Sichuan pepper extracts block the PAK1/cyclin D1 pathway and the growth of NF1-deficient cancer xenograft in mice.
There is increasing evidence that more than 70% of cancers including pancreatic, breast and prostate cancers as well as neurofibromatosis (NF) are highly addicted to abnormal activation of the Ser/Thr kinase PAK1 for their growth. So far FK228 is the most potent among the HDAC (histone deacetylase) inhibitors that block the activation of both PAK1 and another kinase AKT, downstream of PI-3 kinase. However, FK228 is still in clinical trials (phase 2) for a variety of cancers (but not for NF as yet), and not available for most cancer/NF patients. Thus, we have been exploring an alternative which is already in the market, and therefore immediately useful for the treatment of those desperate cancer/NF patients. Here we provide the first evidence that extracts of Chinese/ Japanese peppercorns (Zanthoxyli Fructus) from the plant Zanthoxylum piperitum called "Hua Jiao"/"Sansho", block selectively the key kinase PAK1, leading to the downregulation of cyclin D1. Unlike FK228, these extracts do not inhibit AKT activation at the concentrations that block either cancer growth or PAK1 activation. The Chinese pepper extract selectively inhibits the growth of NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells, without affecting the growth of normal fibroblasts, and suppresses the growth of NF1-deficient human breast cancer (MDA-MB-231) xenograft in mice. Our data suggest that these peppercorn extracts would be potentially useful for the treatment of PAK1-dependent NF such as MPNST, in addition to a variety of PAK1-dependent cancers including breast cancers.
Hirokawa
Yumiko
Y
Ludwig Institute for Cancer Research, Parkville/Melbourne, Australia.
Nheu
Thao
T
Grimm
Kirsten
K
Mautner
Victor
V
Maeda
Satoko
S
Yoshida
Minoru
M
Komiyama
Kanki
K
Maruta
Hiroshi
H
D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D018317:Nerve Sheath Neoplasms / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000188:drug therapy* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D032106:Zanthoxylum / Q000737:chemistry*; D054462:p21-Activated Kinases
D050256:Antimitotic Agents; D004791:Enzyme Inhibitors; D025542:Neurofibromin 1; D010936:Plant Extracts; D019938:Cyclin D1; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases