Suberoyl bishydroxamic acid activates notch1 signaling and suppresses tumor progression in an animal model of medullary thyroid carcinoma.
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.


CONCLUSIONS
These results demonstrate that SBHA inhibits MTC growth in vivo. SBHA is a promising candidate for further preclinical and clinical studies in MTC.
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
L
Ning
Renata
R
Jaskula-Sztul
Muthusamy
M
Kunnimalaiyaan
Herbert
H
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015153:Blotting, Western; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D051792:Basic Helix-Loop-Helix Proteins; D020169:Caspases; D053379:Chromogranin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006877:Hydroxamic Acids; D011065:Poly(ADP-ribose) Polymerases; D051881:Receptor, Notch1; D000077337:Vorinostat; C499317:Ascl1 protein, mouse; C493957:Cdkn1a protein, mouse