New Generation of Anti-Malaria Drugs Blocking PAK1-MEK: Propolis and other anti-PAK1 drugs/products such as FK228.

In 2005 Pundi Rangarajan's group at Indian Institute of Science discovered
the first clue as to how to handle the drug-resistance of malaria (1). They
showed that curcumin inhibits the chloroquine-resistant malaria infection
in cell culture (IC50 around 5 micro M). As described previously, curcumin
blocks the oncogenic kinase PAK1.

So, during 2005-2006, in collaboration with Alan Cowman's group at WEHI
in Melbourne, we discovered that the most potent HDAC inhibitor "FK228" (IC50
around 1 nM), which eventually blocks the PAK1, inhibits the "Chloroquine-resistant"
malaria-infection in cell culture, strongly suggesting
that PAK1 is essential for malaria infection.

In 2011, using the direct PAK1-inhibitor "IPA-3" (IC50 around 2 micro M), Christian
Doerig's group at University of Glasgow/EPFL in Lausanne finally confirmed
that Malaria-infection indeed requires this kinase and its target "MEK" (1).
Thus, it is now crystal-clear that FK228 and a variety of other anti-PAK1
drugs/products including propolis would be useful for the treatment of Malaria
resistant to Chloroquine and other conventional anti-malaria drugs.

Interestingly, the reverse also seems to be true. For example, the anti-malaria/
anti-arthritis drug "Hydroxychlorine" (HC), was recently found to suppress
the growth of human pancreatic cancer grafted in mice, according to the
2011 study by a group at Dana-Farber Cancer Center in Boston. Since malaria
infection, inflammatory diseases such as arthritis and growth of pancreatic
cancer require PAK1, it is almost certain that the HC also blocks PAK1,
as FK228 and propolis. In fact, around 2004, we found that an old anti-malaria drug
called "Quinidine" (IC50, around 25 micro M) blocks PAK1, and suppresses
the growth of NF2 tumor cells selectively, without any effect on normal cell growth.


Reference:

1. Reddy, R., Vatsala, P., Keshamouni, V., Padmanaban, G. et al. Curcumin for
malaria therapy. Biochem. Biophys. Res. Comm. 2005, 326, 472-4

2. Sicard, A., Semblat, JP., Doerig, C., Hamelin, R. et al. Activation
of PAK-MEK signaling pathway in Malaria parasite-infected erythrocytes.
Cell Microbiol. 2011, in press.