Abstract of Our 2017 Brief Research Article (DDT-17-01011-BR)

Accepted for the publication (April 9, 2017):

Frondoside A from Sea Cucumber and Nymphaeols from Okinawa Propolis: 
Natural anti-cancer agents that selectively inhibit PAK1 in vitro

BC. Nguyen¹, K. Yoshimura², S. Kumazawa², S. Tawata¹, H. Maruta^3,*

¹PAK Research Center, University of the Ryukyus, Okinawa 903-0213, Japan

²Dept of Food and Nutritional Sci, University of Shizuoka, Shizuoka 422-8526, Japan

³PAK Research Center, Melbourne, Australia 3055

ABSTRACT

A sulfated saponin called “Frondoside A” (FRA) from sea cucumber and ingredients from Okinawa propolis (OP) have been previously shown to suppress the PAK1-dependent growth of A549 lung cancer as well as pancreatic cancer cells. However, the precise molecular mechanism underlying their anti-cancer action still remains to be clarified. In this study, for the first time, we found that both FRA and OP directly inhibit PAK1 in vitro in a selective manner (far more effectively than two other oncogenic kinases, LIMK and AKT). Furthermore, at least two major anti-cancer ingredients of OP, Nymphaeols A and C, also directly inhibit PAK1 in vitro in a selective manner. To the best of our knowledge, FRA is the first marine compound that selectively inhibits PAK1. Likewise, these Nymphaeols are the first propolis ingredients that selectively inhibit PAK1. 

Table 1

Anti-cancer activity and anti-kinase specificity of Frondoside A and Okinawa propolis (OP) ingredients (nymphaeols)

	Anti-cancer (IC50)	Anti-PAK1 (IC50)	Anti-LIMK (IC50)	Anti-AKT (IC50)
Frondoside A	0.6	1.2	60	59
Okinawa propolis	12	10	39	30
Nymphaeol A	3.6	9.6	161	42
Nymphaeol C	6.5	9.8	171	74
Curcumin	23	16	30	44

IC₅₀ value is in μM, except forOkinawa propolis (OP) in μg/mL.

Note: In an attempt to determine the specific role of geranyl side chains in either anti-cancer/cell-permeability or anti-PAK1 activity/kinase specificity if any, we are planning to study the potential anti-cancer and anti-PAK1 activity of far simpler flavonoids such as naringenin and sakuranetin which contain no geranyl side chain.