A c-Myc Activation Sensor-Based High-Throughput Drug Screening Identifies an Antineoplastic Effect of Nitazoxanide
| Autor: | Alice C. Fan, Hua Fan-Minogue, Sanjiv S. Gambhir, Ramasamy Paulmurugan, Dean W. Felsher, Sandhya Bodapati, Tarik F. Massoud, David E. Solow-Cordero |
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| Rok vydání: | 2013 |
| Předmět: |
Drug
Cancer Research media_common.quotation_subject Cell Clone (cell biology) Mice Nude Antineoplastic Agents Breast Neoplasms Pharmacology Biology medicine.disease_cause Article Proto-Oncogene Proteins c-myc Mice Breast cancer Cell Line Tumor medicine Animals Humans IC50 Cell Proliferation media_common Nitazoxanide Nitro Compounds medicine.disease High-Throughput Screening Assays Molecular Imaging Disease Models Animal Thiazoles medicine.anatomical_structure Oncology Apoptosis Heterografts Female Drug Screening Assays Antitumor Carcinogenesis Neoplasm Transplantation medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics. 12:1896-1905 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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. Mol Cancer Ther; 12(9); 1896–905. ©2013 AACR. |
| Databáze: | OpenAIRE |
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