• Journal of Pharmaceutical Investigation
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• v.31 no.3
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• pp.167-172
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• 2001

All-trans retinoic acid (ATRA), vitamin A acid, has been shown to exert anticancer activity in a number of types of cancers, particularly in acute promyelocytic leukaemia (APL). Due to its highly variable bioavailability and induction of its own metabolism after oral treatment, development of parenteral dosage forms are required. However, its poor aqueous solubility and chemical unstability give major drawbacks in parenteral administration. This study was undertaken to investigate a possibility to develop a parenteral formulation of ATRA by employing solid lipid nanoparticle (SLN) as a carrier. By optimizing the production parameters and the composition of SLNs, SLNs with desired mean particle size (<100 nm) as a parenteral dosage form could be produced from trimyristin (as solid lipid), Egg phosphatidylcholine and Tween 80 (as SLN stabilizer). The mean particle size of SLN formulation of ATRA was not changed during storage, suggesting its physical stability. Thermal analysis confirmed that the inner lipid core of SLNs exist at solid state. The mean particle size of ATRA-loaded SLNs was not significantly changed by the lyophilization process. ATRA could be efficiently loaded in SLNs, while maintaining its anticancer activity against HL-60, a well-known APL cell line. Furthermore, by lyophilization, ATRA loaded in SLN could be retained chemically stable during storage. Taken together, our present study demonstrates that physically and chemically stable ATRA formulation adequate for parenteral administration could be obtained by employing SLN technology.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.6
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• pp.1507-1515
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• 2006

Angelica gigantis (AG), Rehamaninae Radix(RR), Paenia japonica (PJ), and Polygoni multiflori Radix (PM) have been used as medicinal plants to tonify the blood. General function of the drugs have been known to nourish blood and control the heart and liver meridians. Recently, several studies have proposed mechanisms by which some oriental medicinal herbs work on the immune system. However, it is uncertain whether aqueous-extract of these drugs has immunomodulatory effect yet. In this study, I investigated the immune promotive effects of the water-extracted AG, RR, PJ and PM. The water-extracted AG, RR, PJ and PM inhibited NO production and iNOS expression in LPS stimulated RAW 264.7 macrophage cell line. Among these extracts, AG and PM induced expression of IL-2 and IFN${\gamma}$ in mouse spleen cells. In the flow cytometry analysis, PM-stimulated mouse spleen cells showed an increase in B-cell phenotype (CD45R/B220). The oral administration of Polygoni multiflori water-extracts to mice having S-180 abdominal dropsy cancer prolonged life-span more than control mice. These data suggest that among these extracts, PM has cellular and humoral immune-enhancement effect through IL-2 and IFN${\gamma}$ cytokine production, the regulation of NO production in macrophage cells and the B cell production in spleen cells.

• Toxicological Research
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• v.35 no.2
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• pp.131-136
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• 2019

Ethylhexyl dimethyl para-aminobenzoic acid (PABA) is an oily yellow liquid derivative of water-soluble PABA commonly used in sunscreen. Ethylhexyl dimethyl PABA is widely used as an ingredient in many cosmetics at an average concentration of 1.25% (0.5-2.0%) in Korea. Previous studies, including those involving animals, have demonstrated that ethylhexyl dimethyl PABA is toxic to the following four organs: testis, epididymis, spleen, and liver. In addition, experiments using human keratinocytes found that ethylhexyl dimethyl PABA inhibits cell growth and DNA synthesis at low concentrations, and halted the cell cycle of MM96L cells (human melanoma cell line) at the G1 phase. Despite limited clinical data in humans, many studies have confirmed increased mutagenicity of ethylhexyl dimethyl PABA following exposure to sunlight, which suggests that this molecule is likely to contribute to onset of sun-induced cancer despite protecting the skin through absorption of UVB. For risk assessment, the no observed adverse effect level (NOAEL) chosen was 100 mg/kg bw/day in a 4 weeks oral toxicity study. Systemic exposure dosage (SED) was 0.588 mg/kg bw/day for maximum use of ethylhexyl dimethyl PABA in cosmetics. Based on the risk assessment and exposure scenarios conducted in this study, the margin of safety (MOS) was calculated to be 180.18 for a sunscreen containing 8% ethylhexyl dimethyl PABA, which is the maximum level allowed by the relevant domestic authorities.

• International Journal of Oral Biology
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• v.36 no.2
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• pp.103-108
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• 2011

Measurement of estrogen concentration in bio-samples are very important for differential diagnosis of various disease or evaluation of health status. However, it is difficult to collect immediate data of estrogen concentration because they are measured by radioimmunoassay or chromatography which need time- and cost-consuming sample pre-treatment. This study was performed for development of new estrogen biosensor employing taste principles, and for evaluation of cross reactivity between various steroid hormones. Gene sequence of ligand binding domain of ${\alpha}$-human estrogen receptor (amino acid 302-553; hER-LBD) was cloned from human breast cancer cell line. The proteins of hER-LBD were produced by T7-E.coli expression system, and isolated by chromatography. hER-LBD were coated on the gold plated quartz crystal (AT-cut 9MHz), and resonance frequencies were measured by universal frequency counter. Estradiol, progesterone, testosterone, and aldosterone were used for cross reactivity of the hER-LBD. We also monitored influences of pH change in resonance frequency. The resonance frequencies of hER-LBD coated quartz crystal were decreased during increase of estrogen concentration from $15 \;{\mu}g/mL$ to $50\;{\mu}g/mL$. However, similar steroid hormones, progesterone and aldosterone, did not elicit the change in resonance frequency. Testosterone evoke weak change in resonance frequency. The new estrogen biosensor was more sensitive in pH 7.2 than in pH 7.6. These results suggest that hER-LBD coated quartz crystal biosensor is a probable estrogen biosensor.

• Journal of Oral Medicine and Pain
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• v.38 no.3
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• pp.221-233
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• 2013

Bile acids are polar derivatives of cholesterol essential for the absorption of dietary lipids and regulate the transcription of genes that control cholesterol homeostasis. Recently it have been identified the synthetic chenodeoxycholic acid (CDCA) derivatives HS-1200 and cisplatin showed apoptisis-inducing activity on various cancer cells in vivo and in vitro. This study was undertaken to investigate the synergistic apoptotic effect of co-treatment with HS-1200 and cisplatin on human tongue squamous cell carcinoma cells (SCC25 cells). To investigate whether the co-treatment with HS-1200 and cisplatin compared to each single treatment efficiently reduces the viability of SCC25 cells, MTT assay was conducted. The induction and augmentation of apoptosis were confirmed by DNA electrophoresis, Hoechst staining and an analysis DNA hypoploidy. Westen blot analysis and immunofluorescent staining were also performed to evaluate the expression levels and the translocation of apoptosis-related proteins following this co-treatment. Furthermore, proteasome activity and mitochondrial membrane potential (MMP) change were also assayed. In this study, co-treatment with HS-1200 and cisplatin on SCC25 cells showed several lines of apoptotic manifestation such as nuclear condensations, DNA fragmentation, reduction of MMP and proteasome activity, the increase of Bax and the decrease of Bcl-2, decrease of DNA content, the release of cytochrome c into cytosol, translocation of AIF and DFF40 (CAD) onto nuclei, and activation of caspase-9, caspase-7, caspase-3, PARP and DFF45 (ICAD) whereas each single treated SCC25 cells did not show these patterns. Although the single treatment of $25{\mu}M$ HS-1200 and $4{\mu}g/ml$ cisplatin for 24 h did not induce apoptosis, the co-treatment of these reagents prominently induced apoptosis. Therefore our data provide the possibility that the combination therapy with HS-1200 and cisplatin could be considered as a novel therapeutic strategy for human squamous cell carcinoma.

• Journal of Physiology & Pathology in Korean Medicine
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• v.27 no.6
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• pp.782-788
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• 2013

Chrysanthemum zawadskii Herbich var. latilobum Kitamura (Compositae), colloquially known "Gujulcho" in Korea, has been used in traditional medicine for the treatment of various diseases, including cough, common cold, bladder-related disorders, gastroenteric disorders, hypertension, and inflammatory diseases, such as pneumonia, bronchitis, pharyngitis, and rheumatoid arthritis (RA) However, the effect of Chrysanthemum zawadskii var. latilobum on breast cancer invasion is unknown. In this study, we investigated the inhibitory effect of Chrysanthemum zawadskii var. latilobum extract (CZE) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-9 (MMP-9) expression and cell invasion, as well as the molecular mechanisms involved in MCF-7 cells. CZE were not cytotoxic up to 100 ${\mu}g/ml$ concentration in the MCF-7 cell line. CZE decreased MMP-9 expression. TPA substantially increased NF-${\kappa}B$ DNA binding activity. Pre-treatment with CZE inhibited TPA-stimulated NF-${\kappa}B$ binding activity and NF-${\kappa}B$ related protein expression. To identify invasion ability of MCF-7 cells decreased by CZE, we used martrigel invasion assay. As a result, it is significantly decreased cell invasion. These results indicate that CZE-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the NF-${\kappa}B$ pathway in MCF-7 cells. Chrysanthemum zawadskii var. latilobum may have potential value in restricting breast cancer metastasis.

• Journal of Physiology & Pathology in Korean Medicine
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• v.22 no.2
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• pp.282-289
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• 2008

We evaluated the effect of SHBCS on adhesion and invasion of colon L5-26 adenocarcinoma cell line in vitro in vitro and experimental liver metastasis in vivo. SHBCS showed little inhibitory effect on colon 26-L5 cell proliferation. At the concentration of up to 500 mg/ml of SHBCS 80% of cells were viable. SHBCS showed no inhibitory effect on adhesion and invasion of colon 26-L5 cells, which were placed on matrigel. In a dose dependent manner, oral administration of SHBCS showed a significantly inhibitory effect on liver metastasis from colon 26-L5 injected mice. When mice were depleted of NK cells or macrophages before tumor inoculation, SHBCS significantly decreased liver metastasis fromf the tumor injected mice. Compared with the control mice, SHBCS increased the populations of macrophages and NK cells by 30%, 18%(10 mg/mouse, 50 mg/mouse) and 5%, 1% (10 mg/mouse, 50 mg/mouse) respectively. Compared with the control mice, SHBCS increased the populations of CD4 cells by 5%, 18% (10 mg/mouse, 50 mg/mouse) respectively. Spelenocytes from mice administerd with SHBCS were stimulated with LPS plus ConA, proliferation of splenocytes from mice administerd with SHBCS was 140%, 146%(10 mg/mouse, 50 mg/mouse) compared with th control mice. In conclusion, the present study suggests that SHBCS may have an inhibitory effect on liver metastasis through immunopotentiating activity which is associated with macrophages and NK cells.

• Journal of Ginseng Research
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• v.17 no.1
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• pp.52-60
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• 1993

Panax ginseng has been extensively used in the traditional oriental medicine as a restorative, tonic and Prophylactic agent. Recently, several reports regarding to anticancer effects of Panax ginseng has accumulated. These studies emphasized the fact that the anticancer activities might be due to a glycoside group called ginsenoside or pan.u saponin which has a water soluble characteristic. However, the authors and collaborates demonstrated that a highly lipid soluble component in extract of Panax ginseng roots contains a considerable cytotoxic activities against marine leukemic cells (L1210, P388) and human censer cells (HRT-18, HT-29, HCT48). This study was devised to observe the cytotoxic activities of Petroleum-ether extract of Panax giuseng roots (crude GBD and its Partially Purified fraction from silicic acid column chromatography (7 : 3 GX) against sarcoma-180 (5-180) and Walker carcinosar- coma 256 (Walker 256) in vivo, and murine leukemic Lymphocytes (L1210) and human rectal cancer cells (HRT-18) and human colon cancer cells (HT-29 and HCT48) in vitro. Each cell-line was cultured in medium containing serial concentration of the crude GX or 7 : 3 GX in vitro. A highly lipid soluble compound in the extract of Panax ginseng root was cytocidal to murine leukemic cells and human colon and rectal cancer cells in vitro. In the meantime, ginseng saponin derivatives did not have cytotoxic effects at its corresponding concentration. The growth rates of the cancer cells in medium containing ginseng extracts were inhibited gradually to a significant degree roughly in proportion to the increase of the extract concentration. The cytotoxic activity of 7 : 3 GX was about 3 times more potent than that of crude GX, one unit of cytotoxic activity against L1210 cells being equivalent to 2.54 Ug and 058 Ug for the crude GX and 7 : 3 GX, respectively. The Ri value of the active compound on silica- gel thin layer chromatography with petroleum-ether/ethyl ether/acetic acid mixture (90 : 10 : 1, v/v/v) as a developing so lvent was 053. While, the Panaxydol and Panaxynol as active compounds were purified from Petroleum-ether extract of Panax ginseng root by Drs. Ahn and Kim, and author found out that the one unit of cytotoxic activity of the Panaxydol and Panaxynol against L1210 cells being equivalent to 056 Ug and 0.3918 respectively. The survival times of mice inoculated with S-180 cells were extended about 1.5 to 2 times by the 7 : 3 GX treatment compared with their control group. The significantly decreased hemoglobin values of rats after inoculation with Walker 256 were recovered to normal range by oral administration of the crude Gt The synthetic levels of protein, DNA and RNA in human colon and rectal cancer cells were significantly diminished by treatment with the crude GX, which can explain a part of the origin of its anticancer activity.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.8
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• pp.3495-3501
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• 2014

Melanoma-associated antigen (MAGE) family genes have been considered as potentially promising targets for anticancer immunotherapy. MAGED4 was originally identified as a glioma-specific antigen. Current knowledge about MAGED4 expression in glioma is only based on mRNA analysis and MAGED4 protein expression has not been elucidated. In the present study, we investigated this point and found that MAGED4 mRNA and protein were absent or very lowly expressed in various normal tissues and glioma cell line SHG44, but overexpressed in glioma cell lines A172,U251,U87-MG as well as glioma tissues, with significant heterogeneity. Furthermore, MAGED4 protein expression was positively correlated with the glioma type and grade. We also found that the expression of MAGED4 inversely correlated with the overall methylation status of the MAGED4 promoter CpG island. Furthermore, when SHG44 and A172 with higher methylation were treated with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) reactivation of MAGED4 mRNA was mediated by significant demethylation in SHG44 instead of A172. However, 5-AZA-CdR treatment had no effect on MAGED4 protein in both SHG44 and A172 cells. In conclusion, MAGED4 is frequently and highly expressed in glioma and is partly regulated by DNA methylation. The results suggest that MAGED4 might be a promising target for glioma immunotherapy combined with 5-AZA-CdR to enhance its expression and eliminate intratumor heterogeneity.