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Thiocoraline activates the Notch pathway in carcinoids and reduces tumor progression in vivo

Cancer Gene Therapy volume 21, pages 518–525 (2014)Cite this article

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Abstract

Carcinoids are slow-growing neuroendocrine tumors (NETs) that are characterized by hormone overproduction; surgery is currently the only option for treatment. Activation of the Notch pathway has previously been shown to have a role in tumor suppression in NETs. The marine-derived thiodepsipeptide thiocoraline was investigated in vitro in two carcinoid cell lines (BON and H727). Carcinoid cells treated with nanomolar concentrations of thiocoraline resulted in a decrease in cell proliferation and an alteration of malignant phenotype evidenced by decrease of NET markers, achaete-scute complex like-1, chromogranin A and neurospecific enolase. Western blotting analysis demonstrated the activation of Notch1 on the protein level in BON cells. Additionally, thiocoraline activated downstream Notch targets HES1, HES5 and HEY2. Thiocoraline effectively suppressed carcinoid cell growth by promoting cell cycle arrest in BON and H727 cells. An in vivo study demonstrated that thiocoraline, formulated with polymeric micelles, slowed carcinoid tumor progression. Thus the therapeutic potential of thiocoraline, which induced activation of the Notch pathway, in carcinoid tumors was demonstrated.

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Acknowledgements

We thank Sarah Tesfazghi and Jacob Eide for technical help in the laboratory. This work was supported by funding from the University of Wisconsin-Madison School of Pharmacy and by grants NIH R01 CA121115 and American Cancer Society, MEN2 Thyroid Cancer Professorship (120319-RPM-11-080-01-TBG) and American Cancer Society, Research Scholar Award (RSGM TBE-121413) to Dr Herbert Chen.

Author Contributions

R Jaskula-Sztul designed the experiments. H Cho designed the thiocoraline formulation. T Wyche, A Dammalapati, H Cho, A Harrison and R Jaskula-Sztul performed the experiments. T Wyche wrote the manuscript with contributions from R Jaskula-Sztul and reviewed by T Bugni, G Kwon and H Chen.

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Authors and Affiliations

  1. Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, USA

    T P Wyche, H Cho, G S Kwon & T S Bugni

  2. Department of Surgery Endocrine Research Laboratories, UW Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA

    A Dammalapati, A D Harrison, H Chen & R Jaskula-Sztul

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  1. T P Wyche
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  2. A Dammalapati
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  3. H Cho
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  7. T S Bugni
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Correspondence to R Jaskula-Sztul.

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Wyche, T., Dammalapati, A., Cho, H. et al. Thiocoraline activates the Notch pathway in carcinoids and reduces tumor progression in vivo. Cancer Gene Ther 21, 518–525 (2014). https://doi.org/10.1038/cgt.2014.57

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