Neurofibromatosis (NF) is a family of
genetic diseases which are caused by dysfunction of either NF1 gene or NF2 gene. One in 3,000 people suffer from this
tumor-carrying NF. NF1 gene product is a
RAS GTPase activating
protein (GAP) of 2,818
amino acids, which normally attenuates the
GTP-dependent signal transducing activity of the
G protein RAS. Dysfunction of this GAP leads to the abnormal activation of RAS, and eventually an oncogenic
kinase called PAK1 as well.
NF2 gene product is ''
Merlin'' which directly inactivates PAK1. Thus, dysfunction of
Merlin causes the abnormal activation of PAK1. In other words, dysfunction of NF1 gene (causing type 1 NF) is basically the same as dysfunction of NF2 gene (causing type 2 NF). In fact the growth of both NF1 and NF2
tumors requires PAK1, and all PAK1 blockers, synthetic chemicals or natural products, suppress the growth of these NF
tumor cells both in vitro (cell culture) and in vivo (mice). However, until recently, no FDA-approved effective NF
therapeutics is available on the market. Here a series of anti-PAK1 products shall be introduced, which would be potentially useful for the life-long treatment of NF patients in the future. These include the most potent HDAC (
histone deacetylase) inhibitor FK228 (IC50: around 1 nM), that eventually blocks PAK1, the direct PAK1 inhibitor
PF3758309 (IC50: around 10 nM), a CAPE (
caffeic acid phenethyl ester)-based
propolis extract called ''Bio 30'' from NZ (New Zealand), and an
ARC (
artepillin C)-based green
propolis extract (GPE) from Brazil. Although the first two drugs are potent, none of them is available on the market as yet. The last two natural (bee-made) products are available on the market, and have been used for the
therapy of NF and
tuberous sclerosis (
TSC) as well as many PAK1-dependent solid
cancers such as breast and
pancreatic cancers as well as
glioma, which altogether represent more than 70% of all human
cancers. Since PAK1 is not essential for the normal cell growth,
propolis extracts cause no side effects.