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

Abstract

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 upstream and downstream of PAK1, respectively. Here we demonstrate that (1) the anti-PAK1 drug FK228 (0.1 nM) completely blocks the growth of both NF1-deficient and NF2-deficient cancer cells in vitro, and that (2) 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.

• Authors: Yumiko Hirokawa, Hidenori Nakajima, C Oliver Hanemann, Andreas Kurtz, Silke Frahm, Victor Mautner, Hiroshi Maruta
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 4 Issue 4 Pg. 379-81 (Apr 2005) ISSN: 1538-4047 [Print] United States
• PMID: 15846074 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Depsipeptides
• Enzyme Inhibitors
• Intracellular Signaling Peptides and Proteins
• Neurofibromin 1
• Neurofibromin 2
• PAK1IP1 protein, human
• romidepsin

Topics

• Animals
• Antibiotics, Antineoplastic (pharmacology, therapeutic use)
• Depsipeptides (pharmacology, therapeutic use)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neurofibromin 1 (deficiency, genetics, metabolism)
• Neurofibromin 2 (deficiency, genetics, metabolism)
• Transplantation, Heterologous
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays