inhibitory effect of chemopreventive agents is influenced by different promotion stages during carcinogenesis. DMBA-TPA-induced skin carcinogenesis was used with ICR mice and chlorophyllin (CHL) was applied as a chemopreventive agent. In vitro assay was performed with Salmonella typhi. TA100 to observe any anti-mutagenic activity of CHL against DMBA. Pre-initiation and pre-promotion effects of CHL were observed by CHL treatment before initiation and before promotion. To evaluate the inhibitory effect at different promotion stages, each group was divided into three subgroups after TPA promotion for 6, 18 and 24 weeks, respectively ; the first subgroup was immediately sacrificed after termination of TPA, the second subgroup was treated with CHL, and the third subgroup was sacrificed 8 weeks after termination of TPA without CHL treatment. The degrees of epithelial dysplasia, papilloma formation, and invasive carcinoma were observed histologically, and GST-Pi expression was observed immunohistochemically. ODC mRNA level was analyzed by reverse transcriptase-polymerase chain reaction. Results showed : CHL dose-dependently inhibited the mutation of Salmonella typhi. TA100; the incidence of epithelial dysplasia and papilloma formation was lower in pre-initiation and pre-promotion CHL-treated mice than DMBA-TPA-treated mice; no invasive carcinoma developed in pre-initiation CHL-treated groups, while 67% of DMBA-TPA treated mice had carcinomas; GST-Pi expression decreased when CHL was treated before initiation and before promotion; and when CHL was treated after termination of TPA application at 18 and 24- week-TPA promotion stages, respectively, the incidence of epithelial dysplasia and papilloma was markedly reduced compared to non-treated groups. When comparing the incidence of epithelial dysplasia and papilloma between the immediately-sacrificed subgroup and the non-treated group with a waiting period, we speculated that the 18-week-TPA promotion stage might belong to the promoter-independent progression stage. At the 18-week-TPA promotion stage, the level of ODC mRNA in the CHL-treated group was clearly reduced to the level of normal tissue. Taking these results together, CHL showed both anti-initiation and anti-promotion effects, while the inhibitory effect of CHL was prominent in the 18-week-TPA promotion stage. However, CHL seems to be incapable of completely blocking the progression in the 24-week-TPA promotion stage.

• Natural Product Sciences
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• v.10 no.6
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• pp.344-346
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• 2004

Eight phenolic compounds (1-8) which were isolated from the barks of Ulmus macrocarpa were evaluated for their inhibitory activities on nitric oxide (NO) and prostagrandin $E_2$ (COX-2) production in $interferon-{\gamma}\;(INF-{\gamma})$ and lipopolysaccharide (LPS)-activated RAW 264.7 cells in vitro. NO and COX-2 levels were moderately reduced by the addition of compounds (1-8). Among them 3,4,5,6,7 and 8 inhibited NO production in a dose dependent manner with an $IC_{50}$ of 92.2, 97.3, 36.1, 43.5, 32.8, 39.4 and 37.1 ${\mu}g/ml$, respectively (positive control, L-NMMA; 36.4 ${\mu}g/ml$), and 3,4,5,6,7 and 8 reduced the COX-2 level in a dose dependent manner with an $IC_{50}$ of 43.2, 24.8, 24.8, 33.4, 44.8 and 22.7 ${\mu}g/ml$, respectively (positive control, indomethacin; 23.4 ${\mu}g/ml$). These results suggest that the phenolic compounds may be developed as potential anti-inflammatory and cancer chemopreventive agents.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2001.11a
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• pp.86-86
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• 2001

Based on the potential inhibitors of cyclooxygenase-2 (COX-2) as anti-inflammatory or cancer chemopreventive agents, we have evaluated the active principles of COX-2 inhibition from natural products. The methanol extract of the cortex of Eugenia caryoplyllata (Myrtaceae) showed the potent inhibition of prostaglandin E$_2$(PGE$_2$) production in lipopolysaccharide (LPS)-activated RAW 264.7 cells (98.3% inhibition at the test concentration of 10 $\mu\textrm{g}$/$m\ell$) Further, hexane-soluble layer was the most active partition compared to ethyl acetate, n-butanol, and water -soluble parts. By bioassay-guided fractionation of hexane-soluble layer, eugenol was isolated and exhibited a significant suppression of PGE$_2$ production (IC$\_$50/=0.06$\mu\textrm{g}$/$m\ell$). In addition, eugenol suppressed the COX-2 gene expression in LPS-stimulated mouse macrop-hage cells. Therfore, eugenol might be a plausible lead candidate for further developing the COX-2 inhibitor as an anti-inflammatory or cancer chemopreventive agent.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.6061-6066
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• 2015

Methotrexate (Mtx), used for its anticancer and immunsuppresive properties, is known to be a nephrotoxic agent. We aimed to investigate the effects of lycopene (Lyc) alone or combined with melatonin (Mel) on Mtxinduced nephrotoxicity since both of these agents have antioxidant and anti-inflammatory effects. Nephrotoxicity was induced by intraperitoneal administration of methotrexate at a dose of 20 mg/kg. Treatment both with Lyc alone and Lyc combined with Mel provided significant reduction in tumor necrosis factor-alpha, interleukin 1-beta and ceruloplasmin levels in Mtx administered rats. Hovewer, Lyc combined with Mel provided a significant reduction also in NO levels. Hstopathological examination showed that there was an obvious improvement in the degenerative changes compared to Mtx administrated group with the Lyc combined Mel group giving best protection. In conclusion Lyc alone and combined with Mel provided significant improvement against renal damage caused by Mtx, preseumably via antioxidant and anti-inflammatory activities.

• Journal of Applied Biological Chemistry
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• v.62 no.4
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• pp.367-374
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• 2019

Euphorbia humifusa Willd (EuH), called Ttang-Bin-Dae in Korea, is a traditional medicinal plant widely used for its anti-inflammatory and antiviral activity. Ethyl acetate (EA) extracts of EuH (EA/EuH) inhibit invasion and metastasis by inhibiting tumor necrosis factor TNFá-induced matrix metalloproteinases (MMP)-9 expression in human breast cancer cells. However, the bioactive components of EA/EuH mediating the inhibition of MMP-9 expression have not been identified. In the present study, three bioactive constituents of EA/EuH were isolated using high-performance liquid chromatography. Nuclear magnetic resonance spectroscopy revealed isoquercetin, avicularin, and astragalin as the bioactive compounds responsible for preventing TNFα-induced MMP-9 mRNA expression in breast cancer cells. These findings suggest that isoquercetin, avicularin, and astragalin could be used as valuable anti-metastatic agents against metastatic cancers.

• The Korean Journal of Oral and Maxillofacial Pathology
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• v.42 no.6
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• pp.167-174
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• 2018

Natural products are vastly utilized as a source of chemotherapeutic agents for human cancers. Kochia scopraia is traditionally used for the cure of urological and dermatological diseases. Recently, methanol extract of Kochia scoparia (MEKS) has been shown to have anti-cancer activity to various human cancers. However, there is no report demonstrating the anti-cancer activity of MEKS in human mucoepidermoid carcinoma (MEC) cells. In this study, the authors studied the effects of MEKS on the cell proliferation and underlying mechanism in YD15 human MEC cells. MEKS decreased YD15 cell proliferation proven by trypan blue exclusion assay and induced apoptosis, evidenced by cell cycle analysis and western blotting. Autophagy induction by MEKS was verified by western blotting. In addition, MEKS regulated the expression of phosphorylated Akt, phosphorylated p38 and Nrf2 protein. This results can imply that MEKS might be a potential candidate for the treatment of human MEC cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.4
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• pp.1757-1762
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• 2014

Development of drugs from natural products has been undergoing a gradual evoluation. Many plant derived compounds have excellent therapeutic potential against various human ailments. They are important sources especially for anticancer agents. A number of promising new agents are in clinical development based on their selective molecular targets in the field of oncology. D-pinitol is a naturally occurring compound derived from soy which has significant pharmacological activitites. Therefore we selected D-pinitol in order to evaluate apoptotic potential in the MCF-7 cell line. Human breast cancer cells were treated with different concentrations of D-pinitol and cytotoxicity was measured by MTT and LDH assays. The mechanism of apoptosis was studied with reference to expression of p53, Bcl-2, Bax and NF-kB proteins. The results revealed that D-pinitol significantly inhibited the proliferation of MCF-7 cells in a concentration-dependent manner, while upregulating the expression of p53, Bax and down regulating Bcl-2 and NF-kB. Thus the results obtained in this study clearly vindicated that D-pinitol induces apotosis in MCF-7 cells through regulation of proteins of pro- and anti-apoptotic cascades.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.298.2-298.2
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• 2002

Bioflavonoids are semi-essential food components that are ubiquitously present in nature. It has been reported that flavonoids act as anti-oxidant as well as anti-cancer agents. Quercetin is one of the most widely distributed bioflavonoids in the plant kingdom. The goal of this study was to investigate effects of quercetin analogs extracted from Lindera erythrocarpa, quercetin 3-O-${\alpha}$-arabinofuranoside and quercetin 3-O-${\alpha}$-L -rhamnoside, on oxidatie stress-induced cell death. (omitted)

• The Journal of Internal Korean Medicine
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• v.25 no.2
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• pp.202-213
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• 2004

Object : Objective: This study was conducted to investigate the anti-cancer effects of Mylabris phalerata (반모) in some kinds of cancer cells. Materials and Methods: Some kinds of cancer cells lines were treated. We used nine kinds of cancer cell lines, such as stomach cancer cells (Kato), lung cancer cells (Calu-1, NCI-H 1395), urinary bladder cancer cells (HS789T), bone cancer cells (Saos-2), brain cancer cells (SK-N-MC), liver cancer cells (Hep-G2), skin cancer cells (Mo-1) and prostate cancer cells (PC-3) with the water decoction of Mylabris phalerata. The histological changes of all cell lines in the media (RPMI-1640) containing the decoction of Mylabris phalerata were observed and we examined cell death assay by trypan blue exclusion testing was examined. Finally, the change of mitochondrial membrane potential was measurd and the inhibitory effect of Mylabris phalerata on cell increase was examined by analyzing the cell cycle. Results: In histologic change all cancer cell lines showed withdrawn and floating appearance that is typical in cellular impairment. Most of the cell lines showed over 50% death rate after 24 hours in trypan blue exclusion tests. Especially the stomach, urinary bladder. brain and liver cell lines showed over 30% death rate after 12 hours. All cell lines treated with Mylabris phalerata were less stained than the control group and the mitochondrial membrane potential in the Mylabris phalerata treated cell lines was markedly lower than that in the control group. The measurement of DNA quantity in all cell lines showed the disappearance of the peak and the thickened left axis, which suggests that all cellular DNA degraded. Conclusion: Mylabris phalerata had cytotoxicity on various kinds of cancer cell lines and the mechanism of that was the impairment of mitochondria by the breakdown of the mitochondrial cell membrane. We propose that this is in part attributable to the destruction of DNA in cancer cells.