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A c-Myc activation sensor-based high-throughput drug screening identifies an antineoplastic effect of nitazoxanide.

ABSTRACT: 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.

SUBMITTER: Fan-Minogue H

PROVIDER: S-EPMC3772774 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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A c-Myc activation sensor-based high-throughput drug screening identifies an antineoplastic effect of nitazoxanide.

Fan-Minogue Hua H Bodapati Sandhya S Solow-Cordero David D Fan Alice A Paulmurugan Ramasamy R Massoud Tarik F TF Felsher Dean W DW Gambhir Sanjiv S SS

Molecular cancer therapeutics 20130703 9

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 ac ...[more]

PMID: 23825064

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Project description:IntroductionSelenium (Se) is an essential trace element that exerts its effects mainly as the proteinogenic amino acid selenocysteine within a small set of selenoproteins. Among all family members, selenoprotein P (SELENOP) constitutes a particularly interesting protein as it serves as a biomarker and serum Se transporter from liver to privileged tissues. SELENOP expression is tightly regulated by dietary Se intake, inflammation, hypoxia and certain substances, but a systematic drug screening has hitherto not been performed.MethodsA compound library of 1861 FDA approved clinically relevant drugs was systematically screened for interfering effects on SELENOP expression in HepG2 cells using a validated ELISA method. Dilution experiments were conducted to characterize dose-responses. A most potent SELENOP inhibitor was further characterized by RNA-seq analysis to assess effect-associated biochemical pathways.ResultsApplying a 2-fold change threshold, 236 modulators of SELENOP expression were identified. All initial hits were replicated as biological triplicates and analyzed for effects on cell viability. A set of 38 drugs suppressed SELENOP expression more than three-fold, among which were cancer drugs, immunosuppressants, anti-infectious drugs, nutritional supplements and others. Considering a 90% cell viability threshold, resveratrol, vidofludimus, and antimony potassium-tartrate were the most potent substances with suppressive effects on extracellular SELENOP concentrations. Resveratrol suppressed SELENOP levels dose-dependently in a concentration range from 0.8 μM to 50.0 μM, without affecting cell viability, along with strong effects on key genes controlling metabolic pathways and vesicle trafficking.ConclusionThe results highlight an unexpected direct effect of the plant stilbenoid resveratrol, known for its antioxidative and health-promoting effects, on the central Se transport protein. The suppressive effects on SELENOP may increase liver Se levels and intracellular selenoprotein expression, thereby conferring additional protection to hepatocytes at the expense of systemic Se transport. Further physiological effects from this interaction require analyses in vivo and by clinical studies.

Dataset Information

A c-Myc activation sensor-based high-throughput drug screening identifies an antineoplastic effect of nitazoxanide.

Publications

A c-Myc activation sensor-based high-throughput drug screening identifies an antineoplastic effect of nitazoxanide.

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