Corresponding Author: Sanjiv S. Gambhir, Molecular Imaging Program at Stanford, Stanford University School of Medicine, 318 Campus Drive, East Wing, 1st Floor, Stanford, CA 94305-5427.
Mol Cancer Ther. 2013 Sep;12(9):1896-905. doi: 10.1158/1535-7163.MCT-12-1243. Epub 2013 Jul 3.
Deregulation of c-Myc plays a central role in the tumorigenesis of many human cancers. Yet, the development of drugs regulating c-Myc activity has been challenging. To facilitate the identification of c-Myc inhibitors, we developed a molecular imaging sensor-based high-throughput screening (HTS) system. This system uses a cell-based assay to detect c-Myc activation in a HTS format, which is established from a pure clone of a stable breast cancer cell line that constitutively expresses a c-Myc activation sensor. Optimization of the assay performance in the HTS format resulted in uniform and robust signals at the baseline. Using this system, we conducted a quantitative HTS against approximately 5,000 existing bioactive compounds from five different libraries. Thirty-nine potential hits were identified, including currently known c-Myc inhibitors. There are a few among the top potent hits that are not known for anti-c-Myc activity. One of these hits is nitazoxanide, a thiazolide for treating human protozoal infections. Validation of nitazoxanide in different cancer cell lines revealed a high potency for c-Myc inhibition with IC50 ranging between 10 and 500 nmol/L. Oral administration of nitazoxanide in breast cancer xenograft mouse models significantly suppressed tumor growth by inhibition of c-Myc and induction of apoptosis. These findings suggest a potential of nitazoxanide to be repurposed as a new antitumor agent for inhibition of c-Myc-associated neoplasia. Our work also demonstrated the unique advantage of molecular imaging in accelerating discovery of drugs for c-Myc-targeted cancer therapy.
c-Myc 的失调在许多人类癌症的肿瘤发生中起着核心作用。然而，调节 c-Myc 活性的药物的开发一直具有挑战性。为了促进 c-Myc 抑制剂的鉴定，我们开发了一种基于分子成像传感器的高通量筛选（HTS）系统。该系统使用基于细胞的测定法在 HTS 格式中检测 c-Myc 激活，该格式是从稳定乳腺癌细胞系的纯克隆中建立的，该细胞系持续表达 c-Myc 激活传感器。在 HTS 格式中优化测定性能可在基线处产生均匀且稳健的信号。使用该系统，我们针对来自五个不同文库的大约 5000 种现有生物活性化合物进行了定量 HTS。鉴定出 39 个潜在的命中化合物，包括目前已知的 c-Myc 抑制剂。在强效命中化合物中有几个以前不知道具有抗 c-Myc 活性。其中一个命中化合物是硝唑尼特，一种用于治疗人类原生动物感染的噻唑烷。硝唑尼特在不同的癌细胞系中的验证表明，其对 c-Myc 抑制具有高活性，IC50 范围在 10 至 500nmol/L 之间。硝唑尼特在乳腺癌异种移植小鼠模型中的口服给药通过抑制 c-Myc 和诱导细胞凋亡显著抑制肿瘤生长。这些发现表明硝唑尼特有可能被重新用作抑制与 c-Myc 相关的肿瘤形成的新型抗肿瘤药物。我们的工作还证明了分子成像在加速发现针对 c-Myc 靶向癌症治疗的药物方面的独特优势。
