Faculty Collaboration Database

Suberoyl bishydroxamic acid activates notch1 signaling and suppresses tumor progression in an animal model of medullary thyroid carcinoma. Ann Surg Oncol 2008 Sep;15(9):2600-5

Date

06/20/2008

Pubmed ID

18563491

Pubmed Central ID

PMC2737668

DOI

10.1245/s10434-008-0006-z

Scopus ID

2-s2.0-50049117726 (requires institutional sign-in at Scopus site)   29 Citations

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 p21(CIP1/WAF1), p27(KIP1), 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-X(L), 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.

Author List

Ning L, Jaskula-Sztul R, Kunnimalaiyaan M, Chen H

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Basic Helix-Loop-Helix Transcription Factors
Blotting, Western
Carcinoma, Medullary
Caspases
Cell Cycle
Cell Proliferation
Chromogranin A
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Disease Models, Animal
Disease Progression
Gene Expression Regulation, Neoplastic
Humans
Hydroxamic Acids
Male
Mice
Mice, Nude
Poly(ADP-ribose) Polymerases
Receptor, Notch1
Thyroid Neoplasms
Tumor Cells, Cultured
Xenograft Model Antitumor Assays