"Combo" Therapy of PAK1-dependent Cancers and NF by Two Inexpensive Natural Products, Bio 30 and Curcumin

NF (neurofibromatosis) tumors and 70% of human cancers require the oncogenic
kinase PAK1 for their growth. We have recently shown that Bio 30, the CAPE
(caffeic acid phenethyl ester) -rich extract of NZ (New Zealand) propolis
almost completely suppresses the growth of NF tumors, glioma, pancreatic
and breast cancer xenografts in mice. Another natural product called curcumin
was also known to block this kinase somehow. This summer Feng Li's group
at China Medical School reported that curcumin inactivates PAK1, at least
in part by down-regulating the Tyr-kinase ErbB2/HER2 (for detail, see the
abstract below). Several years ago we have shown that both ErbB1 (EGF receptor)
and ErbB2 are required for PAK1 activation (Hong He et al, 2001).

The major problem of curcumin alone for clinical application is its poor
bioavailability (mainly due to its water-insolubility) as previously discussed.
In the future, liposome or CD (cyclodextrin) could be used to solubilize
curcumin for clinical application. Interestingly, CAPE alone shares the same
problem. However, if CAPE is taken with several other anti-cancer polyphenols
in CAPE-based propolis extracts such as Bio 30, both its bioavailability
and anti-cancer potential are dramatically (over 600 times) improved (Maria
Demestre et al, 2009). Considering this finding, it would be worth to combine
curcumin and Bio 30 not only for improving the bioavailability of curcumin,
but also for creating its potential synergy with CAPE and several other
anti-cancer ingredients such as pinocembrin (PIN) in Bio 30.


Cancer Biol Ther. 2009 Jul 13;8(14).

Curcumin suppresses proliferation and invasion in human gastric cancer cells
by downregulation of PAK1 activity and cyclin D1 expression.

Cai XZ, Wang J, Li XD, Wang GL, Liu FN, Cheng MS, Li F.

Department of Cell Biology, Key Laboratory of Cell Biology of Ministry of
Public Health of China, China Medical University, Shenyang, China.

Curcumin (diferuloylmethane), is a natural chemopreventive agent known to
inhibit the proliferation of several cancer cell lines. It has been previously
demonstrated that curcumin is a potent inhibitor of EGF-receptor (EGFR)
tyrosine kinase, but its inhibitive effect on PAK1, a downstream protein
of EGFR, has not been defined. In this paper

we found that curcumin repressed the expression of HER2 and inhibited the
kinase activity of PAK1 without affecting its expression. Silencing HER2
in gastric cancer cells showed that even if PAK1 activity was transiently
strengthened by EGF, curcumin still had a strong inhibitive effect. It should
be emphasized that kinase assay in vitro showed that curcumin could act as
an ATP-competitive inhibitor, which was supported by computer-aided molecular
modeling. Curcumin also downregulated the mRNA and the protein expression
of cyclin D1 and suppressed transition of the cells from G(1) to S phase.
Therefore, curcumin inhibited the proliferation and invasion of gastric
cancer cells. Overall, these results provided novel insights into the mechanisms
of curcumin inhibition of gastric cancer cell growth and potential therapeutic
strategies for gastric cancer.