Near infrared fluorescent imaging of choline kinase alpha expression and inhibition in breast tumors.
Near infrared fluorescent imaging of choline kinase alpha expression and inhibition in breast tumors.
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DOI：
10.18632/oncotarget.14965
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发表时间：
2017-03-07
期刊：
影响因子：
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通讯作者：
Delikatny EJ
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文献类型：
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作者：
Arlauckas SP;Kumar M;Popov AV;Poptani H;Delikatny EJ
胆碱激酶α（ChoKα）过表达与侵袭性肿瘤表型相关。ChoKα抑制剂可诱导肿瘤细胞凋亡，但其特异性在体内的验证是困难的。我们报告了使用光学成像来评估细胞中的ChoKα状态，并使用JAS 239（一种具有固有近红外荧光的基于羰花青的ChoKα抑制剂）在体内进行评估。JAS 239减弱了一组人乳腺癌细胞系中的胆碱磷酸化和活力。抗体阻断阻止了JAS 239的细胞滞留，表明与ChoKα的直接相互作用不依赖于胆碱转运蛋白和分解代谢胆碱途径。在携带原位MCF 7乳腺异种移植物的小鼠中，JAS 239的光学成像将过表达ChoKα的肿瘤与其空载体对应物区分开来，并描绘了肿瘤边缘。通过确立的抑制剂MN 58 b对ChoK的药理学抑制导致4175-Luc+肿瘤的生长抑制，伴随着JAS 239摄取的减少和使用磁共振光谱测量的总胆碱代谢物水平的降低。在较高的治疗剂量下，JAS 239在抑制肿瘤生长和诱导MDA-MB-231肿瘤细胞凋亡方面与MN 58 b一样有效，显著降低肿瘤胆碱低于基线水平，而没有可观察到的全身毒性。这些数据介绍了一种新的方法来监测治疗有效的胆碱代谢抑制剂在乳腺癌中使用的小分子伴随诊断。
Choline kinase alpha (ChoKα) overexpression is associated with an aggressive tumor phenotype. ChoKα inhibitors induce apoptosis in tumors, however validation of their specificity is difficult in vivo. We report the use of optical imaging to assess ChoKα status in cells and in vivo using JAS239, a carbocyanine-based ChoKα inhibitor with inherent near infrared fluorescence. JAS239 attenuated choline phosphorylation and viability in a panel of human breast cancer cell lines. Antibody blockade prevented cellular retention of JAS239 indicating direct interaction with ChoKα independent of the choline transporters and catabolic choline pathways. In mice bearing orthotopic MCF7 breast xenografts, optical imaging with JAS239 distinguished tumors overexpressing ChoKα from their empty vector counterparts and delineated tumor margins. Pharmacological inhibition of ChoK by the established inhibitor MN58b led to a growth inhibition in 4175-Luc+ tumors that was accompanied by concomitant reduction in JAS239 uptake and decreased total choline metabolite levels as measured using magnetic resonance spectroscopy. At higher therapeutic doses, JAS239 was as effective as MN58b at arresting tumor growth and inducing apoptosis in MDA-MB-231 tumors, significantly reducing tumor choline below baseline levels without observable systemic toxicity. These data introduce a new method to monitor therapeutically effective inhibitors of choline metabolism in breast cancer using a small molecule companion diagnostic.