• 대한의생명과학회지
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• 제20권2호
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• pp.85-95
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• 2014

Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the head and neck tumors. To investigate the mechanism of antiproliferation to EGFR inhibition in oral cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-$3{\beta}$ (GSK-$3{\beta}$). We have demonstrated that ZD1839 induces growth arrest and apotosis in oral cancer cell lines by independent of EGFR-mediated signaling. An exposure of oral cancer cells to ZD1839 resulted in a dose dependent up-regulation of the cyclin-dependent kinase inhibitor p21 and p27, down regulation of cyclin D1, inactivation of GSK-$3{\beta}$ and of active MAPK. In resistant cells, GSK-$3{\beta}$ is constitutively active and its activity is negatively regulated primarily through Ser 9 phosphorylation and further enhanced by Tyr216 phosphorylation. These results showed that the resistance to the antiproliferative effects of ZD1839, in vitro was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-$3{\beta}$ activation and degradation of its target cyclin D1 were indicators of high cell sensitivity to ZD1839. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in oral cancer.

• Archives of Pharmacal Research
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• 제29권5호
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• pp.354-362
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• 2006

Dietary flavonoids have attracted a great deal of attention as agents for preventing estrogen-related diseases, such as postmenopausal symptoms, and for reducing the risk of estrogen-dependent cancer. Kaempferol is one of the most commonly found dietary phytoestrogen. The aim of this study was to investigate the estrogenic and/or antiestrogenic effect of kaempferol, which can confirm its potency as a preventive agent against estrogen-related diseases. Kaempferol has both estrogenic and antiestrogenic activity, which are biphasic response on estrogen receptor. The estrogenic activity of kaempferol induced via ER-mediated pathway depending on $E_2$ concentration $(\leq\;10^{-12}M)$. Kaempferol $(10^{-5}\;M)$ also caused antiproliferative effect on MCF-7 cell in the presence of $E_2\;(10^{-11}\;M)$ and restored to the addition of excess $E_2\;(10^{-7}\;M)$, which confirms that antiproliferation of kaempferol was induced via ER-dependent pathway. However, at $10^{-4}\;M$, concentration higher than the concentrations at which the estrogenic effects of kaempferol are detected $(10^{-5}\;M)$, kaempferol induced strong antiproliferative effect, but were unaffected by the addition of excess $E_2\;(10^{-7}\;M)$ indicating that kaempferol exerts antiproliferation via ER-independent pathway. In particular, kaempferol blocked the focus formation induced by $E_2$, which confirms that kaempferol might inhibit the malignant transformation caused by estrogens. Therefore, we suggested that kaempferol might regulate a suitable level of estrogenic activity in the body and is expected to have potential beneficial effects in preventing estrogen imbalance diseases (breast cancer, osteoporosis, cardiovascular disease and etc.).

• 생명과학회지
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• 제25권9호
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• pp.1051-1058
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• 2015

본 연구에 평가된 감귤 돌연변이는 기존 궁천조생 품종에서 유래된 방사선 돌연변이체로 선행 연구에서 다양한 생리활성 및 기능성 성분이 함유되어 있다는 것을 보고한 이래로, 감귤 돌연변이의 항암 제제로써 활용 가능성을 검증하였다. 여러 암종(HCT116, 인간대장암세포; A375, 인간흑색종세포; Hela, 인간자궁경부암세포; MCF-7, 인간유방암세포; A549, 인간폐암세포; HepG2, 인간간암세포)을 대상으로 감귤 돌연변이의 항암 활성을 기존 궁천조생 품종(방사선 무처치군)과 비교 분석한 결과 그 효용 가치가 높게 나타났을 뿐 아니라 자연사멸 유도 메커니즘을 탐색하였을 때 감귤 돌연변이에 의해 야기된 apoptosis에 IAP family의 발현 저해와 NO^• pathway 증강에 따라 세포 고사가 촉진됨을 확인할 수 있었다. 또한 감귤 돌연변이가 정상 세포에 대한 독성을 유발하지 않는 것으로 나타나, 암세포 선택성이 높은 chemopreventive 및 chemotherapeutic agent로 개발 가능할 것으로 예상되며 이를 위해 향후 보다 정밀한 자연사멸의 분자생물학적 기전 규명이 수반되어야 할 것으로 사료된다.

• Archives of Pharmacal Research
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• 제27권10호
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• pp.1043-1047
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• 2004

Thirteen compounds were isolated from the $CH_2Cl_2$ fraction of Machilus thunbergii as phospholipase $C{\Upsilon}1\;(PLC{\Upsilon}1)$ inhibitors. These compounds were identified as nine lignans, two neolignans, and two flavans by spectroscopic analysis. Of these, 5,7-di-O-methyl-3',4'-methylenated (-)-epicatechin (12) and 5,7,3'-tri-O-methyl (-)-epicatechin (13) have not been reported previously in this plant. In addition, seven compounds, machilin A (1), (-)-sesamin (3), machilin G (5), (+)-galbacin (9), licarin A (10), (-)-acuminatin (11) and compound 12 showed dose-dependent potent inhibitory activities against $PLC{\Upsilon}1$ in vitro with $IC_{50}$ values ranging from 8.8 to 26.0 ${\mu}M$. These lignans, neolignans, and flavans are presented as a new class of $PLC{\Upsilon}1$ inhibitors. The brief study of the structure activity relationship of these compounds suggested that the benzene ring with the methylene dioxy group is responsible for the expression of inhibitory activities against $PLC{\Upsilon}1$. Moreover, it is suggested that inhibition of $PLC{\Upsilon}1$ may be an important mechanism for an antiproliferative effect on the human cancer cells. Therefore, these inhibitors may be utilized as cancer chemotherapeutic and chemopreventive agents.

• 한국식품과학회지
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• 제36권6호
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• pp.1001-1007
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• 2004

암세포 성장 억제효과가 인정된 산수유 methanol 추출물의 chloroform층으로부터 silica gel column과 thin layer chromato-grapies를 이용하여 항암활성물질을 분리하고, IR, mass spectrometer, $^1H-NMR$ 및 $^{13}C-NMRs$을 통해 순수물질을 동정하였다. 이 물질은 triterpenoid로서 $C_{30}H_{48}O_3$의 구조식을 가진 화합물로 분자량이 456인 ursolic acid($3{\beta}$-hydroxyrus-12-ene-28-oic acid)로 동정되었다. 정제된 화합물을 A549 및 MCF-7 암세포주에 48시간동안 처리한 결과 농도 의존적으로 암세포주의 성장을 억제하였으며, 화합물을 처리하지 않은 대조구에 비하여 $30\;{\mu}g/mL$농도로 처리시 40% 이상 그 성장을 억제하였으며, $100\;{\mu}g/mL$농도로 처리시 90% 이상 그 성장을 억제하였다. 정제 화합물을 처리한 암세포를 광학현미경으로 관찰한 결과 뚜렷한 세포수의 감소와 함께 심한 형태학적 변화가 관찰되었다. 암세포 주에 정제시료를 $10\;{\mu}g/mL$농도로 처리하고, 15시간 배양한 후 세포주기를 분석한 결과 sub-G1 phase의 비율이 A549의 경우는 대조구에서 4.0%이었던 것이 11.7%로, MCF-7의 경우는 대조구에서 2.1%이었던 것이 처리구에서는 11.2%로 각각 증가된 것으로 나타나 정제물질은 apoptosis에 의한 세포사멸 유도를 시사하였다.

• Journal of Microbiology and Biotechnology
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• 제14권3호
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• pp.628-630
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• 2004

Antitumor activities of a peptide fraction isolated from traditional Korean soy sauce (SSP) were investigated in vitro and in vivo using cancer cell lines and F9 teratocarcinoma-bearing BALB/c mice. SSP exerted a dose-dependent antiproliferative effect on P388D1 mouse lymphoma, F9 mouse teratocarcinoma, and DLD-l human colon cancer cells with $IC_{50}$ values of 11, 50, and $50\mug/ml$, respectively. Tumor growth in F9 teratocarcinoma-bearing BALB/c mice, orally administered with 80 and 200 mg/kg/day of SSPs, was inhibited 10.3% and 52.4%, respectively, and survival days increased by 11.9% and 22.1%, respectively, compared to the control group. The results of antitumor activities exerted by SSP in vitro and in vivo suggest the feasibility of using SSP as an antitumor agent.

• Asian Pacific Journal of Cancer Prevention
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• 제17권7호
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• pp.3559-3567
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• 2016

Background: In recent years, there has been considerable research on recycling of agro-industrial waste for production of bioactive compounds. The food processing industry produces large amounts of citrus peels that may be an inexpensive source of useful agents. Objective: The present work aimed to explore the phytochemical content, antioxidant, anticancer, antiproliferation, and antigenotxic activities of lemon, grapefruit, and mandarin peels. Materials and Methods: Peels were extracted using 98% ethanol and the three crude extracts were assessed for their total polyphenol content (TPC), total flavonoid content (TFC), and antioxidant activity using DPPH (1, 1-diphenyl-2-picrylhydrazyl). Their cytotoxic and mitogenic proliferation activities were also studied in human leukemia HL-60 cells and mouse splenocytes by CCK-8 assay. In addition, genotoxic/antigenotoxic activity was explored in mouse splenocytes using chromosomal aberrations (CAs) assay. Results: Lemon peels had the highest of TPC followed by grapefruit and mandarin. In contrast, mandarin peels contained the highest of TFC followed by lemon and grapefruit peels. Among the extracts, lemon peel possessed the strongest antioxidant activity as indicated by the highest DPPH radical scavenging, the lowest effective concentration 50% ($EC_{50}=42.97{\mu}g\;extract/mL$), and the highest Trolox equivalent antioxidant capacity (TEAC=0.157). Mandarin peel exhibited moderate cytotoxic activity ($IC_{50}=77.8{\mu}g/mL$) against HL-60 cells, whereas grapefruit and lemon peels were ineffective anti-leukemia. Further, citrus peels possessed immunostimulation activity via augmentation of proliferation of mouse splenocytes (T-lymphocytes). Citrus extracts exerted non-cytotoxic, and antigenotoxic activities through remarkable reduction of CAs induced by cisplatin in mouse splenocytes for 24 h. Conclusions: The phytochemical constituents of the citrus peels may exert biological activities including anticancer, immunostimulation and antigenotoxic potential.

• 대한의생명과학회지
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• 제11권2호
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• pp.175-183
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• 2005

The two major isoflavones in soy, genistein and daidzein, are well known to prevent hormone-dependent cancers by their anti estrogenic activity. The exact molecular mechanisms for the protective action are, however, not provided yet. It has been reported that genistein and daidzein have a potential anticancer activity through their antiproliferative effect in many hormone-dependent cancer cell lines. Transforming growth $factor-\beta1(TGF-\beta1)$ has also been found to have cell growth inhibitory effect, especially in mammary epithelial cells. This knowledge led to a hypothetical mechanism that the soy isoflavones-induced growth inhibitory effect can be derived from the regulation of $TGF-\beta1$ and $TGF-\beta$ receptors. In order to test this hypothesis, the effects of the soy isoflavones at various concentrations and periods on the expression of $TGF-\beta1$and $TGF-\beta$ receptors were investigated by using Northern blot analysis in human breast carcinoma epithelial cell lines, an estrogen receptor positive cell line (MCF-7) and an estrogen receptor negative cell line (MDA-MB-231). As a result, only genistein has shown a profound dose-dependent effect on $TGF-\beta1$ expression in the $ER^+$ cell line within the range of doses tested, and the expression levels are correspondent to their inhibitory activities of cell growth. Moreover, daidzein showed down-regulated $TGF-\beta1$ expression at a low dose, the cell growth proliferation was promoted at the same condition. Therefore, antiproliferative activity of the soy isoflavones can be mediated by $TGF-\beta1$ expression, and the effects are mainly, if not all, occurred by ER dependent pathway. The expression of $TGF-\beta$ receptors was induced at a lower dose than the one for $TGF-{\beta}1$ induction regardless of the presence of ER, and the expression patterns are similar to those of the cell growth inhibition. These results indicated that the regulation of $TGF-\beta$ receptor expression as well, prior to $TGF-\beta1$ expression, may be involved in the antiproliferative activity of soy isoflavones. Little or no expression of $TGF-\beta$ receptors was found in the MCF-7 and MDA-MB-231 cells, suggesting refractory properties of the cells to growth inhibitory effect of the $TGF-\beta$. The soy isoflavones can seemingly restore the sensitivity of growth inhibitory responses to $TGF-\beta1$ by re-inducing $TGF-\beta$ receptors expression. In conclusions, our findings presented in this study show that the antitumorigenic activity of the soy isoflavones could be mediated by not only $TGF-\beta1$induction but $TGF-\beta$ receptor restoration. Thus, soy isoflavones could be good model molecules to develop new nonsteroidal antiestrogenic chemopreventive agents, associated with, regulation of $TGF-\beta$ and its receptors.

• 생명과학회지
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• 제31권2호
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• pp.149-157
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• 2021

매실은 주로 한국, 일본, 중국 같은 동아시아에 분포하고, 매실 나무의 열매는 한약재나 식재료로 쓰여왔다. 그러나 매실 열매를 이용한 이전의 연구는 대부분 추출물 형태로 진행하였기에, 많은 식품학적인 활용을 위해 매실 열매의 다양한 가공형태에서의 연구가 필요한 실정이다. 본 연구에선 분무 건조한 매실 식초 분말(SPP)의 이화학적 특성과 생리활성을 평가하였다. SPP의 이화학적 특성에서 당도, pH, 총산도 및 수분 함량은 각각 8.90 °Brix, 3.19, 1.05% 및 3.07%로 확인되었다. SPP의 항산화 활성은 DPPH 라디칼 소거활성, 환원력 및 H2O2 소거활성에서 각각 65.55%, 1.48 및 48.07%로 양성 대조군과 비슷하거나 다소 낮게 유의적으로 높은 항산화 활성을 나타냈다. 또한 SPP를 농도별로 처리함에 따라 MDA-MB-231 인체 유방암 세포에서 유의적인 세포 증식 억제 활성을 보였다. 형태학적 연구에서 MDA-MB-231 세포에서 농도의존적으로 세포의 형태학적 변화가 확인되었고, apoptotic body와 핵의 응축을 나타냈다. 총 폴리페놀 및 플라보노이드 함량은 59.58 ㎍/g과 57.56 ㎍/g으로 확인되었다. 이러한 연구 결과를 통해 분무 건조한 매실 식초 분말은 항산화 및 암세포 증식억제능이 있는 기능성 식품 및 천연 의약품 소재로 활용이 가능할 것으로 생각된다.

• 한국식품영양과학회지
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• 제38권11호
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• pp.1478-1484
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• 2009

목련 꽃 에탄올 추출물과 용매분획물에 대한 항산화활성, 항암활성 및 항염증활성을 살펴본 결과는 다음과 같다. 목련꽃 추출물의 총 폴리페놀과 플라보노이드 함량은 216.14 및 86.93 mg/g이었고, DPPH법에 의한 항산화활성의 $IC_{50}$값은 0.232 mg/mL이었으며, 용매분획물 중 에틸아세테이트 분획물이 우수한 항산화활성을 보였다($IC_{50}$: 0.197 mg/mL, AEAC: 0.90 mg AA eq/100 mg). 또한 에탄올 추출물 및 용매분획물은 대장암, 폐암 그리고 간암세포에 대하여 선택적으로 낮은 농도에서 증식억제효과를 보였으며, 클로로포름 분획물은 리포폴리사카라이드 유도 일산화질소 생성 저해효과를 보였다($IC_{50}$: 49.5 $\mu$g/mL).