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Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation

Cancer Gene Therapy volume 22, pages 410–416 (2015)Cite this article

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Abstract

To develop novel therapies for aggressive thyroid cancers, we have synthesized a collection of histone deacetylase (HDAC) inhibitor analogs named AB1 to AB13, which have different linkers between a metal chelating group and a hydrophobic cap. The purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy. AB2, AB3 and AB10 demonstrated the lowest half-maximal inhibitory concentration (IC50) values in one metastatic follicular and two anaplastic thyroid cancer cell lines. Treatment with each of the three ABs resulted in an increase in apoptosis markers, including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3. Additionally, the expression of cell-cycle regulatory proteins p21WAF1 and p27Kip1 increased with the treatment of ABs while cyclin D1 decreased. Furthermore, AB2, AB3 and AB10 were able to induce thyrocyte-specific genes in the three thyroid cancer cell lines indicated by increased expression levels of sodium iodide symporter, paired box gene 8, thyroid transcription factor 1 (TTF1), TTF2 and thyroid-stimulating hormone receptors. AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell-cycle arrest and apoptosis. They also induce cell re-differentiation, which could make aggressive cancer cells more susceptible to radioactive iodine therapy.

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Acknowledgements

This study was supported by American Cancer Society Research Scholar Grant (HC); American Cancer Society MEN2 Thyroid Cancer Professorship (HC); R01 CA121115 (HC); NIH T35 DK062709 Surgery Summer Research Experience for Medical Students (SJ).

Precis: Compounds targeting histone deacetylases (HDAC) have shown promising antitumor activities in other cancers. Here, we report a screening study on the novel synthesized HDAC inhibitor analogs, which demonstrate the potential to suppress proliferation and induce re-differentiation in aggressive thyroid cancers.

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Authors and Affiliations

  1. Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    S Jang, X-M Yu, S Odorico, M Clark, R Jaskula-Sztul, A D Harrison & H Chen

  2. Department of Chemistry, University of Wisconsin School of Pharmacy, Madison, WI, USA

    C M Schienebeck, G N Winston-McPherson & W Tang

  3. Promega Corporation, Madison, WI, USA

    K R Kupcho

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  1. S Jang
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Correspondence to X-M Yu or H Chen.

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Jang, S., Yu, XM., Odorico, S. et al. Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation. Cancer Gene Ther 22, 410–416 (2015). https://doi.org/10.1038/cgt.2015.37

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