日本にも”緑の党”！

東京新聞の今日の朝刊によれば、日本にも、いよいよ”緑の党”が今月２８日に結成される。　２００８年に発足された”みどりの未来”が母体。まず、参議院の比例代表で最低一議席を獲得することが当面の目標。マニフェストの一つは、脱原発を目指す事。

詳しくは、http://www.greens.gr.jp/

もっとも、（民主党を離党する）小沢一郎とその一族郎党が”緑の党”に合流すると言う噂は全くない。　彼は”ぶっ壊し屋”だから、誰にももはや歓迎されない。。。

ところで、豪州（タスマニア島出身）の”緑の党”の創立者、ボッブ＝ブラウン医師は、今年党首を勇退して、女性に党首の席を譲った。　http://greens.org.au/

私は豪州メルボルンに２５年近く永住している。 豪州を永住地に選んだ理由の一つは、
このオセアニア大陸で世界に先駆けて、最初の「みどりの党」が、ボッブ＝ブラウンによって、
ダム建設、森林の乱伐などに反対して、２０年前に結成されたからである。その後、
豪州の「みどりの党」は、政界で躍進を続けし、労働党、自由党に次いで第３政
党として、現在の少数与党（労働党）を助けて、ジュリア＝ギラード（初の女性
首相）内閣の革新政策の推進役をつとめている。

従って、欧州大陸（独仏など）における「みどりの党」の成功にならって、日本
でも「みどりの党」が再度結成され、一般市民の意志を無視した民主／自民（大
連立）による横暴（「原発」の再開）などを阻止するために、戦いましょう！　
そして、先達「紋次郎」（中村敦夫さん）の意志を継ぎましょう！　

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.

5. Mollaoglu H, Gokcimen A, Ozguner F, Oktem F, Koyu A, Kocak A, et al.

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. 

“ＮＦ１患者(特にＭＰＮＳＴ患者)のＧＰＥによる治療 (治験)” に関するお知らせ

ＧＰＥ (ブラジル産グリーンプロポリスエキス)は、ＮＺ産のプロポリス(Ｂｉｏ　３０）と同様、動物（マウス）実験で、ＮＦ腫瘍の増殖を強く抑えた（１、２）。ＧＰＥの抗腫瘍作用は主に、エキスに含まれるＡＲＣ（Artepillin C)と呼ばれるポリフェノールのＰＡＫ遮断作用による(２）。

さて、最近、Ｂｉｏ　３０による世界規模のＮＦ患者を対象とする治療(治験)が成功裡にほぼ完了したのに伴い（３）、山田養蜂場が自社のＧＰＥ製品（「Ｐ３００」と呼ばれるカプセル剤）を無償で提供、８ー１０名の重症ＮＦ１患者(特にＭＰＮＳＴ患者)を対象とする半年間にわたる治験をできるだけ早期に開始したい意向である。

予備実験として、「Ｐ３００」（毎日６粒づつ経口）が「Ｂｉｏ　３０」 同様、ＮＦ１患者の皮膚腫瘍 (いわゆる「ブク」) を一ヶ月以内に縮小することは実証済み（３）。更に、Ｐ３００とＢｉｏ　３０の併用で、ＭＰＮＳＴの再発が少なくとも３か年予防される、という欧米の例もある。

そこで、この治験に参加したい患者を、今月から募集開始する予定である。希望者が８名に達し次第、然るべきＮＦ１専門医の指導下に、治験を早急に開始したい。希望者は下記にメールで応募されたし。

maruta20420@yahoo.co.jp

なお応募の際、病名（MPNST)、腫瘍がどこにあり、今までどんな治療を受けてきたか、氏名、年令、
体重、住所などをご連絡下さい。担当医の名前と病院名（所在地）もお知らせ下さい。

文責：　「NF/TSC　Cure　Org」　マネジャー, (薬学博士) 丸田 浩
(元ルードビッヒ国際癌研究所, 制癌剤開発部長)


参考文献：

１。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.

２。Messerli, S., Ahn, MR., Kunimasa, K., Yanagihara, M. et al. Artepillin C (ARC) in
Brazilian Green Propolis Selectively Blocks the Oncogenic PAK1 Signaling and
Suppresses the Growth of NF Tumors in Mice. Phytother. Res. 2009, 23, 423-27.

３。Maruta, H. Effective NF therapeutics blocking PAK1. Drug Disc. Ther. 2011, 5,
266-78. http://www.ddtjournal.com/action/downloaddoc.php?docid=482

Too Much (Iron-Rich) “Red” Meat Shortens Our Lifespan! :

http://health.usnews.com/health-news/diet-fitness/diabetes/articles/2009/03/23/too-much-red-meat-may-shorten-lifespan

A new “scientific” evidence by Mitoferrin KO in C. elegans

Mitoferrin is an iron importer into mitochondria, essential for the hemoglobin synthesis. Therefore, dysfunction (or knock-out) of mitoferrin in Zebrafish causes hypochromic anaemia and erythroid maturation arrest (1).

Interestingly, however, in the beginning of this year a Chinese group led by JianXin Lu, an “Iron Man”, at Wenzhou Medical College report that the reduction of mitoferrin (mfn) by the mfn siRNA treatment of C. elegans extends the lifespan of this worm by 50-80%, along with smaller body size, smaller progeny number (litter size), and slower movement (2). These effects have nothing to do with the so-called anti-oxidant effect (a “myth”!), because vitamin C, a typical anti-oxidant, does not cause any of these effects. More interestingly, these effects on this worm are apparently similar to those what CR (calorie restriction)-induced activation of the tumor suppressive kinase AMPK, dysfunction of IR (insulin-like receptor, DAF2), AGE-1 (PI3 kinase), TOR (target of rapamycin), or PAK1 genes would cause.

The latter “kinase” effects are executed through the tumor suppressing transcription factor FOXO, which is essential for both the longevity and expression of heat shock (chaperon) genes. Thus, it is conceivable that mitoferrin and these oncogenic kinases (IR, PI3 kinase, TOR and PAK1) are somehow linked to each other. However, unlike PAK1, mitoferrin has no effect on Hsp16 gene (unpublished observation), suggesting that mitoferrin's effect may be independent of both FOXO and heat shock (Hsp)genes.

I shall remind you that there are so many natural products, such as curcumin in Indian curry, propolis (bee-made antibiotics) and bitter melon (“Goya”), which suppress these oncogenic kinases without any adverse effect.

Thus, if you wish to live longer in a good health, I would recommend you to take a plenty of these natural products, and certainly less of red meat. However, if you have a great ambition to win a 100 m race, or have a dozen of children in your family, please don’t take these natural products, simply because you might suffer from fatique before reaching the goal, and dysfunction of your sperms which requires mitoferrin for their maturation. So it might be wise to take a sufficient red meat before you complete a family plan with a few children, and then switch a gear by taking these life-extending natural products, instead of red meat, to enjoy the remaining longer and healthier live.

References:

1. Shaw, G., Cope, J., Li, LT., Corson, K. et al. Mitoferrin is essential for erythroid iron assimilation. Nature, 2006, 440, 96-100.

2. Ren, YG., Yang, S., Tan, GQ., Ye, W. et al. Reduction of mitoferrin results in abnormal development and extended lifespan in C. elegans. PLoS One, 2012, 7, e29666.

Trihydrophobin 1 (TH1): a tumor suppressor that inactivates the kinase PAK1, and is blocked by the oncogenic kinase SRC.

For a decade since 2002, Jianxin Gu’s group at Fudan University in Shanghai has extensively studied the biological function of an ubiquitous protein called trihydrophobin 1 (TH1), present in a variety of animals from Drosophila to human, and found that TH1 inactivates the oncogenic kinase PAK1 and its downstream effectors MEK/ERK as well (1, 2), and is inactivated by the oncogenic Tyr-kinase SRC which phosphorylates Tyr 6 of TH1 (2). In addition, TH1 inactivates another oncogenic kinase A-Raf, but neither B-Raf nor C-Raf (3). Over-expression of TH1 in breast cancer cells blocks both their growth and migration which depend on PAK1 (4). Thus, like Merlin, TH1 is a tumor suppressor that down-regulates PAK1 and its effectors, and its dysfunction probably causes cancer development, and shortens our lifespan.

Back to 2000, we found that PP1, an inhibitor of SRC family kinases, blocks the activation of PAK1, with the IC50 around 10 nM, and the PAK1-dependent growth of RAS-transformants such as pancreatic and colon cancers (5). Recently it was found that the major target of PP1 is FYN, a member of SRC family.  Thus, PP1 reactivates TH1 by blocking FYN, and TH1 in turn inactivates PAK1…

In this context, it should be worth noting that EGF, a ligand for the cell surface Tyr-kinase ErbB1 (EGF receptor), stimulates the TH1 phosphorylation by SRC family kinases, clearly indicating that SRC acts downstream of ErbB1 (2). We found that inactivation of PAK1 by PP1 is not affected by AG 1478, an ErbB1-specific inhibitor, but markedly enhanced by AG 879, an inhibitor of ETK, another Tyr-kinase (6, 7), strongly suggesting that the PP1-induced PAK1 inactivation involves the TH1 phosphorylation by FYN. The combination of PP1 and AG 879 completely blocks both PAK1 and the growth of RAS-transformants in vivo (xenografts mice).

References:

1. Cheng, CM., Kong, XF., Wang, HZ., Gan, HC. et al. Trihydrophbin 1 interacts with
PAK1 and regulates ERK/MAPK activation and cell migration. J. Biol. Chem. 2009,
284, 8786-96.

2. Wu, W., Sun, Z., Wu, J., Peng, X. et al. Trihydrophobin 1 Phosphorylation by c-Src
Regulates MAPK/ERK Signaling and Cell Migration. PLoS One. 2012, 7, e29920.

3. Liu, W., Shen, WY., Yang, YZ., Yin, XL. et al. Trihydrophobin 1 Is a New Negative
Regulator of A-Raf Kinase. J. Biol. Chem 2004, 279, 10167-75.

4. Zou, WY., Yang, YZ., Wu, YH., Sun, LL. et al. Negative role of trihydrophobin 1
in breast cancer growth and migration. Cancer Sci. 2010, 101, 2156–62.

5. He, H., Hirokawa, Y., Levitzki, A., Maruta, H. An anti-Ras cancer potential of PP1,
an inhibitor specific for Src family kinases: in vitro and in vivo studies. Cancer J.
2000, 6, 243-8.

6. He, H., Hirokawa, Y., Manser, E., Lim, L. et al. Signal therapy for RAS induced
cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src
family kinases, that block PAK activation. Cancer J. 2001, 7, 191-202.

7. He, H., Hirokawa, Y., Gazit, A., Yamashita, Y. et al. The Tyr-kinase inhibitor AG879,
　that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1activation
and malignant transformation. Cancer Biol Ther. 2004, 3, 96-101.

「ＰＡＫ遮断薬」時代がいよいよ到来！

ＭＩＴ／理研の利根川　進教授（１９８７年ノーベル受賞者）が２、３年前に
カルフォルニア州のサンディエゴに創立したベンチャー製薬会社「Ａｆｒａｘｉｓ」
が最近、ＰＡＫ１に特異的な阻害剤（ＩＣ５０が１０　ｎＭ前後）を２、３種類
開発し、特許を申請したそうです。 最近（医者向けに）市販された点滴用
（ＰＡＫ遮断）薬ＦＫ２２８ (商標イストダックス) と違い、経口用で、血管脳関門を
通過しうるので、将来、(癌ばかりではなく) ＮＦ２やＴＳＣ などの脳腫瘍や
(利根川教室の専門である) 自閉症などの脳内に発生するＰＡＫ１依存性の難病
の治療にも役立つ可能性があります。

Website of Afraxis: http://www.afraxis. com

The 2011 patent on PAK1 inhibitors:

8-(2'-HETEROCYCYL)PYRIDO[2.3-D]PYRIMIDIN-7(8H)-ONES
FOR THE TREATMENT OF CNS DISORDERS

Inventors:
CAMPBELL, David (13318 Seagrove Street, San Diego, CA, 92130, US)
DURON, Sergio, G. (1605 Neale Street, San Diego, CA, 92103, US)
VOLLRATH, Benedikt (4704 Niagara Avenue, San Diego, CA, 92107, US)
WADE, Warren (10940 Shy Bird Lane, San Diego, CA, 92128, US)

Application Number: US2011/040075
Publication Date: December 15, 2011
Filing Date: June 10, 2011

Assignee:
AFRAXIS, INC. (11099 N. Torrey Pines Road, Suite 290, La Jolla, CA, 92037, US)
and the above four inventors

ＦＫ２２８点滴薬、商標「Ｉｓｔｏｄａｘ」で発売がＦＤＡにより許可される！

http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1574933&highlight=

使用対象は、目下、Ｔ細胞リンパ腫 (皮膚性 および末梢性、ＣＴＣＬ／ＰＴＣＬ）
という稀少悪性腫瘍の治療のみ。米国製薬会社「Ｃｅｌｇｅｎｅ」から医者向け
に発売される。従って、市販の価格についてはまだ不明。将来はＮＦ１患者の
ＭＰＮＳＴ (悪性腫瘍)　及び　表皮のいわゆる「ブク」やこぶ (Plexi-form) にも、
使用されうるが、この薬剤は血管脳関門を通過しないので、ＮＦ２患者の脳腫瘍
( メニンジオーマとシュワノーマ) には効かないし、ＮＦ１患者の脳腫瘍には
効かない。 さらに、プロポリスと違って、いくつかの副作用、例えば貧血性疲労や
胃腸障害などが生じるといわれている。

【製剤】１バイアル2 mL中 Istodax 10 mg　
【用法用量】28日サイクルで1, 8, 15日目に１回４時間以上で 14 mg/m2を静注する。

世界に先駆けて、「イストダックス」によるＮＦ１（特にＭＰＮＳＴ）の治験を
開始しよう！

強い抗癌作用のある抗生物質「FK228=Istodax」を世界に先駆けて１９９３年ごろ
に発見したのは、実は藤沢薬品（合併後、改名して「アステラス」製薬）だった。
更に、その標的がＨＤＡＣ (ヒストン脱アセチラーゼ) であることを１９９８年
に発見したのは、当時東大農学部の吉田　稔博士（ＨＤＡＣ阻害剤の専門家で、
現在は理研勤務) と藤沢薬品の共同研究によるものだった。更に、この薬剤が
最終的には、発癌キナーゼ「ＰＡＫ」を遮断することを発見すると共に、少なくとも
ＮＦ１（神経線維腫症タイプ１）のＭＰＮＳＴという悪性固形癌の治療に強い
効果があることを、２００５年に動物実験で実証したのは、我々のグループである。

従って、最初の発見から十数年後、ようやく市販にたどり着いた新薬（Istodax)
のＮＦ１腫瘍に対する薬効を調べる治験（臨床実験）が、世界に先駆けて、日本で
まず開始されることは、歴史的にみて、(誰の目にも) 極めて道理にかなっていると
思われる。今のところ、ミツバチの産物「プロポリス」以外には、ＮＦ１に効く
（厚生省認可の）薬は皆無であるから、Istodax　の日本での治験開始は「急務」
であると言わざるをえない。稀少難病「ＮＦ」の治療に携わる医療関係者たち
(日本レックリングハウゼン病学会)や厚生労働省に、早期の治験開始を強く訴えたい。