Signal therapy of NF1-deficient tumor xenograft in mice by the anti-PAK1 drug FK228

PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for the malignant growth of RAS transformants as well as both NF1-deficient and NF2-deficient cancer cells. FK228, a histone deacetylase (HDAC) inhibitor, suppresses the growth of more than 70% of human cancers in vivo including RAS transforman...

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Bibliographic Details
Published in:Cancer biology & therapy 2005-04, Vol.4 (4), p.379-381
Main Authors: Hirokawa, Yumiko, Nakajima, Hidenori, Hanemann, C Oliver, Kurtz, Andreas, Frahm, Silke, Mautner, Victor, Maruta, Hiroshi
Format: Article
Language:English
Subjects:
Animals
Antibiotics, Antineoplastic - pharmacology
Antibiotics, Antineoplastic - therapeutic use
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cycle
Depsipeptides - pharmacology
Depsipeptides - therapeutic use
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
Intracellular Signaling Peptides and Proteins - antagonists & inhibitors
Landes
Mice
Mice, Nude
Neoplasm Transplantation
Neurofibromin 1 - deficiency
Neurofibromin 1 - genetics
Neurofibromin 1 - metabolism
Neurofibromin 2 - deficiency
Neurofibromin 2 - genetics
Neurofibromin 2 - metabolism
Organogenesis
Proteins
Transplantation, Heterologous
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
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Summary:PAK1, a Rac/CDC42-dependent Ser/Thr kinase, is required for the malignant growth of RAS transformants as well as both NF1-deficient and NF2-deficient cancer cells. FK228, a histone deacetylase (HDAC) inhibitor, suppresses the growth of more than 70% of human cancers in vivo including RAS transformants, breast cancers and prostate cancers by activating a set of genes including the tumor suppressors gelsolin and p21/WAF1, that block up-stream and down-stream of PAK1, respectively. Here we demonstrate that (i) the anti-PAK1 drug FK228 (0.1 nM) completely blocks the growth of both NF1-deficient and NF2-deficent cancer cells in vitro, and that (ii) FK228 (2.5 mg/kg, i.p., twice a week) causes the complete regression of an NF1-deficient human malignant peripheral nerve sheath tumor (MPNST) xenograft in nude mice. This is the very first case where a chemical drug in clinical trials for cancers has ever worked so effectively on neurofibromatosis (experimental neurofibromas) in vivo.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.4.4.1649