• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6317-6325
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• 2015

Ginkgo biloba extract (GBE) is a popular phytomedicine and has been used for disorders of the central nervous system, cardiovascular, renal, respiratory, and circulatory diseases. Although GBE is a complex mixture of over 300 compounds, its major components are 24% flavonoids and 6% terpene lactones. In this study, we tested the inhibitory effects of the three major flavonoids (kaempferol, quercetin, and isorhamnetin) from GBE, independently and as mixtures, on aromatase activity using JEG-3 cells (human placental cells) and recombinant proteins (human placental microsome). In both systems, kaempferol showed the strongest inhibitory effects among the three flavonoids; the flavanoid mixtures exerted increased inhibitory effects. The results of exon I.1-driven luciferase reporter gene assays supported the increased inhibitory effects of flavonoid mixtures, accompanied by suppression of estrogen biosynthesis. In the RT-PCR analysis, decreased patterns of aromatase promoter I.1 mRNA expressions were observed, which were similar to the aromatase inhibition patterns of flavonoids and their mixtures. The present study demonstrated that three flavonoids synergistically inhibit estrogen biosynthesis through aromatase inhibition, decrease CYP19 mRNA, and induce transcriptional suppression. Our results support the usefulness of flavonoids in adjuvant therapy for breast cancer by reducing estrogen levels with reduced adverse effects due to estrogen depletion.

• Archives of Pharmacal Research
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• 제22권3호
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• pp.309-312
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• 1999

In searching for potent cancer chemopreventive agents from synthetic or natural products, 28 randomly selected flavonoids were screened for inhibitory effects against partially purified aromatase prepared form human placenta. Over 50% of the flavonoids significantly inhibited aromatase activity, with greatest activity being demonstrated with apigenin $(IC_{50}: 0.9{\mu}/mL)$, chrysin $(IC_{50}: 1.1{\mu}/mL)$ , and hesperetin $(IC_{50}:1.0{\mu}/mL)$.

• 생명과학회지
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• 제18권4호
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• pp.503-508
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• 2008

동해 해양심층수의 유방암예방 효능과 전이에 미치는 영향을 알아보기 위해 cytochrome P450 1A1 활성과 aromatase 활성 및 유방암세포의 침윤성, 이와 관련된 MMP-9 의 활성과 그 단백질 발현에 미치는 영향을 조사하였다. 해양심층수는 체내외의 여러 화학물질을 체내에서 활성화시켜 발암이나 돌연변이 등을 유발시키는 것으로 알려진 cytochrome P450 1A1을 경도의존적으로 저해시켰다. 또한 호르몬 의존성 유방암의 진행에 관여하는 aromatase의 활성도 경도의존적으로 저해시켰다($5.6{\sim}51.9%$). 해양심층수 처리에 의해 사람유방암세포인 MDA-MB-231 세포의 침윤성은 $73.7{\sim}29.4%$로 감소하였으며, 세포의 침윤시 작용하는 단백질 분해 효소인 MMP-9의 활성과 단백질 발현도 경도의존적으로 억제되었다. 따라서 해양심층수는 유방암 예방과 전이관련의 더 많은 연구에 의해 유방암 예방과 전이 억제작용을 증명할 수 있을 것으로 보인다.

• Environmental Analysis Health and Toxicology
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• 제18권2호
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• pp.95-100
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• 2003

본 연구는 환경호르몬(endocrine disruptors)으로 분류되었으며, 제초제로 널리 사용되었던 Dichlorodiphenyltrichloroethane(DDT)가 설치류의 생식세포 중 Leydig 세포의 testosterone(T)생성억제 및 그 관련 작용메카니즘을 규명코자 수행되었다. 먼저 흰쥐의 웅성 생식세포주인 R2C세포에 T의 양 및 aromatase 활성도를 radio immunoassay (RIA)방법을 이용하여 측정하였다. 그 결과 R2C 세포에 황체형성호르몬(LH)를 처리하여 testosterone생성을 증가시킨 후, DDT를 처리한 군들은 대조군에 비하여 농도 의존적으로 T의 양은 감소하였으며, aromatase 활성도는 증가하였다. 또한 DDT자체만 처리한 군에서도 대조군에 비하여 testosterone의 생성이 감소하였다. 이러한 aromatase활성 증가가 estradiol receptor(ER)와의 상호 관련성을 확인하기 위해 ER antagonist인 ICI 182.780를 처리한 후 T의 양 및 aromatase 활성도를 측정한 결과 DDT에 의해 증가된 aromatase활성도가 ICI 182.780에 의해 다시 감소됨을 확인하였다. 또한 DDT에 의해 감소된 T의 양도 ICI 182.780에 의해 다시 회복되었다. In vivo실험으로 흰쥐에 DDT를 직접 투여한 후 정소 내 성 호르몬들을 측정해 본 결과 T의 양은 유의성 있게 감소하였으며, estradiol(E$_2$)의 양은 증가하였으며, aromatase 활성도도 감소하였다. 이러한 결과를 종합해 볼 때 DDT는 aromatase를 감소시키고, 이렇게 감소된 aromatase에 의해 testosterone 생성량을 억제하고, 이러한 DDT의 aromatase의 감소는 ER을 경유하는 것으로 추정할 수 있다.

• 환경생물
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• 제21권3호
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• pp.308-312
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• 2003

Various pesticides known or suspected to interfere with steroid hormone function were screened toy effects in leydig cells on catalytic activity and mRNA expression of aromatase. Dichlorodiphenyltrichloroethane (DDT) is a widespread environmental pollutant. In this study, we investigated the effect of DDT on testosterone production through aromatase activity and its molecular mechanism in testicular leydig cell, R2C by using radioimmunoassay (RIA). As the results, the potent leydig: cell activator LH increased testosterone production compared to the control. DDT exposure significantly decreased testosterone production in R2C cell. In addition, DDT was found to increase aromatase gene expression and activity in R2C cell in a dose dependent manner. In order to assess whether the suppressive effects of DDT on LH-inducible testosterone (T) production might be influenced by the ER, ICI 182.780 was used, and it was found that these inhibitory effects of DDT were antagonized by ICI 182.780, implying that the estrogen receptor (ER) mediates the suppressive effects of DDT. Furthermore, the inducible effects of DDT on aromatase gene expression might be influenced by the ER, ICI 182.780 was used, and it was found that these enhancing effects of DDT were antagonized by ICI 182.780, implying that the ER mediates the inducible effects of DDT. Our results indicated that DDT inhibition of luteinizing hormone (LH) -inducible T production in R2C cell is mediated through aromatase. However, the precise mechanisms by which DDT enhance in R2C cell remains unknown. The current study suggests the possibility that DDT might act as a modulator aromatase gene transcription.

• Archives of Pharmacal Research
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• 제23권3호
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• pp.243-245
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• 2000

The diethyl ether extract of isodon excisus var. coreanus exhibited significant inhibitory activity in aromatase assay. Bioactivity-guided fractionation of the extract led to the isolation of three active compounds: inflexin(ent-1${\alpha}$-hydroxy-3${\beta}$,6a-diacetoxykau r-16-en-11,15-dione) (1), ursolic acid (2), and ursolic acid 3-O-acetate (3).

• Journal of Microbiology and Biotechnology
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• 제16권9호
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• pp.1405-1409
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• 2006

Polysaccharides from the starfish Asterina pectinifera were assessed in vitro for their chemopreventive potential in human breast cancer. The polysaccharides from A. pectinifera inhibited cell proliferation in the estrogen receptor-positive (MCF-7) and estrogen receptor-negative (MDA-MB-231) human breast carcinoma cell lines. In addition, the polysaccharides were found to be an inhibitor of cytochrome P450 1A1-mediated ethoxyresorufin O-deethylase activity, and caused a dose-dependent inhibition of aromatase activity in microsomes isolated from a human placenta. There was a significant reduction in the ornithine decarboxylase activity to 30.7% of the control in the polysaccharide-treated MCF-7 breast cancer cells. Therefore, the polysaccharides from A. pectinifera merit further investigation with respect to breast cancer chemoprevention.

• Genomics & Informatics
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• 제21권2호
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• pp.20.1-20.10
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• 2023

Aromatase inhibitors (AI) are drugs that are widely used in treating estrogen receptor (ER)-positive breast cancer patients. Drug resistance is a major obstacle to aromatase inhibition therapy. There are diverse reasons behind acquired AI resistance. This study aims at identifying the plausible cause of acquired AI resistance in patients administered with non-steroidal AIs (anastrozole and letrozole). We used genomic, transcriptomic, epigenetic, and mutation data of breast invasive carcinoma from The Cancer Genomic Atlas database. The data was then separated into sensitive and resistant sets based on patients' responsiveness to the non-steroidal AIs. A sensitive set of 150 patients and a resistant set of 172 patients were included for the study. These data were collectively analyzed to probe into the factors that might be responsible for AI resistance. We identified 17 differentially regulated genes (DEGs) among the two groups. Then, methylation, mutation, miRNA, copy number variation, and pathway analyses were performed for these DEGs. The top mutated genes (FGFR3, CDKN2A, RNF208, MAPK4, MAPK15, HSD3B1, CRYBB2, CDC20B, TP53TG5, and MAPK8IP3) were predicted. We also identified a key miRNA - hsa-mir-1264 regulating the expression of CDC20B. Pathway analysis revealed HSD3B1 to be involved in estrogen biosynthesis. This study reveals the involvement of key genes that might be associated with the development of AI resistance in ER-positive breast cancers and hence may act as a potential prognostic and diagnostic biomarker for these patients.

• Archives of Pharmacal Research
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• 제24권6호
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• pp.473-484
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• 2001

There is clearly a need for novel breast cancer chemopreventive agents with enhanced potency and specificity with tittle or no side effects. To this end, several new chemical moieties have been synthesized or isolated from natural sources. In this reviewal we have described some agents currently in use or under development for treatment or prevention of breast cancer, as well as our own strategies for the discovery of natural product modulators of estrogen biosynthesis and function. In particulars bioassay-guided fractionation of active plant extracts is a unique method for identifying agents with novel mechanisms of action, some of which should be useful for prevention of human cancer. Further, with the advent of combinatorial chemistry and high throughput screening, even greater progress may now be expected with natural product leads.

• Asian Pacific Journal of Cancer Prevention
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• 제16권15호
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• pp.6359-6364
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• 2015

Background: Preclinical studies have shown that the combination of an aromatase inhibitor (AI) and capecitabine in estrogen receptor (ER)- positive cell lines enhance antitumor efficacy. This retrospective analysis of a group of patients with metastatic breast cancer (MBC) evaluated the efficacy and safety of combined AI with capecitabine. Materials and Methods: Patients with hormone receptor-positive metastatic breast cancer treated between 1st January 2005 and 31st December 2010 with a combination of capecitabine and AI were evaluated and outcomes were compared with those of women treated with capecitabine in conventional dose or AI as a monotherapy. Results: Of 72 patients evaluated, 31 received the combination treatment, 22 AI and 19 capecitabine. The combination was used in 20 patients as first-line and 11 as second-line treatment. Mean age was 46.2 years with a range of 28-72 years. At the time of progression, 97% had a performance status of <2 and 55% had visceral disease. No significant difference was observed between the three groups according to clinical and pathological features. Mean follow up was 38 months with a range of 16-66 months. The median PFS of first-line treatment was significantly better for the combination (PFS 21 months vs 8.0 months for capecitabine and 15.0 months for AI). For second-line treatment, the PFS was longer in the combination compared with capecitabine and Al groups (18 months vs. 5.0 months vs. 11.0 months, respectively). Median 2 year and 5 year survival did not show any significant differences among combination and monotherapy groups. The most common adverse events for the combination group were grade 1 and 2 hand-for syndrome (69%), grade 1 fatigue (64%) and grade 1 diarrhoea (29%). Three grade 3 hand-foot syndrome events were reported. Conclusions: Combination treatment with capecitabine and AI used as a first line or second line treatment was safe with much lowered toxicity. Prospective randomized clinical trials should evaluate the use of combination therapy in advanced breast cancer to confirm these findings.