• Archives of Pharmacal Research
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• 제22권4호
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• pp.372-379
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• 1999

A series of disubstituted 4,5-polymethylenepyrazoles were synthesized and evaluated their inhibitory activities against COX-2. Some compounds showed strong (0.3 nM) inhibitory activity on COX-2 and were found somewhat selective (up to 16) on COX-2 over COX-1.

• 약학회지
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• 제43권6호
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• pp.776-781
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• 1999

Dockings of 4,5-diarylpyrroles into cyclooxygenase-1 and cyclooxygenase-2 were carried out by GOLD program. The sulfonyl groups bonded to 5-phenyl ring of 4,5-diarylpyrroles are directed to Arg513 of COX-2 and Tyr385 of COX-2 docking modes of pyrroles are different from COX-1. Tyr385 and Arg120 of COX-1 and COX-2 have been recognized as important residues. Val523 of COX-2 may be also important. A new COX-2 selective inhibitors could be designed from the docking study.

• Clinical and Experimental Reproductive Medicine
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• 제25권1호
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• pp.25-33
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• 1998

Cyclooxygenase (COX) is an enzyme involved in the conversion of arachidonic acid to prostaglandins (PGs), and exists in two forms, COX-1 and COX-2. COX has been reported to be involved in early implantation by secretion of PGs which causes permeability of vessels and reaction of decidual cells around the implantation site. Recently, in mice and sheep studies, COX-1 and COX-2 expression in the endometrium has been reported to be different according to implantation and stages of the estrous cycle, but expression of COX-1 and COX-2 in human endometrium during the menstrual cycle has not yet been established. The purpose of this study was to observe the variances of COX-1 and COX-2 expression by immunohistochemical staining in endometrial samples obtained from human hysterectomy specimens and biopsies of women of reproductive age according to different stages of the menstrual cycle. Also, we attempted to observe COX-1 and COX-2 expression in the epithelial and stromal cells of the endometrium obtained during the mid-secretory phase, which were cultured separately. COX-2 showed a cyclic pattern of expression according to the different stages of the menstrual cycle and was strongly expressed particularly at the mid-secretory phase which corresponds to the time of implantation. However, COX-1 tended to be increased in the early proliferative, and mid- and late secretory phases, but was also expressed in the whole menstrual cycle showing no particular pattern. In the separately cultured cells COX-1 was expressed in epithilial cells and COX-2 in the stromal cells. The above results suggest that since COX-2 is expressed at the same time as implantation and cultured cells display a specific secretory pattern, COX-2 has inductive endocrine enzyme properties and has an important effect on endometrial cells during implantation. Also, COX-2 expression in endometrial cells may be utilized as a useful marker of endometrial maturation.

• 대한약학회:학술대회논문집
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• 대한약학회 2002년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.2
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• pp.320.2-320.2
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• 2002

Macrophages activated by lipopolysaccharide (LPS) are known to induce several proinflammatory proteins including COX-2. iNOS and TNF which produce chemical mediators involved in inflammatory response. Sophoricoside and its analogs (genistin, genistein and orobol) from Sophora japonica (Leguminosae) showed differential inhibitory effects on COX-1 and 2 activities. Sophoricoside and genistin shwoed IC50 values of 4 uM and 6 uM on COX-2 activity and of 1,497 uM and 135 uM on COX-1 activity, respectively. Genistein and orobol showed IC50 values of 3 uM on COX-2 activity and of 28 uM and 18 uM on COX-1 activity. respectively. Therefore. the legume isoflavonoids to be selective COX-2 inhibitors. However. sophoricoside and its analogs did not show inhibitory effects of COX-2, iNos and TNF transcripts. which were identified by the RT-PCR.

• Journal of Yeungnam Medical Science
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• 제17권1호
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• pp.1-11
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• 2000

Inhibition of cyclooxygenase(COX), and thus prevention of the formation of prostaglandins, provided a unifying explanation of the therapeutic and toxic actions of nonsteroidal anti-inflammatory drugs (NSAIDs). Recently, the discovery of the two isoforms of COX was made by molecular biologists studying neoplastic transformation in chick embryo cells. The constitutive enzyme, COX-1, is obviously responsible for the production of prostaglandins involved in housekeeping functions such as maintenance of integrity of the gastric mucosa, renal blood flow and platelet aggregation. The inducible form of COX (COX-2) is responsible for the formation of prostaglandins that pathologically affects inflammation, pain and fever. Clearly, all the experimental and clinical data support the hypothesis that the beneficial effects of NSAIDs are due to inhibition of the COX-2 enzyme, whereas the gastrotoxicity is due to inhibition of COX-1. The cox-2/COX-1 ratios of the NSAIDs in common use have been measured and compared with epidemiological data on their side effects. There is little evidence to suggest that one NSAID is clearly more effective than another, But substantial individual variability is present with respect to the pharmacology and pharmacokinetics of these drugs: therefore it is essential to adjust the dosage and choose specific drug to the patient's response.

• Natural Product Sciences
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• 제3권1호
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• pp.19-28
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• 1997

Constitutive cyclooxygenase (COX-I) is present in cells under physiological conditions, whereas inducible cyclooxygenase (COX-II) is induced by some cytokines, mitogens, and endotoxin presumably in pathological conditions such as inflammation. We have evaluated the inhibitory effects of solvent fractionated extracts of natural products on the activities of COX-I and COX-II. Oxygen uptake COX assay was performed, as a primary screening from the tissue extracts of bovine seminal vesicles (BSV), by monitoring the initial rate of oxygen uptake using an oxygen electrode. Additionally, we evaluated plant extracts for the inhibitory effects of COX-I (in HEL cells) and COX-II (in lipopolysaccharide activated J774A.1 macrophages) using thin layer chromatography of prostanoids produced from $^{14}C-labelled$ arachidonic acid (AA). The use of such models of COX-I and COX-II assay will lead to the identification of specific inhibitors of cyclooxygenases with presumably less side effects than present therapies. Inhibitory effects of 50 kinds of plant extracts on the COX-I and COX-II activities were determined and the active fractions were found in the ethyl acetate fractions of Dryopteris crassirhizoma (roots), Amomum cardamomum (roots), Triticum aestivum (seeds), Perilla sikokiana (leaves), Anemarrhena asphodeloides (roots). Especially, the ethyl acetate fraction of Dryopteris crassirhizoma (roots), which exhibited the strong inhibition against BSV COX $(IC_{50},\;65.4\;{\mu}g/ml)$, COX-I $(IC_{50},\;8.5\;{\mu}g/ml)$, and COX-II $(IC_{50},\;17.2\;{\mu}g/ml)$, is under investigation to isolate active principles using activity-guided fractionation method.

• Asian Pacific Journal of Cancer Prevention
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• 제16권4호
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• pp.1553-1558
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• 2015

Background: COX-2 has been shown to play an important role in the development of breast cancer and increased expression has been mooted as a poor prognostic factor. The purpose of this study was to investigate the relationship between COX-2 immunohistochemical expression and known predictive and prognostic factors in breast cancer in a routine diagnostic histopathology setting. Materials and Methods: Formalin-fixed paraffin-embedded tumour tissue of 144 no special type (NST) invasive breast carcinomas histologically diagnosed between January 2009 and December 2012 in Hospital Sultanah Bahiyah, Alor Setar, Kedah were immunostained with COX-2 antibody. COX-2 overexpression was analysed against demographic data, hormone receptor status, HER2-neu overexpression, histological grade, tumour size and lymph node status. Results: COX-2 was overexpressed in 108/144 (75%) tumours and was significantly more prevalent (87%) in hormone receptor-positive tumours. There was no correlation between COX-2 overexpression and HER2/neu status. Triple negative cancers had the lowest prevalence (46%) (p<0.05). A rising trend of COX-2 overexpression with increasing age was observed. There was a significant inverse relationship with tumour grade (p<0.05), prevalences being 94%, 83% and 66% in grades 1, 2 and 3 tumours, respectively. A higher prevalence of COX-2 overexpression in smaller size tumours was observed but this did not reach statistical significance. There was no relationship between COX-2 expression and lymph node status. Conclusions: This study did not support the generally held notion that COX-2 overexpression is linked to poor prognosis, rather supporting a role in tumorigenesis. Larger scale studies with outcome data and basic studies on cancer pathogenetic pathways will be required to cast further light on whether COX-2 inhibitors would have clinical utility in cancer prevention or blockage of cancer progression. In either setting, the pathological assessment for COX-2 overexpression in breast cancers would have an important role in the selection of cancer patients for personalized therapy with COX-2 inhibitors.

• Journal of Yeungnam Medical Science
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• 제23권1호
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• pp.36-44
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• 2006

진통과 해열작용을 가진 NSAIDs는 소화기계에 대한 부작용 때문에 COX-2 선택성 억제제로 대체되고 있다. 그러나 COX-2 선택적 억제제는 심혈관계에 대한 부작용이 보고되고 있어 혈관 평활근에 대한 직접적인 연구가 필요하다. 이에 본 연구에서는 혈관 반응성에 미치는 celecoxib와 aspirin, indomethacin의 영향을 비교 분석하였다. 또한 COX-1, COX-2 단백질 발현에 대한 indomethacin과 NO 공여제의 영향을 조사하였다. Phenylephrine 유발 수축반응에서 전처치 된celecoxib, indometacin, aspirin 순서로 혈관 반응성을 증가시켜, cyclooxygenase를 억제하면 혈관 수축성물질에 대한 반응성이 커질 수 있음을 나타낸다. 이중 cyclooxygenase에 대해 비가역적으로 강한 억제를 나타내는 aspirin이 제일 강한 효과를 나타내어 여기에 대한 연구는 더 필요할 것으로 생각된다. 혈관평활근 세포의 COX-2 단백질 발현은 indomethacin과 SNP, NOR-3 처치에 의해 증가되었으며, LPS를 이용하여 혈관염증을 유발 시키는 경우 혈관평활근 세포의 COX-2 단백질 발현이 증가되었고, 이 상태에서 SNP $100{\mu}M$ 전처치로 COX-2 단백질 발현을 감소되었으며, NOR-3 $100{\mu}M$은 COX-2 단백질 발현을 증가시켰다. LPS 유도 nitrite 생성에서 NOR-3는 SNP 보다 더 많은 nitrite를 생성시켰다. 이는 혈관의 수축반응에서 aspirin은 강한 상승작용을 유발하고, 혈관평활근 세포의 COX-2 발현은 NO 공여제, 혈관염증 유무에 따라 차이가 있는 것을 나타낸다.

• Radiation Oncology Journal
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• 제22권4호
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• pp.307-315
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• 2004

목적: 한국인은 젊은 여성 유방암의 비율이 높으며 저자들의 선행 연구에서 HER-2/neu 과발현이 백인에 비해 높았으며 나쁜 예후 인자였다. 이 환자들을 대상으로 COX-2 발현의 비교와 HER-2/neu 과발현의 관계를 비교하고 한국인에서 COX-2의 예후인자로서의 역할을 알아보기 위해 이 연구를 시행하였다. 대상 및 방법: 45세 이하의 한국인 여성 유방암 환자와 같은 나이의 백인 여성 환자 60명의 파라핀 포매조직을 이용하여 COX-2 염색을 시행하였다. COX-2 발현을 판독하고 한국인과 백인의 발현 비율을 비교하였다 그리고 한국인 환자의 추적 검사 결과와 COX-2를 관계를 조사하여 예후인자로서의 역할을 연구하였다. 결과: 판독이 가능한 전체 환자의 COX-2 발현 비율은 $27.6\%$이었으며 한국인은 $37.9\%$37.9%, 백인은 $20.8\%$로 한국인 젊은 여성의 비율이 다소 높았으나 통계적인 유의성은 없었다(p=0.090). 전체 환자의 COX-2 발현과 HER-2/neu 과발현의 상관 관계는 발견하지 못하였지만 에스트로겐 수용체 음성과 COX-2 발현은 통계적으로 유의한 관계가 있었다. (p=0.046) COX-2 양성의 5년 무병 생존율은 $67.9\%$로 COX-2 음성의 $81.6\%$에 비해 낮았으나 통계적인 유의성이 없었다(p=0.3607). 결론: 젊은 여성 유방암 환자에서 한국인과 백인간의 COX-2 발현 비율의 차이는 통계적으로 유의하지 않았으며 HER-2/neu 과발현과의 관련성도 없었으며 예후와의 관련성도 통계적으로 유의하지 않았고 에스트로겐 수용체 음성과의 관련성은 있었다. COX-2 발현과 다른 임상적 병리적 인자와의 관계나 예후인자로서의 역할을 찾기 위해 보다 많은 환자를 대상으로 한 연구가 필요하며 COX-2 발현에 따라 방사선치료가 예후에 미치는 영향에 관한 연구도 필요하다.

• Tuberculosis and Respiratory Diseases
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• 제67권4호
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• pp.303-310
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• 2009

Background: Elevated expression of cyclooxygenase-2 (COX-2) and Polo-like kinase-1 (PLK-1) is observed in a wide variety of cancers. Augmented expression of COX-2 and enhanced production of prostaglandin $E_2(PGE_2)$ are associated with increased tumor cell survival and malignancy; COX-2 has been implicated in the control of human non-small cell lung carcinoma (NSCLC) cell growth. PLK-1 siRNA induced the cell death of lung cancer cells and the systemic administration of PLK-1 siRNA/atelocollagen complex inhibited the growth of lung cancer in a liver metastatic murine model. COX-2 and PLK-1 are involved in proliferation and in cell cycle regulation, and there is a significant correlation between their interaction in prostate carcinoma. Methods: In this study, we investigated the pattern of COX-2 and PLK-1 expression in NSCLC, after treatment with IL-1$\beta$, COX-2 inhibitor and PLK-1 siRNA. Results: Expression of PLK-1 was decreased in A549 COX-2 sense cells, and was increased in A549 COX-2 anti-sense cells. Knock out of PLK-1 expression by PLK-1 siRNA augmented COX-2 expression in A549 and NCl-H157 cells. When A549 and NCI-H157 cells were treated with COX-2 inhibitor on a dose-dependent basis, PLK-1 and COX-2 were reduced. However, when the expression of COX-2 was induced by IL-1$\beta$, the production of PLK-1 decreased. Conclusion: These results demonstrate that COX-2 and PLK-1 are regulated and inhibited by each other in NSCLC, and suggest that these proteins have a reverse relationship in NSCLC.