From Bench (Laboratory) to Bed (Hospital/Home):
How to Explore Effective Natural and Synthetic PAK1-blockers/Longevity-promoters
for
Cancer Therapy.
Hiroshi Maruta a*, Mok-Ryeon Ahn b
a PAK Research Center, Melbourne, Australia
b Dong-A
University, Busan, Korea
* Corresponding author.
E-mail address: maruta20420@yahoo.co.jp
ABSTRACT
PAK family kinases are RAC/CDC42-activated
kinases that were first found in a soil amoeba 4 decades ago, and 2 decades
later, were discovered in mammals as well. Since then at least 6 members of
this family have been identified in mammals. One of them called PAK1 has been best studied so far,
mainly because it is essential not only
for malignant cell growth and metastasis, but also for many other diseases/disorders
such as diabetes (type 2), AD (Alzheimer’s disease), hyper-tension, and a variety
of inflammatory or infectious diseases, which definitely shorten our lifespan.
Moreover,
PAK1-deficient mutant of C. elegans
lives longer than the wild-type by 60%, clearly indicating that PAK1 is not
only an oncogenic but also ageing kinase. Thus, in theory, both anti-oncogenic
and longevity-promoting activities are among the “intrinsic” properties or
criteria of “clinically useful’ PAK1-blockers. There are a variety of PAK1-blocking natural products such as
propolis and curcumin which
indeed extend the healthy lifespan of small animals such as C. elegans by
inducing the autophagy.
Recently, we managed to synthesize a series of potent water-soluble and highly cell-permeable
triazolyl esters of COOH-bearing PAK1-blockers such as Ketorolac, ARC
(artepillin C) and CA (caffeic acid) via “Click Chemistry” that
boosts their anti-cancer activity over 500-fold, mainly by increasing their
cell-permeability, and one of them called 15K indeed extends the lifespan of C. elegans. In this mini-review we shall discuss both
synthetic and natural PAK1-blockers, some of which would be potentially useful
for cancer therapy with least side effect (rather promoting the longevity as
well).
Acknowledgment
We are grateful to Dr. Yoshihiro Uto and Mr. Hideaki Takahashi for their
synthesis of a series of triazolyl esters of COOH-bearing PAK1-blockers discussed in this review, and Dr. Binh Nguyen for
his unpublished observations on 15K and YK155.
Table 1
Anti-cancer activity (IC50)
of natural and synthetic PAK1-blockers
“Natural” PAK1-blockers
|
Anti-cancer
(IC50)
|
“Synthetic” PAK1-blockers
|
Anti-cancer
(IC50)
|
|
FK228
Daumone
Triptolide
Cucurbitacins
Mycophenolate
Frondoside A
DIF-3 Nymphaeols
CAPE
Curcumin
Ursolic acid
|
0.025-0.05
0.02
0.03
0.14
0.05-0.5
0.6
2-3
4-7
10
16
20
|
AG879/GL2003
15K*
PP1/PP2
PP12
YM155
2013UA*
15C*
NOV-3
FRAXs/G-5555
CEP-1347
MIA-602
|
0.005
0.006-0.024
0.01
0.05
0.134
0.1
0.225
0.25
>1
1
1-5
|
|
ARC
|
25
|
WR-PAK18
|
5
|
|
Resveratrol
|
30
|
Selbex (GGA)
|
10
|
|
Melatonin
|
1300
|
IPA-3
|
30
|
IC50 value (against
the growth of A549 cancer cells etc ) is in μM.
*Triazolyl esters
of COOH-bearing PAK1-blockers
