Document Detail

A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo.
MedLine Citation:
PMID:  21134556     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Most medullary thyroid carcinomas (MTC) recur or progress despite curative resection. Current targeted therapies show promise but lack durable efficacy and tolerability. The purpose of this study was to build on previous in vitro work and evaluate withaferin A (WA), a novel RET inhibitor, in a metastatic murine model of MTC.
METHODS: A total of 5 million DRO-81-1 human MTC cells injected in the left posterior neck of nu/nu mice generated metastases uniformly to the liver, spleen, and/or lungs. Treatment with WA (8 mg/kg/day, intraperitoneally, for 21 days) was started for neoplasms > 100 mm(3). Endpoints were survival, neoplasm > 15,00 mm(3), decreased body weight, or body score (all measured three times/wk).
RESULTS: All controls (saline; n = 5) died or deteriorated from metastatic disease by 7 weeks postinjection. All treated animals were alive (WA; n = 5), having tumor regression and growth delay without toxicity or weight loss at 6 weeks posttreatment (P < .01). Tumor cells treated with WA demonstrated inhibition of total and phospho-RET levels by Western blot analysis in a dose-dependent manner (almost complete inhibition with treatment of 5 μM WA) as well as potent inhibition of phospho-ERK and phospho-Akt levels.
CONCLUSION: WA is a novel natural-product RET-inhibitor with efficacy in a metastatic murine model of MTC. Further long-term efficacy/toxicity studies are warranted to evaluate this compound for clinical translation.
Abbas K Samadi; Ridhwi Mukerji; Anuj Shah; Barbara N Timmermann; Mark S Cohen
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Surgery     Volume:  148     ISSN:  1532-7361     ISO Abbreviation:  Surgery     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-07     Completed Date:  2011-01-14     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  0417347     Medline TA:  Surgery     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1228-36; discussion 1236     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2010 Mosby, Inc. All rights reserved.
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MeSH Terms
Antineoplastic Agents / therapeutic use
Biopsy, Fine-Needle
Calcitonin / blood
Mice, Nude
Neural Crest / pathology
Proto-Oncogene Proteins c-ret / antagonists & inhibitors*
Thyroid Neoplasms / blood,  drug therapy,  pathology
Transplantation, Heterologous / methods,  pathology
Withanolides / therapeutic use*
Grant Support
L30 CA136330-02/CA/NCI NIH HHS; P20 RR015563/RR/NCRR NIH HHS; P20 RR015563-105577/RR/NCRR NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/Withanolides; 5119-48-2/withaferin A; 9007-12-9/Calcitonin; EC Proteins c-ret; EC protein, mouse

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