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10.1245/s10434-008-0006-z
Annals of Surgical Oncology 15:2600-2605 (2008)
© 2008 Society of Surgical Oncology
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Original Article

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

Li Ning, MD1, Renata Jaskula-Sztul, PhD1, Muthusamy Kunnimalaiyaan, PhD1,2 and Herbert Chen, MD, FACS1,3

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
2 K4/638 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-7375, USA
3 H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-7375, USA

Correspondence: Address correspondence and reprint requests to: Herbert Chen, MD, FACS; E-mail: chen{at}surgery.wisc.edu

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 achaetescute 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. More-over, 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.

Key Words: Histone deacetylase inhibitor • Suberoyl bishydroxamic acid (SBHA) • Medullary thyroid carcinoma • Local delivery • Notch1 • Apoptosis






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