Document Detail

Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells.
MedLine Citation:
PMID:  19880792     Owner:  NLM     Status:  MEDLINE    
CONTEXT: The V600E mutation accounts for the vast majority of thyroid carcinoma-associated BRAF mutations.
OBJECTIVE: The aim was to study the effects of the two BRAF V600E ATP-competitive kinase inhibitors, PLX4032 and PLX4720, in thyroid carcinoma cell lines.
EXPERIMENTAL DESIGN: We examined the activity of PLX4032 and PLX4720 in thyroid carcinoma cell lines harboring BRAF V600E (8505C, BCPAP, SW1736, BHT101), NRAS Q61R (HTH7), KRAS G12R (CAL62), HRAS G13R (C643), or RET/PTC1 (TPC-1) oncogenes. Normal thyrocytes (PC Cl 3) were used as control.
RESULTS: Both compounds inhibited the proliferation of BRAF mutant cell lines, but not normal thyrocytes, with a half maximal effective concentration (EC(50)) ranging from 78-113 nm for PLX4720 and from 29-97 nm for PLX4032. Doses equal to or higher than 500 nm were required to achieve a similar effect in BRAF wild-type cancer cells. Phosphorylation of ERK 1/2 and MAPK kinase (MEK) 1/2 decreased upon PLX4032 and PLX4720 treatment in BRAF mutant thyroid carcinoma cells but not in normal thyroid cells or in cell lines harboring mutations of RAS or RET/PTC1 rearrangements. PLX4032 and PLX4720 treatment induced a G(1) block and altered expression of genes involved in the control of G(1)-S cell-cycle transition. 8505C cell tumor xenografts were smaller in nude mice treated with PLX4032 than in control mice. This inhibition was associated with reduction of phospho-ERK and phospho-MEK levels.
CONCLUSIONS: This study provides additional evidence of the promising nature of mutant BRAF as a molecular target for thyroid carcinoma cells.
Paolo Salerno; Valentina De Falco; Anna Tamburrino; Tito Claudio Nappi; Giancarlo Vecchio; Rebecca E Schweppe; Gideon Bollag; Massimo Santoro; Giuliana Salvatore
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-10-30
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  95     ISSN:  1945-7197     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-08     Completed Date:  2010-02-01     Revised Date:  2012-06-21    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  450-5     Citation Subset:  AIM; IM    
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita Federico II, 80131 Naples, Italy.
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MeSH Terms
Adenosine Triphosphate / antagonists & inhibitors,  metabolism
Binding, Competitive / drug effects
Carcinoma / genetics,  pathology*
Cell Proliferation / drug effects
Cytostatic Agents / pharmacology*
Drug Evaluation, Preclinical
Extracellular Signal-Regulated MAP Kinases / metabolism
Indoles / pharmacology*
Mutant Proteins / antagonists & inhibitors,  genetics
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*,  genetics
Serum / physiology
Sulfonamides / pharmacology*
Thyroid Neoplasms / genetics,  pathology*
Tumor Cells, Cultured
Reg. No./Substance:
0/Cytostatic Agents; 0/Indoles; 0/Mutant Proteins; 0/PLX 4720; 0/Protein Kinase Inhibitors; 0/Sulfonamides; 56-65-5/Adenosine Triphosphate; EC protein, human; EC Proteins B-raf; EC Signal-Regulated MAP Kinases
Comment In:
J Clin Endocrinol Metab. 2010 Jan;95(1):60-1   [PMID:  20056810 ]

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

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