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Suberoyl Bishydroxamic Acid Activates Notch1 Signaling and Suppresses Tumor Progression in an Animal Model of Medullary Thyroid Carcinoma

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Abstract

Background

Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy that frequently metastasizes and has few treatments. This study was aimed at assessing the antitumor effects of suberoyl bishydroxamic acid (SBHA) in an in vivo model of MTC.

Methods

Nude mice were injected with human MTC cells, and the groups were treated with SBHA (200 mg/kg) or vehicle (dimethyl sulfoxide) in saline injection every other day for 12 days. Tumors were measured every 4 days and collected at 12 days for Western blot analysis.

Results

Treatment with SBHA resulted in an average 55% inhibition of tumor growth in the treatment group (P < .05). Analysis of SBHA-treated MTC tumors revealed a marked increase in the active form of Notch1 (NICD) with a concomitant decrease in achaete-scute complex-like 1 (ASCL1), a downstream target of Notch1 signaling, as well as the neuroendocrine tumor marker chromogranin A. Importantly, SBHA treatment resulted in an increase in protein levels of p21CIP1/WAF1, p27KIP1, cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase and concomitant with a decrease in cyclin D1 and cyclin B1, indicating that the growth inhibition was due to both cell cycle arrest and apoptosis. Moreover, SBHA downregulated cell survival proteins Bcl-2 and Bcl-XL, but upregulated apoptotic proteins Bax, Bad, and Bmf.

Conclusion

These results demonstrate that SBHA inhibits MTC growth in vivo. SBHA is a promising candidate for further preclinical and clinical studies in MTC.

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Acknowledgments

Supported by American Cancer Society Research Scholars Grant 05-08301TBE; National Institutes of Health RO1 CA109053; NIH-R21CA117117; American College of Surgeons George H. A. Clowes Jr. Memorial Research Career Development Award; Vilas Foundation Research Grant; Carcinoid Cancer Foundation Research Award; Doctors Cancer Foundation Award; and the Society of Surgical Oncology Clinical Investigator Award. The authors thank Eric Wendt for editing the article.

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Authors and Affiliations

  1. Endocrine Surgery Research Laboratories, Department of Surgery, University of Wisconsin School of Medicine and Public Health, and the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI, USA

    Li Ning MD, Renata Jaskula-Sztul PhD, Muthusamy Kunnimalaiyaan PhD & Herbert Chen MD, FACS

  2. K4/638 Clinical Science Center, 600 Highland Avenue, Madison, WI, 53792-7375, USA

    Muthusamy Kunnimalaiyaan PhD

  3. H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI, 53792-7375, USA

    Herbert Chen MD, FACS

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  1. Li Ning MD
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  2. Renata Jaskula-Sztul PhD
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  3. Muthusamy Kunnimalaiyaan PhD
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  4. Herbert Chen MD, FACS
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Corresponding author

Correspondence to Herbert Chen MD, FACS.

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Ning, L., Jaskula-Sztul, R., Kunnimalaiyaan, M. et al. Suberoyl Bishydroxamic Acid Activates Notch1 Signaling and Suppresses Tumor Progression in an Animal Model of Medullary Thyroid Carcinoma. Ann Surg Oncol 15, 2600–2605 (2008). https://doi.org/10.1245/s10434-008-0006-z

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  • DOI: https://doi.org/10.1245/s10434-008-0006-z

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