"Anti-PAK Index" : the International standard of PAK1-blocking herbal products such as propolis for quality control

There is a wide variety of edible PAK1-blocking herbal products such as propolis available on the market world-wide which could be very useful for improving our health and even therapy of cancer and many other PAK1-dependent diseases/disorders such as Alzheimer’s disease (1). However, unlike FDA-approved drugs, none of them is associated with any reliable international quality control standard such as IC₅₀ or ED (effective dose). For instance, the quality of propolis depends on the sources of plants where bees harvest from, and the actual content of PAK1-blocking ingredients such CAPE, apigenin, ARC (artepillin C) and propolin G (=nymphaeol C) in each propolis. However, since 1960s till present, the only available quality stardard used for propolis is just “the total flavonoid content” for CAPE-based propolis or the ARC content in Brazillian green propolis. If these “herbal” health-promoting products are regulated by a single reliable pharmacological quality standard, we could compare the quality or effectiveness from one sample to another quite objectively, regardless of their detailed content.

Hence, we would propose here for the fist time to use a universal standard called “Anti-PAK Index” which is the 100 X reciprocal of the IC₅₀ in ppm (micro g/ml). For instance, “Anti-PAK Index” of Bio 30 (CAPE-based propolis from New Zealand) , (propolin G-based) Okinawa propolis (OP) and (ARC-based ) Brazilian green propolis (GP) are 12.5, 8 and 1, respectively, since their IC₅₀ for A549 cancer cells are around 8, 12 and 100 ppm, respectively, whereas the “Anti-PAK Index” of the “pure” compound "Cucurbitacin" (CB) is around 1400, as the IC₅₀ for A549 is around 140 nM (0.07 ppm). The higher the Anti-PAK Index, the more potent a given sample. In other words, 1 mg of CB is equivalent to 112 mg of Bio 30 for therapy of cancers and many other PAK1-dependent diseases/disorders. This rough estimation is not far from the actual  in vivo data where the daily dose of  CB (1 mg/kg),  and that of Bio 30 (50 mg/kg) are their effective dose to suppress the PAK1-dependent growth of pancreatic cancers or NF tumors in mice (1), suggesting that their in vivo bioavailability is quite similar.

The only difference between these two is that Bio 30 has been available on the market world-wide for clinical uses for almost a decade, but CB is not as yet.  The only way for us to take CB is to eat the edible bitter melon (Goya) grown in Okinawa (which contains around 1 g of CB per kg) or drink Goya teas. Since roughly 90% of Goya is water, the “Anti-PAK Index”of Goya extract/tea could be around 14, pretty close to that of Bio 30.

We recently managed to synthesize a highly cell-permeable and water-soluble compound whose IC50 is around 24 nM (0.01 ppm) against the growth of A549 cancer cells (2). Its "Anti-PAK Index" is 10,000, several times more potent than CB, and we have filed a US patent on this new PAK1- blocker called "15K" for its clinical application (The related Japanese patent was granted). It is derived from an old FDA-approved synthetic anti-inflammatory pain killer (Ketorolac).  It passes the BBB (blood brain barrier), and could be useful for treating a variety of PAK1-dependent neuronal diseases/disorders such as brain tumors, AD (Alzheimer's disease), PD (Parkinson's disease), epilepsy, depression,  schizophrenia and even autism. Furthermore, it extends the healthy lifespan of C. elegans by 30% at 50 nM, clearly indicating that "15K"  causes no side effect!

I bet that leading pharmaceutical giants such as Pfeizer, Roche and Novartis, who are currently racing for developing potent PAK1-blockers which would be useful for clinical application, would be most likely keen to buy an exclusive license (worth more than 200 million USD) from this patent of ours. 

References:

１．Maruta H. Herbal therapeutics that block the oncogenic kinase PAK1: A practical approach towards PAK1-dependent diseases and longevity. Phytother Res. 2014; 28:656-672..

2.    Nguyen BC, Takahashi H, Uto Y, Shahinozzaman MD, Tawata S, Maruta H. Chemistry"-based highly potent PAK1-blocking cancer-killer. Eur J Med Chem. 2016 ; 126: 270-6.