人々の “健康促進” のために!

人々の “健康促進” のために!
2015年春、沖縄の琉球大学キャンパス内 (産学共同研究棟) に立ち上げた “PAK研究センター” の発足メンバー(左から4人目が、所長の多和田真吉名誉教授)
For detail, click the above image.

2012年5月23日水曜日

Tetrandrine(Tet) : a new natural PAK blocker?

Two separate groups recently claimed that PAKs, in particular PAK1 and PAK2, are involved in the development of cardiomyocyte hypertrophy, but rather mysteriously in entirely “opposite” ways.

Xin Wang’s group at University of Manchester in UK reported that PAK1-deficiency in mice causes the hypertrophy, while a sphingolipid called “FTY720” reverses the hypertrophy (1). Misunderstanding that FTY720 is a PAK1 activator, they concluded that PAK1 prevents the hypertrophy. However, actually, FTY720 is a PAK1 inhibitor which suppresses the growth of pancreatic and colon cancers as well as melanin synthesis. Thus, their claim is clearly a "self-conflicting" (making no sense!)...
On the other hand, Thomas Wieland’s group at University of Heidelberg in Germany found that PAK2 is essential for catecolamine-induced hyperdrophy (2). In other words, PAK2 blockers could serve as potential therapeutics for the hypertrophy.

In this light, I have searched a reported few “natural” therapeutics for the hypertrophy, and found that curcumin, berberine, CAPE (caffeic acid phenethyl ester) and tetrandrine (Tet) could reverse the hypertrophy in mice or rats (3-6). What is the common (biological property) to these four anti-hypertrophic natural products?  Curcumin is known to inhibit both PAK1 and PAK2 directly (7).  Berberine down-regulates RAC and CDC42, activators of PAKs, and therefore blocking both PAK1 and PAK2 (8).  CAPE down-regulates RAC, and therefore blocking PAK1-3 (9). How about Tetrandrine (Tet)?  Tet is known to block the activation of beta-catenine, an oncogenic transcription factor which is activated directly by PAK1 or PAK2 (10). Thus, it is most likely, if not proven as yet,  that Tet also blocks both PAK1 and PAK2.

If  PAK1 alone were able to prevent effectively the hypertrophy, these anti-PAK compounds would have worsen the hypertrophy. However, if PAK2 is causing the hypertrophy, these anti-PAK compounds could improve the conditions of hypertrophy, as have been reported. In other words, it is most likely that the force of PAK2 to cause the hypertrophy is far “superior” to the power of PAK1 to reverse the hypertrophy. Thus, in my opinion, we should first focus our attention on PAK2’s hypertrophic effect. For PAK1-deficiency is rarely found in human beings, whereas hyper-activation of PAK1 or PAK2 as well as PAK4 is quite often found in human beings suffering from cancers or a variety of other PAK-dependent diseases.

Thus, it would be worth testing/proving directly if Tet blocks PAK1 and PAK2 in cardiomyocytes or colon cancer cells, as expected.

Lastly, in support of this notion, back to more than 2 decades ago, Tet was shown to block the chloroquine (CQ)-resistant malaria and reduce the effective dose of CQ by 40 times (11). Recently Christian Doerig’s group in Switzerland found that malaria infection requires PAK1 in host cells (12), strongly suggesting that Tet blocks PAK1 as well as PAK2. 


References:  

1.     Liu, W., Zi, M., Naumann, R., Ulm, S., Jin, J., Taglieri, DM. et al. Pak1 is a novel signaling regulator attenuating cardiac hypertrophy in mice. Circulation. 2011,124: 2702-15.

2. Vettel C, Wittig K, Vogt A, Wuertz CM, El-Armouche A, Lutz S, Wieland T. A novel player in cellular hypertrophy: G(i)βγ/PI3K-dependent activation of the RacGEF TIAM-1 is required for α(1)-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes J Mol Cell Cardiol. 2012, in press.

3.  Li HL, Liu C, de Couto G, Ouzounian M, Sun M, Wang AB, et al. Curcumin prevents and reverses murine cardiac hypertrophy. J Clin Invest. 2008, 118, 879-93.

 

4.  Hong Y, Hui SC, Chan TY, Hou JY. Effect of berberine on regression of pressure-overload induced cardiac hypertrophy in rats. Am J Chin Med. 2002, 30, 589-99.

Caffeic acid phenethyl ester (CAPE) prevents cadmium-induced cardiac impairment in rat. Toxicology. 2006, 227, 15-20.

6. Zhou DX, Yang GT, He XX, Liu Q. Effects of tetrandrine on Ang II-induced cardiomyocyte hypertrophy and p-ERK1/2 expression. Zhongguo Zhong Yao Za Zhi. 2007, 32, 1921-4.

7. Cai, XZ., Wang, J., Li, XD., Wang, GL. et al. Curcumin suppresses proliferation and
      invasion in human gastric cancer cells by down-regulation of PAK1 activity and
      cyclin D1 expression. Cancer Biol Ther. 2009, 8, 1360-8.

8. Tsang,  CM., Lau, EP., Di, K., Cheung, PY. et al. Berberine inhibits Rho GTPases
       and cell migration at low doses but induces G2 arrest and apoptosis at high doses in
       human cancer cells.  Int J Mol Med. 2009, 24, 131-8.

9. Demestre, M. Messerli, S., Celli, N., Shahhossini, M. et al. CAPE (Caffeic Acid
      Phenethyl Ester)-based Propolis Extract (Bio 30) Suppresses the Growth of Human
      Neurofibromatosis (NF) Tumor Xenografts in Mice. Phytother. Res. 2009, 23, 226-
      30.

10. He BC, Gao JL, Zhang BQ, Luo Q, Shi Q, Kim SH, et al. Tetrandrine (Tet) inhibits Wnt/β-catenin signaling and suppresses tumor growth of human colorectal cancer. Mol Pharmacol. 2011, 79, 211-9. 

 

11. Ye ZG, Van Dyke K, Castranova V. The potentiating action of tetrandrine in combination with chloroquine or qinghaosu against chloroquine-sensitive and resistant falciparum malaria. Biochem Biophys Res Commun. 1989, 165, 758-65.

12. Sicard A, Semblat JP, Doerig C, Hamelin R, Moniatte M, Dorin-Semblat D, et al. Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes. Cell Microbiol. 2011, 13, 836-45.