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Targeted Detection of Cyclooxygenase-1 in Ovarian Cancer
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2019-07-24 , DOI: 10.1021/acsmedchemlett.9b00280
Paola Malerba 1, 2 , Brenda C Crews 1 , Kebreab Ghebreselasie 1 , Cristina K Daniel 1 , Elma Jashim 1 , Ansari M Aleem 1 , Redoan A Salam 1, 3 , Lawrence J Marnett 1 , Md Jashim Uddin 1
Affiliation  

Overexpression of cyclooxygenase-1 (COX-1) is associated with the initiation and progression of ovarian cancer, and targeted imaging of COX-1 is a promising strategy for early detection of this disease. We report the discovery of N-[(5-carboxy-X-rhodaminyl)but-4-yl]-3-(1-(4-methoxyphenyl)-5-(p-tolyl)-1H-pyrazol-3-yl)propenamide (CMP) as the first COX-1-targeted optical agent for imaging of ovarian cancer. CMP exhibits light emission at 604 nm (λmax), thereby minimizing tissue autofluorescence interference. In both purified enzyme and COX-1-expressing human ovarian adenocarcinoma (OVCAR-3) cells, CMP inhibits COX-1 at low nanomolar potencies (IC50 = 94 and 44 nM, respectively). CMP’s selective binding to COX-1 in OVCAR-3 cells was visualized microscopically as intense intracellular fluorescence. In vivo optical imaging of xenografts in athymic nude mice revealed COX-1-dependent accumulation of CMP in COX-1-expressing mouse ovarian surface epithelial carcinoma (ID8-NGL) and OVCAR-3 cells. These results establish proof-of-principle for the feasibility of targeting COX-1 in the development of new imaging and therapeutic strategies for ovarian cancer.

中文翻译:

卵巢癌中 Cyclooxygenase-1 的靶向检测

环氧合酶-1 (COX-1) 的过度表达与卵巢癌的发生和发展有关,而 COX-1 的靶向成像是早期检测该疾病的有希望的策略。我们报告了N -[(5-carboxy-X-rhodaminyl)but-4-yl]-3-(1-(4-methoxyphenyl)-5-( p - tolyl)-1 H -pyrazol-3- 的发现yl)propenamide (CMP) 作为第一个用于卵巢癌成像的 COX-1 靶向光学试剂。CMP 在 604 nm (λ max )处发光,从而最大限度地减少组织自发荧光干扰。在纯化的酶和表达 COX-1 的人卵巢腺癌 (OVCAR-3) 细胞中,CMP 以低纳摩尔效价抑制 COX-1 (IC 50= 94 和 44 nM,分别)。CMP 在 OVCAR-3 细胞中与 COX-1 的选择性结合在显微镜下显示为强烈的细胞内荧光。无胸腺裸鼠异种移植物的体内光学成像揭示了 CMP 在表达 COX-1 的小鼠卵巢表面上皮癌 (ID8-NGL) 和 OVCAR-3 细胞中的 COX-1 依赖性积累。这些结果为靶向 COX-1 在卵巢癌新成像和治疗策略开发中的可行性建立了原理验证。
更新日期:2019-07-24
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