Document Detail


Pazopanib enhances paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer.
MedLine Citation:
PMID:  23283368     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects in ATC cells and xenografts that were associated with potentiated mitotic catastrophe. We hypothesized that combined effects may reflect enhanced paclitaxel-induced cytotoxicity mediated by cell cycle regulatory kinase inhibition by pazopanib. Indeed, pazopanib potently inhibited aurora A, with pazopanib/paclitaxel synergy recapitulated by aurora A short hairpin RNA knockdown or by specific aurora A pharmacological inhibition. Pazopanib/paclitaxel synergy was reversed by aurora A knockdown. Moreover, aurora A (but not B or C) message and protein levels were significantly increased in patient ATCs, and durable benefit resulted from pilot clinical translation of pazopanib/paclitaxel therapy in a patient with metastatic ATC. Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC.
Authors:
Crescent R Isham; Ayoko R Bossou; Vivian Negron; Kelly E Fisher; Rakesh Kumar; Laura Marlow; Wilma L Lingle; Robert C Smallridge; Eric J Sherman; Vera J Suman; John A Copland; Keith C Bible
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Science translational medicine     Volume:  5     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-03     Completed Date:  2013-06-24     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  166ra3     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Combined Chemotherapy Protocols
Aurora Kinase A
Aurora Kinases
Cell Cycle
Cell Line, Tumor
Cell Separation
Dose-Response Relationship, Drug
Drug Synergism*
Female
Humans
Mice
Mice, Nude
Mitosis
Neoplasm Metastasis
Neoplasm Transplantation
Paclitaxel / pharmacology*
Protein-Serine-Threonine Kinases / pharmacology
Pyrimidines / therapeutic use*
RNA, Small Interfering / metabolism
Sulfonamides / therapeutic use*
Thyroid Neoplasms / drug therapy*
Time Factors
Tubulin Modulators / therapeutic use
Grant Support
ID/Acronym/Agency:
CA125750/CA/NCI NIH HHS; CA136665/CA/NCI NIH HHS; R01 CA104505/CA/NCI NIH HHS; R01 CA125750/CA/NCI NIH HHS; R01 CA136665/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Pyrimidines; 0/RNA, Small Interfering; 0/Sulfonamides; 0/Tubulin Modulators; 33069-62-4/Paclitaxel; 7RN5DR86CK/pazopanib; EC 2.7.11.1/Aurka protein, mouse; EC 2.7.11.1/Aurora Kinase A; EC 2.7.11.1/Aurora Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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