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Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells.

AbstractCONTEXT:
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.
AuthorsPaolo Salerno, Valentina De Falco, Anna Tamburrino, Tito Claudio Nappi, Giancarlo Vecchio, Rebecca E Schweppe, Gideon Bollag, Massimo Santoro, Giuliana Salvatore
JournalThe Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 95 Issue 1 Pg. 450-5 (Jan 2010) ISSN: 1945-7197 [Electronic] United States
PMID19880792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cytostatic Agents
  • Indoles
  • Mutant Proteins
  • PLX 4720
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Adenosine Triphosphate
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
Topics
  • 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)
  • Humans
  • 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

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