JP5217436B2 - Akt activation inhibitor - Google Patents
Akt activation inhibitor Download PDFInfo
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- JP5217436B2 JP5217436B2 JP2007529634A JP2007529634A JP5217436B2 JP 5217436 B2 JP5217436 B2 JP 5217436B2 JP 2007529634 A JP2007529634 A JP 2007529634A JP 2007529634 A JP2007529634 A JP 2007529634A JP 5217436 B2 JP5217436 B2 JP 5217436B2
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- Prior art keywords
- akt
- leucine
- isoleucine
- valine
- apoptosis
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Description
本発明は、新規のＡｋｔ活性化抑制剤、並びに高インスリン血症を示すか又は高インスリン血症の危険性のある患者における癌の発生及び／又は進展を抑制するための薬剤に関する。 The present invention relates to a novel Akt activation inhibitor and a drug for suppressing the occurrence and / or progression of cancer in a patient who exhibits or is at risk for hyperinsulinemia.
肥満は、糖尿病、高血圧、高脂血症などの生活習慣病を起こしやすいことが知られている。特に内臓脂肪型肥満は、耐糖能異常、インスリン抵抗性を併発しやすく、体脂肪量とインスリン抵抗性は有意な正の相関を示す。肥満のモデル動物（ｏｂ／ｏｂマウスやＺｕｃｋｅｒ ｆａｔｔｙラット）では、肥満とともに著しい高インスリン血症が見られることが証明されている。臨床的にも、肥満者では空腹時の血中インスリン値が高く、グルコース負荷後のインスリン反応も亢進している。すなわち、血糖曲線を一致させて肥満者と非肥満者を比較すると、どの時点でも肥満者のインスリン値は高い（Ｆｕｊｉｏｋａ Ｓ，Ｍａｔｓｕｚａｗａ Ｙ，Ｔｏｋｕｎａｇａ Ｋ，ｅｔ ａｌ．Ｃｏｎｔｒｉｂｕｔｉｏｎ ｏｆ ｉｎｔｒａ−ａｂｄｏｍｉｎａｌ ｆａｔ ａｃｃｕｍｕｌａｔｉｏｎ ｔｏ ｔｈｅ ｉｍｐａｉｒｍｅｎｔ ｏｆ ｇｌｕｃｏｓｅ ａｎｄ ｌｉｐｉｄ ｍｅｔａｂｏｌｉｓｍ ｉｎ ｈｕｍａｎ ｏｂｅｓｉｔｙ．Ｍｅｔａｂｏｌｉｓｍ ３６：５４ １９８７）。
一方、２型糖尿病の特徴的病態はインスリン作用の低下であるが、糖尿病発症前に空腹時および糖負荷時の血中インスリン濃度の増加が長期間にわたって認められることが報告されている（Ｍｅｒｔｉｎ ＢＣ，Ｗａｒｒａｍ ＪＨ，ｅｔ ａｌ．Ｒｏｌｅ ｏｆ ｇｌｕｃｏｓｅ ａｎｄ ｉｎｓｕｌｉｎ ｒｅｓｉｓｔａｎｃｅ ｉｎ ｄｅｖｅｌｏｐｍｅｎｔ ｏｆ ｔｙｐｅ ２ ｄｉａｂｅｔｅｓ ｍｅｌｌｉｔｕｓ：ｒｅｓｕｌｔｓ ｏｆ ａ ２５−ｙｅａｒ ｆｏｌｌｏｗ−ｕｐ ｓｔｕｄｙ．Ｌａｎｃｅｔ ３４０：９２５−９２９ １９９２）。
近年、これらの疾患と癌の関連が明らかとなってきた。すなわち、９０万人の米国民を１６年間追跡したところ、肥満度が高くなるほど全がん死亡率が高くなることが報告された（Ｃａｌｌｅ ＥＥ，ｅｔ ａｌ．Ｏｖｅｒｗｅｉｇｈｔ，ｏｂｅｓｉｔｙ，ａｎｄ ｍｏｒｔａｌｉｔｙ ｆｒｏｍ ｃａｎｃｅｒ ｉｎ ａ ｐｒｏｓｐｅｃｔｉｖｅｌｙ ｓｔｕｄｉｅｄ ｃｏｈｏｒｔｓ ｏｆ Ｕ．Ｓ．ａｄｕｌｔｓ．Ｎｅｗ Ｅｎｇｌ ａｎｄ Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎｅ ２００３；３４８；１６２５−１６３８）。
また別の報告では、糖尿病は癌のリスクファクターであることが示された（Ｎａｔｈ ｅｔ ａｌ．Ｆａｓｔｉｎｇ Ｓｅｒｕｍ Ｇｌｕｃｏｓｅ Ｌｅｖｅｌ ａｎｄ Ｃａｎｃｅｒ Ｒｉｓｋ ｉｎ Ｋｏｒｅａｎ Ｍｅｎ ａｎｄ Ｗｏｍｅｎ，ＪＡＭＡ．２００５；２９３：２２１０−２２１１）。
糖尿病や肥満における発癌のメカニズムの１つとして、高インスリン血症が想定される。インスリンには、細胞増殖作用があることはよく知られており（Ｇｕｐｔａ Ｋ，Ｋｒｉｓｈｎａｓｗａｍｙ Ｇ，Ｋａｒｎａｄ Ａ，Ｐｅｉｒｉｓ ＡＮ．Ｉｎｓｕｌｉｎ：Ａ ｎｏｖｅｌ ｆａｃｔｏｒ ｉｎ ｃａｒｃｉｎｏｇｅｎｅｓｉｓ．Ａｍ．Ｊ．Ｍｅｄ．Ｓｃｉ ３２３：１４０−１４５；２００２）、有糸分裂誘発作用はＩＧＦ−１受容体、インスリン受容体を介して作動するが、この作用は血中インスリン値が正常よりも高い場合により強く生じやすい。インスリンのシグナルにおいて、細胞増殖の中心を担っている分子のひとつとしてＡｋｔが報告されている（Ｌａｗｌｏｒ ＭＡ ａｎｄ Ａｌｅｓｓｉ ＤＲ．ＰＫＢ／Ａｋｔ，：ａ ｋｅｙ ｍｅｄｉａｔｏｒ ｏｆ ｃｅｌｌ ｐｒｏｌｉｆｅｒａｔｉｏｎ，ｓｕｒｖｉｖａｌ ａｎｄ ｉｎｓｕｌｉｎ ｒｅｓｐｏｎｓｅｓ？ Ｊ．Ｃｅｌｌ Ｓｃｉ．１１４：２９０３−２９１０；２００１）。Obesity is known to easily cause lifestyle-related diseases such as diabetes, hypertension, and hyperlipidemia. In particular, visceral fat obesity tends to cause abnormal glucose tolerance and insulin resistance, and the body fat mass and insulin resistance show a significant positive correlation. In obese model animals (ob / ob mice and Zucker fatty rats), it has been proved that marked hyperinsulinemia is observed with obesity. Clinically, obese subjects have high fasting blood insulin levels and an increased insulin response after glucose loading. That is, when obese and non-obese are compared by matching the blood glucose curve, the obese person's insulin level is high at any time point (Fujioka S, Matsuzawa Y, Tokunaga K, et al. Tribulation of intra-abdominal fat accumulation to accumulation imperment of glucose and lipid metabolism in human obesity. Metabolism 36:54 1987).
On the other hand, the characteristic pathology of
In recent years, the relationship between these diseases and cancer has become clear. In other words, when 900,000 Americans were followed for 16 years, it was reported that as the degree of obesity increases, the overall cancer mortality rate increases (Calle EE, et al. Overweight, obesity, and Mortality from Cancer in a. prospective studied cohorts of U. S. adults. New Engl and Journal of Medicine 2003; 348; 1625-1638).
Another report showed that diabetes is a risk factor for cancer (Nath et al. Fasting Serum Glucose Level and Cancer Risk in Korean Men and Women, JAMA. 2005; 293: 2210-2211).
Hyperinsulinemia is assumed as one of the mechanisms of carcinogenesis in diabetes and obesity. It is well known that insulin has a cell proliferative effect (Gupta K, Krishnaswamy G, Karnad A, Peiris AN. Insulin: A novel factor in carcinogenesis. Am. J. Med. Sci 323: 140-1 45: 2002), the mitogenic action works via the IGF-1 receptor and insulin receptor, but this action is more likely to occur more strongly when the blood insulin level is higher than normal. In insulin signals, Akt has been reported as one of the molecules that play a central role in cell proliferation (Lawlor MA and Alessi DR. PKB / Akt, a key mediator of cell proliferation, survival and insulin responses? J). Sci. 114: 2903-2910; 2001).
本発明は、Ａｋｔの活性化を抑制することによって、高インスリン血症を示すか又は高インスリン血症の危険性のある患者における癌の発生及び／又は進展を抑制する薬剤を提供することを目的とする。
本発明者は、上記課題を解決するために鋭意研究した結果、イソロイシン、ロイシン、及びバリンから選ばれる少なくとも１種の分岐鎖アミノ酸を有効成分とする組成物が、Ａｋｔ活性化を抑制する作用を有することを見出し、本発明を完成するに至った。
すなわち、本発明は、以下の通りである：
（１）イソロイシン、ロイシン、及びバリンから選ばれる少なくとも１種の分岐鎖アミノ酸を有効成分とする、Ａｋｔ活性化抑制剤。
（２）少なくともロイシンを含む、（１）に記載のＡｋｔ活性化抑制剤。
（３）イソロイシン、ロイシン、及びバリンの３種からなる、（１）に記載のＡｋｔ活性化抑制剤。
（４）イソロイシン、ロイシン、及びバリンの重量比が、１：１．５〜２．５：０．８〜１．７であることを特徴とする、（３）に記載のＡｋｔ活性化抑制剤。
（５）高インスリン血症を示すか又は高インスリン血症の危険性のある患者における癌の発生及び／又は進展を抑制するために用いられる、（１）〜（４）のいずれかに記載のＡｋｔ活性化抑制剤。
（６）前記高インスリン血症を示すか又は高インスリン血症の危険性のある患者が、インスリン抵抗性、糖代謝異常、及び／又は脂質代謝異常の症状を有する、（５）に記載のＡｋｔ活性化抑制剤。
（７）前記高インスリン血症を示すか又は高インスリン血症の危険性のある患者が、肥満、糖尿病、非アルコール性脂肪性肝炎に罹患している、（５）に記載のＡｋｔ活性化抑制剤。
（８）前記癌が、肝癌である、（５）〜（７）のいずれかに記載のＡｋｔ活性化抑制剤。
（９）アポトーシスを促進するために用いられる、（１）〜（４）のいずれかに記載のＡｋｔ活性化抑制剤（すなわち、アポトーシス促進剤）。
（１０）アポトーシスの促進がアポトーシス抑制遺伝子発現の抑制によるものである、（９）に記載のＡｋｔ活性化抑制剤。
（１１）アポトーシス抑制遺伝子がＭｃｌ−１またはＩＡＰ−１である、（１０）に記載のＡｋｔ活性化抑制剤。
（１２）高インスリン血症を示すか又は高インスリン血症の危険性のある患者における癌の発生及び／又は進展を抑制するために用いられる、（９）に記載のＡｋｔ活性化抑制剤。
（１３）前記高インスリン血症を示すか又は高インスリン血症の危険性のある患者が、インスリン抵抗性、糖代謝異常、及び／又は脂質代謝異常の症状を有する、（１２）に記載のＡｋｔ活性化抑制剤。
（１４）前記高インスリン血症を示すか又は高インスリン血症の危険性のある患者が、肥満、糖尿病、非アルコール性脂肪性肝炎に罹患している、（１２）に記載のＡｋｔ活性化抑制剤。
（１５）前記癌が、肝癌である、（１２）〜（１４）のいずれかに記載のＡｋｔ活性化抑制剤。
（１６）有効量のイソロイシン、ロイシン、及びバリンから選ばれる少なくとも１種の分岐鎖アミノ酸を被験体に投与することを含む、Ａｋｔ活性化の抑制方法。
（１７）Ａｋｔ活性化抑制剤の製造における、イソロイシン、ロイシン、及びバリンから選ばれる少なくとも１種の分岐鎖アミノ酸の使用。
（１８）イソロイシン、ロイシン、及びバリンから選ばれる少なくとも１種の分岐鎖アミノ酸および医薬として許容される担体を含有してなる医薬組成物、ならびに当該組成物をＡｋｔ活性化の抑制に使用し得るまたは使用すべきであることを記載した記載物を含む、商業的パッケージ。An object of the present invention is to provide a drug that suppresses the development and / or progression of cancer in a patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia by suppressing Akt activation. And
As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a composition containing at least one branched chain amino acid selected from isoleucine, leucine, and valine as an active ingredient has an effect of suppressing Akt activation. As a result, the present invention has been completed.
That is, the present invention is as follows:
(1) An Akt activation inhibitor comprising as an active ingredient at least one branched chain amino acid selected from isoleucine, leucine, and valine.
(2) The Akt activation inhibitor according to (1), comprising at least leucine.
(3) The Akt activation inhibitor according to (1), comprising three types of isoleucine, leucine, and valine.
(4) The Akt activation inhibitor according to (3), wherein the weight ratio of isoleucine, leucine, and valine is 1: 1.5 to 2.5: 0.8 to 1.7. .
(5) The use according to any one of (1) to (4), which is used for suppressing the occurrence and / or progression of cancer in a patient who exhibits hyperinsulinemia or is at risk for hyperinsulinemia. Akt activation inhibitor.
(6) The Akt according to (5), wherein the patient who exhibits or is at risk for hyperinsulinemia has symptoms of insulin resistance, abnormal glucose metabolism, and / or abnormal lipid metabolism. Activation inhibitor.
(7) Inhibition of Akt activation according to (5), wherein the patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia suffers from obesity, diabetes, non-alcoholic steatohepatitis Agent.
(8) The Akt activation inhibitor according to any one of (5) to (7), wherein the cancer is liver cancer.
(9) The Akt activation inhibitor (ie, apoptosis promoter) according to any one of (1) to (4), which is used for promoting apoptosis.
(10) The Akt activation inhibitor according to (9), wherein the promotion of apoptosis is due to suppression of apoptosis-suppressing gene expression.
(11) The Akt activation inhibitor according to (10), wherein the apoptosis suppressing gene is Mcl-1 or IAP-1.
(12) The Akt activation inhibitor according to (9), which is used for suppressing the occurrence and / or progression of cancer in a patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia.
(13) The Akt according to (12), wherein the patient who exhibits or is at risk for hyperinsulinemia has symptoms of insulin resistance, abnormal glucose metabolism, and / or abnormal lipid metabolism. Activation inhibitor.
(14) The suppression of Akt activation according to (12), wherein the patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia suffers from obesity, diabetes, non-alcoholic steatohepatitis Agent.
(15) The Akt activation inhibitor according to any one of (12) to (14), wherein the cancer is liver cancer.
(16) A method for inhibiting Akt activation, comprising administering an effective amount of at least one branched-chain amino acid selected from isoleucine, leucine, and valine to a subject.
(17) Use of at least one branched-chain amino acid selected from isoleucine, leucine, and valine in the production of an Akt activation inhibitor.
(18) A pharmaceutical composition comprising at least one branched-chain amino acid selected from isoleucine, leucine, and valine and a pharmaceutically acceptable carrier, and the composition can be used for inhibiting Akt activation or A commercial package containing a statement stating that it should be used.
図１は、ＨＥＫ２９３細胞の増殖に対する、ＢＣＡＡ混合物の抑制効果を示す。
図２は、Ａｋｔ活性化に対する、ロイシンの抑制効果を示す。
図３は、アポトーシス抑制遺伝子発現に対する、ＢＣＡＡ混合物の抑制効果を示す。FIG. 1 shows the inhibitory effect of the BCAA mixture on the growth of HEK293 cells.
FIG. 2 shows the inhibitory effect of leucine on Akt activation.
FIG. 3 shows the inhibitory effect of the BCAA mixture on apoptosis inhibitor gene expression.
以下に本発明の実施の形態について説明する。
「Ａｋｔ」とは、セリンスレオニンプロテインキナーゼＢ（ＰＫＢ）とも呼ばれ、リン酸化されることにより活性化する酵素であり、活性化したＡｋｔは、細胞内の種々の機構の調節に関与しており、例えば、インスリン刺激による細胞増殖の促進やアポトーシスの抑制などに関与していることが知られている（Ｌａｗｌｏｒ ＭＡ ａｎｄ Ａｌｅｓｓｉ ＤＲ．ＰＫＢ／Ａｋｔ，：ａ ｋｅｙ ｍｅｄｉａｔｏｒ ｏｆ ｃｅｌｌ ｐｒｏｌｉｆｅｒａｔｉｏｎ，ｓｕｒｖｉｖａｌ ａｎｄ ｉｎｓｕｌｉｎ ｒｅｓｐｏｎｓｅｓ？ Ｊ．Ｃｅｌｌ Ｓｃｉ．１１４：２９０３−２９１０；２００１）。従って、本明細書において「Ａｋｔ活性化」とは、Ａｋｔのリン酸化を指標とする。
本明細書中において「高インスリン血症を示すか又は高インスリン血症の危険性のある患者」とは、インスリン抵抗性、糖代謝異常、脂質代謝異常などの症状を有する患者のことをいい、例えば、肥満、糖尿病、非アルコール性脂肪性肝炎（ＮＡＳＨ）などに罹患した患者がこのような症状を有する。
「高インスリン血症」とは、血液中のインスリン量が正常値よりも異常に高い状態のことをいう。高インスリン血症は、インスリンの過剰シグナルによりＡｋｔの活性化を生じ、その結果として、癌（例えば、肝癌、膵癌、大腸癌、肺癌、胃癌、胆嚢・胆管癌、乳癌、子宮癌など）を引き起こす危険性がある。
ところで、癌は細胞の生と死のバランスが崩れた病態である。すなわち、正常な細胞ではＤＮＡに損傷が蓄積すると自らアポトーシスを誘導し細胞死に至るが、癌細胞においてはアポトーシスに対して耐性を獲得し細胞死を免れていることが明らかになってきており、これが癌発生進展の原因の１つと考えられている。アポトーシスを制御する経路は、ＴＮＦ−αなどのデスレセプター、ＪＵＮＫ、ｐ３８などのＭＡＰキナーゼ、Ｂｃｌ−２ファミリータンパク質、ｐ５３など各種知られているが、ＰＩ３Ｋ−Ａｋｔ経路も重要である。Ｂａｄ（Ｂｃｌ−２ ａｎｔａｇｏｎｉｓｔ ｏｆ ｃｅｌｌ ｄｅａｔｈ）は、Ｂｃｌ−２やＢｃｌ−ｘＬと結合してそれらを不活性化することでアポトーシスを誘導するが、ＡｋｔはＢａｄのＳｅｒ１３６をリン酸化して不活性化する。またＡｋｔは、ＪＮＫの上流であるＡＳＫ１（ａｐｏｐｔｏｓｉｓ ｓｉｇｎａｌ−ｒｅｇｕｌａｔｉｎｇ ｋｉｎａｓｅ １）のＳｅｒ８３をリン酸化することでその下流で誘導されるアポトーシスを抑制する。また、Ａｋｔは膜上で活性化すると一部が核に移行し、ＦＯＸＯ１，３，４をリン酸化して不活性化するが、ＦＯＸＯは、ＦａｓリガンドやＢｉｍ（Ｂｃｌ−２ ｉｎｔｅｒａｃｔｉｎｇ ｍｅｄｉａｔｏｒ ｏｆ ｃｅｌｌ ｄｅａｔｈ）といったアポトーシスを誘導する因子の転写を活性化するため、ＡｋｔによるＦＯＸＯの不活性化は、アポトーシスの抑制につながる。またｐ５３やｐ７３は、Ｂａｘ、Ｐｕｍａ、Ｎｏｘａなどのアポトーシス促進因子の転写を活性化するが、Ａｋｔはｐ５３やｐ７３に対して抑制的に働くことが知られている。すなわち、ｐ５３を負に制御しているＭＤＭ２（ｍｏｕｓｅ ｄｏｕｂｌｅ ｍｉｎｕｔｅ ２）をＡｋｔがリン酸化して活性を上昇させることや、ｐ７３のコアクチベーターであるＹＡＰ（ｙｅｓ−ａｓｓｏｃｉａｔｅｄ ｐｒｏｔｅｉｎ）をＡｋｔはリン酸化して核外移行を促すことによりアポトーシス促進因子の転写活性化が抑制される。さらには、転写因子ＮＦ−κＢは阻害因子であるＩκＢがＩＫＫによりリン酸化されることにより活性化されるが、ＡｋｔはＩＫＫをリン酸化して活性化する。ＮＦ−κＢはＩＡＰやＡ１およびＢｃｌ−ｘＬを転写活性化することでアポトーシスを抑制する（Ｒｏｍａｓｈｋｏｖａ，Ｊ．Ａ．，ａｎｄ Ｍａｋａｒｏｖ，Ｓ．Ｓ．（１９９９）ＮＦ−κＢ ｉｓ ａ ｔａｒｇｅｔ ｏｆ ＡＫＴ ｉｎ ａｎｔｉ−ａｐｏｐｔｏｔｉｃ ＰＤＧＦ ｓｉｇｎａｌｌｉｎｇ．Ｎａｔｕｒｅ ４０１：８６−９０、Ｃｈｕ ＺＬ，ＭｃＫｉｎｓｅｙ ＴＡ，Ｌｉｕ Ｌ，Ｇｅｎｔｒｙ ＪＪ，Ｍａｌｉｍ ＭＨ，ａｎｄ Ｂａｌｌａｒｄ ＤＷ（１９９７）Ｓｕｐｐｒｅｓｓｉｏｎ ｏｆ ｔｕｍｏｒ ｎｅｃｒｏｓｉｓ ｆａｃｔｏｒ−ｉｎｄｕｃｅｄ ｃｅｌｌ ｄｅａｔｈ ｂｙ ｉｎｈｉｂｉｔｏｒ ｏｆ ａｐｏｐｔｏｓｉｓ ｃ−ＩＡＰ２ ｉｓ ｕｎｄｅｒ ＮＦ−ｋａｐｐａＢ ｃｏｎｔｒｏｌ．Ｐｒｏｃ Ｎａｔｌ Ａｃａｄ Ｓｃｉ ＵＳＡ ９４：１００５７−１００６２）。また、ＡｋｔはＣＲＥＢ（ｃ ＡＭＰ−ｒｅｓｐｏｎｓｉｖｅ ｅｌｅｍｅｎｔ ｂｉｎｄｉｎｇ ｐｒｏｔｅｉｎ）のＳｅｒ１３３をリン酸化して活性化することが知られているが、ＣＲＥＢはアポトーシス抑制因子であるＢｃｌ−２やＭｃｌ−１の転写を活性化する（Ｔｈｅ ａｎｔｉａｐｏｐｔｏｔｉｃ ｇｅｎｅ ｍｃｌ−１ ｉｓ ｕｐ−ｒｅｇｕｌａｔｅｄ ｂｙ ｔｈｅ ｐｈｏｓｐｈａｔｉｄｙｌｉｎｏｓｉｔｏｌ３−ｋｉｎａｓｅ／Ａｋｔ ｓｉｇｎａｌｉｎｇ ｐａｔｈｗａｙ ｔｈｒｏｕｇｈ ａ ｔｒａｎｓｃｒｉｐｔｉｏｎ ｆａｃｔｏｒ ｃｏｍｐｌｅｘ ｃｏｎｔａｉｎｉｎｇ ＣＲＥＢ．Ｍｏｌ Ｃｅｌｌ Ｂｉｏｌ．１９９９ Ｓｅｐ；１９（９）：６１９５−２０６）。
このように、Ａｋｔは多くの段階、多様なターゲットでアポトーシスを抑制している。したがって、Ａｋｔの活性化を抑制することは、アポトーシスの抑制を解除することになり、癌発生抑制、進展抑制につながることが期待できる。よって、本発明のＡｋｔ活性化抑制剤は、アポトーシスの促進、癌発生または進展の抑制に用いることもでき、これらの態様も本発明の権利に包含される。
本発明の有効成分（分岐鎖アミノ酸）である、イソロイシン、ロイシン及びバリンは、それぞれ、Ｌ−体、Ｄ−体、ＤＬ−体のいずれも使用可能であるが、好ましくは、Ｌ−体、ＤＬ−体であり、さらに好ましくは、Ｌ−体である。
また、イソロイシン、ロイシン、及びバリンは、それぞれ、遊離体のみならず、塩の形態でも使用することができる。塩の形態としては、酸付加塩や塩基との塩等を挙げることもでき、イソロイシン、ロイシン、及びバリンの医薬品として許容される塩を選択することが好ましい。
イソロイシン、ロイシン、及びバリンにそれぞれ付加して医薬として許容される塩を形成する酸としては、例えば、塩化水素、臭化水素、硫酸、リン酸等の無機酸；酢酸、乳酸、クエン酸、酒石酸、マレイン酸、フマル酸、モノメチル硫酸等の有機酸が挙げられる。
イソロイシン、ロイシン、及びバリンにそれぞれ付加して医薬として許容される塩基を形成する塩基の例としては、例えば、ナトリウム、カリウム、カルシウム等の金属の水酸化物または炭酸化物、あるいはアンモニア等の無機塩基；エチレンジアミン、プロピレンジアミン、エタノールアミン、モノアルキルエタノールアミン、ジアルキルエタノールアミン、ジエタノールアミン、トリエタノールアミン等の有機塩基が挙げられる。
上記塩は水和物（含水塩）であってもよい。また、水和物としては、例えば１〜６水和物などが挙げられる。これらの塩、水和物も本発明の権利に包含されるものである。
本発明の薬剤は、イソロイシン、ロイシン、及びバリンのいずれか１種以上が分岐鎖アミノ酸として含有されていればよく、イソロイシン、ロイシン、及びバリンの３種全てが含有されていてもよい。
好適な実施形態では、本発明の薬剤は、少なくともロイシンを含有する。別の好適な実施形態では、本発明の製剤は、イソロイシン、ロイシン、及びバリンの３種全てを含有する。
イソロイシン、ロイシン、及びバリンの３種全てを用いる場合、イソロイシンと、ロイシンと、バリンの重量比は、１：１．５〜２．５：０．８〜１．７であり、特に１：１．９〜２．２：１．１〜１．３の範囲が好ましい。
本発明の薬剤の投与形態・剤型は、経口投与、非経口投与のいずれでもよく、経口投与剤としては、散剤、顆粒剤、カプセル剤、錠剤、チュアブル剤などの固形剤、溶液剤、シロップ剤などの液剤が、また、非経口投与剤としては、注射剤、スプレー剤などが挙げられる。
本発明の薬剤は、動物（好ましくは、ヒト等の哺乳動物）に投与することができる。
本発明の薬剤は、経口、注射、あるいは局所投与等の任意の投与方法によって投与することができる。
投与量は、対象患者の年齢、体重もしくは病態、剤形、または投与方法などによっても異なるが、通常１日量として、イソロイシン０．５〜３０．０ｇ、ロイシン１．０〜６０．０ｇ、バリン０．５〜３０．０ｇを目安とする。一般の成人の場合、好ましくは、一日量として、イソロイシン２．０〜１０．０ｇ、ロイシン３．０〜２０．０ｇ、バリン２．０〜１０．０ｇ、より好ましくは、イソロイシン２．５〜３．５ｇ、ロイシン５．０〜７．０ｇ、バリン３．０〜４．０ｇであり、アミノ酸の全体量としては１日当たり２．０ｇ〜５０．０ｇ程度が好ましく、これを１〜６回、好ましくは１〜３回に分割して投与する。
本発明の有効成分である分岐鎖アミノ酸の投与量（摂取量）について算出する際、その値は、本発明が目的とする疾患の治療または予防等の目的で使用される薬剤の有効成分の量として前記の算定方法が決められているので、これとは別目的で、例えば、通常の食生活の必要から、あるいは別の疾患の治療目的のために、摂取又は投与される分岐鎖アミノ酸については、前記算定に含める必要はない。
例えば、通常の食生活から摂取される一日あたりの分岐鎖アミノ酸の量を、前記本発明における有効成分の１日あたりの投与量から控除して算定する必要はない。
本発明の有効成分であるイソロイシン、ロイシン、及びバリンは、それぞれが単独で、若しくは任意の組合わせで製剤に含有されていてもよいし、全てが１種の製剤中に含有されていてもよい。別途製剤化して投与する場合、それらの投与経路、投与剤形は同一であっても、異なっていてもよい。また各々を投与するタイミングも、同時であっても別々であってもよい。これらは、併用する薬剤の種類や効果なども考慮して、適宜決定され得る。
即ち、本発明の薬剤は、２種以上の分岐鎖アミノ酸を含有する場合、複数の分岐鎖アミノ酸を同時に含有する製剤であってもよいし、それぞれを別途製剤化して併用するような併用剤であってもよく、これらの形態全てを包含するものである。特に、同一製剤中に全ての分岐鎖アミノ酸を含有する態様が、簡便に投与できるため好ましい。
本発明において、「重量比」とは、製剤中のそれぞれの成分の重量の比を示す。例えば、イソロイシン、ロイシンおよびバリンの各有効成分を１つの製剤中に含めた場合には、個々の含有量の比であり、各有効成分のそれぞれを単独でまたは任意の組み合わせで複数製剤中に含めた場合には、各製剤に含められる各有効成分の重量の比である。なお、本明細書中において各アミノ酸の重量は、遊離アミノ酸としてのものである。
また本発明において、実際の投与量の比は、投与対象（即ち患者）あたりの各有効成分１回投与量あるいは１日投与量の比である。例えば、イソロイシン、ロイシンおよびバリンの各有効成分を１つの製剤中に含め、それを投与対象に投与する場合には、重量比が投与量比に相当する。各有効成分を単独でまたは任意の組み合わせで複数の製剤中に含めて投与する場合には、１回あるいは１日投与した各製剤中の各有効成分の合計量の比が重量比に相当する。
イソロイシン、ロイシン、およびバリンは既に、医薬・食品分野において広く用いられていて、安全性は確立している。例えば、これらのアミノ酸を１：２：１．２の比で含有する製剤の急性毒性（ＬＤ５０）は、マウスの経口投与において１０ｇ／Ｋｇ以上である。
本発明の薬剤は、通常の方法によって、散剤、顆粒剤、カプセル剤、錠剤、チュアブル剤などの固形剤、溶液剤、シロップ剤などの液剤、または、注射剤、スプレー剤などに製剤化することができる。
このような製剤は、必要に応じて、薬学的に許容される担体、例えば、賦形剤、結合剤、滑沢剤、溶剤、崩壊剤、溶解補助剤、懸濁化剤、乳化剤、等張化剤、安定化剤、無痛化剤、防腐剤、抗酸化剤、矯味矯臭剤、着色剤などを配合される。
賦形剤としては、乳糖、ブドウ糖、Ｄ−マンニトールなどの糖類、でんぷん類、結晶セルロースなどのセルロース類などの有機系賦形剤、炭酸カルシウム、カオリンなどの無機系賦形剤などが挙げられる。
結合剤としては、α化デンプン、ゼラチン、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、Ｄ−マンニトール、トレハロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコールなどが挙げられる。
滑沢剤としては、ステアリン酸、ステアリン酸塩などの脂肪酸塩、タルク、珪酸塩類などが挙げられる。
溶剤としては、精製水、生理的食塩水などが挙げられる。
崩壊剤としては、低置換度ヒドロキシプロピルセルロース、化学修飾されたセルロースやデンプン類などが挙げられる。
溶解補助剤としては、ポリエチレングリコール、プロピレングリコール、トレハロース、安息香酸ベンジル、エタノール、炭酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム、酢酸ナトリウムなどが挙げられる。
懸濁化剤あるいは乳化剤としては、ラウリル硫酸ナトリウム、アラビアゴム、ゼラチン、レシチン、モノステアリン酸グリセリン、ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウムなどのセルロース類、ポリソルベート類、ポリオキシエチレン硬化ヒマシ油などが挙げられる。
等張化剤としては、塩化ナトリウム、塩化カリウム、糖類、グリセリン、尿素などが挙げられる。
安定化剤としては、ポリエチレングリコール、デキストラン硫酸ナトリウム、その他のアミノ酸類などが挙げられる。
無痛化剤としては、ブドウ糖、グルコン酸カルシウム、塩酸プロカインなどが挙げられる。
防腐剤としては、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸などが挙げられる。
抗酸化剤としては、亜硫酸塩、アスコルビン酸などが挙げられる。
矯味矯臭剤としては、医薬および食品分野において通常に使用される甘味料、香料などが挙げられる。
着色剤としては、医薬および食品分野において通常に使用される着色料が挙げられる。
本発明のＡｋｔ抑制剤には、他の薬剤、例えば、糖尿病用剤、高脂血症治療剤、高血圧用治療剤、肝臓病用剤、抗がん剤（例えば、カルボプラチン、テガフール、パクリタキセル、酢酸リュープロレリンなど）などを配合してもよい。
以下の実施例により本発明をより具体的に説明するが、実施例は本発明の単なる例示を示すものにすぎず、本発明の範囲を何ら限定するものではない。Embodiments of the present invention will be described below.
“Akt”, also called serine threonine protein kinase B (PKB), is an enzyme that is activated by phosphorylation. Activated Akt is involved in the regulation of various intracellular mechanisms. For example, it is known to be involved in the promotion of cell proliferation and suppression of apoptosis by insulin stimulation (Lawlor MA and Alessi DR. PKB / Akt, a key mediator of cell proliferation, survival and insulin responses?). J. Cell Sci. 114: 2903-2910; Therefore, in the present specification, “Akt activation” uses Akt phosphorylation as an index.
As used herein, “a patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia” refers to a patient having symptoms such as insulin resistance, abnormal glucose metabolism, and abnormal lipid metabolism. For example, patients suffering from obesity, diabetes, non-alcoholic steatohepatitis (NASH), etc. have such symptoms.
“Hyperinsulinemia” refers to a state in which the amount of insulin in the blood is abnormally higher than the normal value. Hyperinsulinemia results in activation of Akt due to an excessive signal of insulin, resulting in cancer (eg, liver cancer, pancreatic cancer, colon cancer, lung cancer, stomach cancer, gallbladder / bile duct cancer, breast cancer, uterine cancer, etc.) There is a risk.
By the way, cancer is a pathological condition in which the balance between cell life and death is lost. That is, when normal cells accumulate damage in DNA, they induce apoptosis and lead to cell death. However, cancer cells have acquired resistance to apoptosis and have escaped cell death. It is considered one of the causes of cancer development. There are various known pathways for controlling apoptosis, such as death receptors such as TNF-α, MAP kinases such as JUNK and p38, Bcl-2 family proteins, and p53, but the PI3K-Akt pathway is also important. Bad (Bcl-2 antagonist of cell death) binds to Bcl-2 and Bcl-x L and inactivates them to induce apoptosis, but Akt phosphorylates Bad Ser136 to inactivate it Turn into. Akt also suppresses apoptosis induced downstream by phosphorylating Ser83 of ASK1 (apoptosis signal-regulating kinase 1) upstream of JNK. In addition, when Akt is activated on the membrane, a part thereof moves to the nucleus and phosphorylates FOXO1, 3 and 4 to inactivate FOXO, but Fax ligand and Bim (Bcl-2 interacting mediator of cell death). Inactivation of FOXO by Akt leads to suppression of apoptosis. In addition, p53 and p73 activate transcription of pro-apoptotic factors such as Bax, Puma, and Noxa, but Akt is known to act suppressively on p53 and p73. That is, Akt phosphorylates MDM2 (mouse double minute 2), which regulates p53 negatively, and increases the activity, and Akt phosphorylates p73 coactivator YAP (yes-associated protein) Thus, the transcriptional activation of the proapoptotic factor is suppressed by promoting nuclear export. Furthermore, the transcription factor NF-κB is activated by phosphorylating the inhibitor IκB by IKK, whereas Akt phosphorylates IKK and activates it. NF-κB suppresses apoptosis by transcriptionally activating IAP, A1 and Bcl-x L (Romashkova, JA, and Makarov, SS (1999) NF-κB is a target of AKT in anti-apoptotic PDGF signalling.Nature 401: 86-90, Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, and Ballard DW (1997) Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control Proc Natl Acad Sci U A 94: 10057-10062). In addition, Akt is known to phosphorylate and activate Ser133 of CREB (c AMP-responsive element binding protein), while CREB activates transcription of Bcl-2 and Mcl-1, which are apoptosis inhibitors. (The antipopative gene mcl-1 is up-regulated by the phosphatidylinosideol 3-Kinase / Akt signaling pathway through the transcript.
Thus, Akt suppresses apoptosis at many stages and various targets. Therefore, suppressing the activation of Akt cancels the suppression of apoptosis, and can be expected to lead to the suppression of cancer occurrence and the suppression of progression. Therefore, the Akt activation inhibitor of the present invention can also be used for promoting apoptosis, suppressing cancer development or progression, and these aspects are also encompassed by the right of the present invention.
The active ingredient (branched chain amino acid) of the present invention, isoleucine, leucine and valine, can be used in any of L-form, D-form and DL-form, respectively, preferably L-form and DL-form. -Form, more preferably L-form.
In addition, isoleucine, leucine, and valine can be used not only in free form but also in salt form. Examples of the salt form include acid addition salts and salts with bases, and it is preferable to select pharmaceutically acceptable salts of isoleucine, leucine, and valine.
Examples of the acid that is added to isoleucine, leucine, and valine to form a pharmaceutically acceptable salt include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; acetic acid, lactic acid, citric acid, and tartaric acid. And organic acids such as maleic acid, fumaric acid and monomethyl sulfuric acid.
Examples of bases that are added to isoleucine, leucine, and valine to form a pharmaceutically acceptable base include, for example, metal hydroxides or carbonates such as sodium, potassium, calcium, or inorganic bases such as ammonia. An organic base such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine;
The salt may be a hydrate (hydrated salt). Moreover, as a hydrate, 1-6 hydrate etc. are mentioned, for example. These salts and hydrates are also included in the rights of the present invention.
Any one or more of isoleucine, leucine, and valine may be contained as a branched chain amino acid in the drug of the present invention, and all three kinds of isoleucine, leucine, and valine may be contained.
In a preferred embodiment, the agent of the present invention contains at least leucine. In another preferred embodiment, the formulations of the present invention contain all three of isoleucine, leucine, and valine.
When all three types of isoleucine, leucine, and valine are used, the weight ratio of isoleucine, leucine, and valine is 1: 1.5 to 2.5: 0.8 to 1.7, particularly 1: 1. .9 to 2.2: The range of 1.1 to 1.3 is preferable.
The dosage form and dosage form of the drug of the present invention may be either oral administration or parenteral administration. Examples of the oral administration agent include solid agents such as powders, granules, capsules, tablets and chewable agents, solutions and syrups. Examples of the liquid preparation such as an agent and parenteral administration agents include injections and sprays.
The agent of the present invention can be administered to animals (preferably, mammals such as humans).
The agent of the present invention can be administered by any administration method such as oral, injection, or topical administration.
The dose varies depending on the age, body weight or pathological condition, dosage form, administration method, etc. of the subject patient, but usually the daily dose is 0.5 to 30.0 g isoleucine, 1.0 to 60.0 g leucine, valine The standard is 0.5 to 30.0 g. In the case of general adults, preferably, as a daily dose, isoleucine 2.0-10.0 g, leucine 3.0-20.0 g, valine 2.0-10.0 g, more preferably isoleucine 2.5- 3.5 g, leucine 5.0 to 7.0 g, valine 3.0 to 4.0 g, and the total amount of amino acids is preferably about 2.0 g to 50.0 g per day, and this is 1 to 6 times. Preferably, it is administered in 1 to 3 divided doses.
When calculating the dose (intake amount) of the branched chain amino acid which is the active ingredient of the present invention, the value is the amount of the active ingredient of the drug used for the purpose of treatment or prevention of the disease targeted by the present invention. As for the branched chain amino acids to be ingested or administered for other purposes, for example, from the necessity of normal eating habits, or for the purpose of treating other diseases. Need not be included in the calculation.
For example, it is not necessary to calculate by subtracting the amount of branched-chain amino acids per day taken from a normal diet from the daily dose of the active ingredient in the present invention.
The active ingredients of the present invention, isoleucine, leucine, and valine, may be contained alone or in any combination in the preparation, or all may be contained in one kind of preparation. . When separately formulated and administered, their administration route and dosage form may be the same or different. Moreover, the timing which administers each may be simultaneous, or may be separate. These can be determined as appropriate in consideration of the types and effects of the drugs used in combination.
That is, when the drug of the present invention contains two or more kinds of branched chain amino acids, it may be a preparation containing a plurality of branched chain amino acids at the same time. It is possible to include all these forms. In particular, an embodiment containing all branched-chain amino acids in the same preparation is preferable because it can be easily administered.
In the present invention, the “weight ratio” indicates the weight ratio of each component in the preparation. For example, when each active ingredient of isoleucine, leucine and valine is included in one preparation, it is the ratio of individual contents, and each active ingredient is included in multiple preparations alone or in any combination The ratio of the weight of each active ingredient included in each formulation. In the present specification, the weight of each amino acid is a free amino acid.
In the present invention, the actual dose ratio is the ratio of a single dose or daily dose of each active ingredient per administration subject (ie, patient). For example, when each active ingredient of isoleucine, leucine and valine is included in one preparation and is administered to an administration subject, the weight ratio corresponds to the dose ratio. When each active ingredient is administered alone or in any combination in a plurality of preparations, the ratio of the total amount of each active ingredient in each preparation administered once or daily corresponds to the weight ratio.
Isoleucine, leucine, and valine have already been widely used in the fields of medicine and food, and safety has been established. For example, the acute toxicity (LD 50 ) of a formulation containing these amino acids in a ratio of 1: 2: 1.2 is 10 g / Kg or more when administered orally to mice.
The drug of the present invention should be formulated into a solid agent such as powder, granule, capsule, tablet, chewable agent, solution such as solution, syrup, or injection, spray, etc. by a conventional method. Can do.
Such preparations may be pharmaceutically acceptable carriers, for example, excipients, binders, lubricants, solvents, disintegrants, solubilizers, suspending agents, emulsifiers, isotonic agents. An agent, a stabilizer, a soothing agent, an antiseptic, an antioxidant, a flavoring agent, a coloring agent, and the like are added.
Examples of the excipient include sugars such as lactose, glucose and D-mannitol, organic excipients such as starches and celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin.
Examples of the binder include pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol.
Examples of the lubricant include fatty acid salts such as stearic acid and stearate, talc, and silicates.
Examples of the solvent include purified water and physiological saline.
Examples of the disintegrant include low-substituted hydroxypropyl cellulose, chemically modified cellulose and starches.
Examples of the solubilizer include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like.
Examples of suspending agents or emulsifiers include sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, polysorbates, polyoxyethylene hydrogenated castor oil, and the like. Can be mentioned.
Examples of isotonic agents include sodium chloride, potassium chloride, saccharides, glycerin, urea and the like.
Examples of the stabilizer include polyethylene glycol, sodium dextran sulfate, and other amino acids.
Examples of soothing agents include glucose, calcium gluconate, procaine hydrochloride and the like.
Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
Examples of the antioxidant include sulfite and ascorbic acid.
Examples of the flavoring agent include sweeteners and fragrances commonly used in the pharmaceutical and food fields.
Examples of the colorant include colorants commonly used in the pharmaceutical and food fields.
Examples of the Akt inhibitor of the present invention include other drugs such as diabetes, hyperlipidemia, hypertension, liver, and anticancer agents (for example, carboplatin, tegafur, paclitaxel, acetic acid). Leuprorelin etc.) may also be blended.
The present invention will be described more specifically with reference to the following examples. However, the examples are merely illustrative of the present invention and do not limit the scope of the present invention.
［実施例１］
Ｓｕｂｃｏｎｆｌｕｅｎｔに培養したＨＥＫ２９３細胞をトリプシン処理し、ＤＭＥＭ＋１０％ＦＣＳ培地中に１ｘ１０５ｃｅｌｌｓ／ｍｌで懸濁し、得られた懸濁液を１ｗｅｌｌあたり１００μｌずつ９６ｗｅｌｌ ｐｌａｔｅにまいた。ＤＭＥＭ＋１０％ＦＣＳ培地で１晩培養後、コントロール群（ｎ＝４）は、ＤＭＥＭ＋１０％ＦＣＳ培地に交換し、５ｍＭ ＢＣＡＡ群（ｎ＝４）は、イソロイシン、ロイシン、及びバリンを重量比１：２：１．２で含有する５ｍＭ ＢＣＡＡ混合物をＤＭＥＭ＋１０％ ＦＣＳに添加した培地に交換し、さらに３日間培養した。培養終了後、Ｃｅｌｌ Ｃｏｕｎｔｉｎｇ Ｋｉｔ−８（和光純薬）を用いてプロトコール通りに細胞数を測定した。
結果を、コントロール群のＯＤ値からバックグラウンドのＯＤ値を引いた値を１００％として、％ ｏｆ ｃｏｎｔｒｏｌとして表す（図１）。図１に示されるように、イソロイシン、ロイシン、及びバリンから構成されるＢＣＡＡ混合物は、有意にＨＥＫ２９３細胞の増殖を抑制した。
［実施例２］
Ｓｕｂｃｏｎｆｌｕｅｎｔに培養したＨ４ＩＩＥ細胞をトリプシン処理し、ＤＭＥＭ＋１０％ＦＣＳ培地中に１ｘ１０５ｃｅｌｌｓ／ｍｌで懸濁し、得られた懸濁液を１ｗｅｌｌあたり１ｍｌずつ２４ｗｅｌｌ ｐｌａｔｅにまいた。ＤＭＥＭ＋１０％ＦＣＳ培地で４時間培養後、以下の５群に分けて、１晩培養した：
（１）ＤＭＥＭ ＦＣＳ（−）培地（ｎ＝２）；
（２）ＤＭＥＭ ＦＣＳ（−）＋インスリン １ｎＭ（ｎ＝２）；
（３）ＤＭＥＭ ＦＣＳ（−）＋インスリン １ｎＭ＋ロイシン ３ｍＭ（ｎ＝２）；
（４）ＤＭＥＭ ＦＣＳ（−）＋インスリン １０ｎＭ（ｎ＝２）；
（５）ＤＭＥＭ ＦＣＳ（−）＋インスリン １０ｎＭ＋ロイシン ３ｍＭ（ｎ＝２）。
培養終了後、ＰａｔｈＳｃａｎ Ｐｈｏｓｐｈｏ−Ａｋｔ１（Ｓｅｒ４７３）
Ｓａｎｄｗｉｃｈ ＥＬＩＳＡ ｋｉｔ（Ｃｅｌｌ Ｓｉｇｎａｌｉｎｇ Ｔｅｃｈｎｏｌｏｇｙ）を用いて、プロトコール通りにリン酸化Ａｋｔを定量した。
結果を図２に示す。Ａｋｔは、インスリン １ｎＭ、１０ｎＭ（図２の（２）及び（４））で用量依存的に活性化されたが、ロイシンは、これらの活性化を抑制した（図２の（３）及び（５））。
［実施例３］
Ｈ４ＩＩＥ細胞をＤ−ＭＥＭ＋１０％ＦＢＳ培地で４×１０５個／ｗｅｌｌで１２ウェルプレートにまき、一晩培養した。翌日Ｄ−ＭＥＭ ＦＣＳ（−）培地に交換し、さらに一晩培養した。
Ｍｃｌ−１：ｓｅｎｓｅ：ＴＧＧＡＣＡＴＴＡＡＡＡＡＣＧＡＧＧＡＣＧ（配列番号：１）
ａｎｔｉｓｅｎｓｅ：ＡＡＧＡＡＣＴＣＣＡＣＡＡＡＣＣＣＡＴＣＣ（配列番号：２）
ＩＡＰ−１：ｓｅｎｓｅ：ｃｇａｇｇａｇｇａｇｇａｇｔｃａｇａｔｇ（配列番号：３）
ａｎｔｉｓｅｎｓｅ：ｇｃａｃｔｔａｇｇａｇｇｃａａｔｃｃａｇ（配列番号：４）
結果はｈｏｕｓｅ ｋｅｅｐｉｎｇ ｇｅｎｅ（Ｒｐｌ３６）の発現量で割り返して、インスリンなし、ＢＣＡＡなし、又はＩＧＦ−１なし、ＢＣＡＡなしの時の値を１００％として％ ｏｆ ｃｏｎｔｒｏｌで表示した（図３）。イソロイシン、ロイシン、及びバリンから構成されるＢＣＡＡ混合物は、アポトーシス抑制遺伝子Ｍｃｌ−１およびＩＡＰ−１の発現を抑制した。[Example 1]
HEK293 cells cultured in Subconfluent were trypsinized, suspended in DMEM + 10% FCS medium at 1 × 10 5 cells / ml, and the resulting suspension was spread on a 96-well plate at 100 μl per well. After overnight culture in DMEM + 10% FCS medium, the control group (n = 4) was replaced with DMEM + 10% FCS medium, and the 5 mM BCAA group (n = 4) contained isoleucine, leucine and valine in a weight ratio of 1: 2: The 5 mM BCAA mixture contained in 1.2 was replaced with a medium supplemented with DMEM + 10% FCS, and further cultured for 3 days. After completion of the culture, the number of cells was measured according to the protocol using Cell Counting Kit-8 (Wako Pure Chemical Industries).
The result is expressed as% of control with the value obtained by subtracting the background OD value from the OD value of the control group as 100% (FIG. 1). As shown in FIG. 1, the BCAA mixture composed of isoleucine, leucine, and valine significantly suppressed the growth of HEK293 cells.
[Example 2]
H4IIE cells cultured in Subconfluent were trypsinized, suspended in DMEM + 10% FCS medium at 1 × 10 5 cells / ml, and the resulting suspension was spread on a 24 well plate, 1 ml per well. After culturing in DMEM + 10% FCS medium for 4 hours, divided into the following 5 groups and cultured overnight:
(1) DMEM FCS (−) medium (n = 2);
(2) DMEM FCS (−) +
(3) DMEM FCS (−) +
(4) DMEM FCS (−) + insulin 10 nM (n = 2);
(5) DMEM FCS (−) + insulin 10 nM +
After the cultivation, PathScan Phospho-Akt1 (Ser473)
Using a Sandwich ELISA kit (Cell Signaling Technology), phosphorylated Akt was quantified according to the protocol.
The results are shown in FIG. Akt was activated in a dose-dependent manner with
[Example 3]
H4IIE cells were seeded in 12-well plates at 4 × 10 5 cells / well in D-MEM + 10% FBS medium and cultured overnight. The next day, the medium was replaced with D-MEM FCS (−) medium, and further cultured overnight.
Mcl-1: sense: TGGACATTAAAAACGAGGACG (SEQ ID NO: 1)
antisense: AAGACTACTCACAAAACCCATCC (SEQ ID NO: 2)
IAP-1: sense: cgaggaggagggagtcagatag (SEQ ID NO: 3)
antisense: gcacttaggaggcaatccag (SEQ ID NO: 4)
The results were divided by the expression level of housekeeping gene (Rpl36) and expressed in% of control with the value at the time of no insulin, no BCAA, no IGF-1 and no BCAA as 100% (FIG. 3). A BCAA mixture composed of isoleucine, leucine, and valine suppressed the expression of apoptosis-suppressing genes Mcl-1 and IAP-1.
本発明により提供される、イソロイシン、ロイシン、及びバリンから選ばれる少なくとも１種の分岐鎖アミノ酸を有効成分とするＡｋｔ活性化抑制剤は、高インスリン血症を示すか又は高インスリン血症の危険性のある患者における癌の発生及び／又は進展を抑制する。
本発明の薬剤は、アミノ酸を有効成分とすることから、安全性が高く、副作用がほとんどないため長期間にわたって投与可能であり、高インスリン血症を示すか又は高インスリン血症の危険性のある患者が癌発生に至るまでの長期経過における予防または治療に有利に用いることができる。
本出願は、日本で出願された特願２００５−２２７７８０（出願日：２００５年８月５日）を基礎としており、その内容は本明細書に全て包含されるものである。
［配列表］
Since the drug of the present invention contains an amino acid as an active ingredient, it is highly safe and can be administered over a long period because it has almost no side effects, and exhibits hyperinsulinemia or is at risk of hyperinsulinemia. It can be advantageously used for prevention or treatment in the long-term course until a patient develops cancer.
This application is based on Japanese Patent Application No. 2005-227780 filed in Japan (filing date: August 5, 2005), the contents of which are incorporated in full herein.
[Sequence Listing]
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| PCT/JP2006/315897 WO2007018281A1 (en) | 2005-08-05 | 2006-08-04 | Akt ACTIVATION INHIBITOR |
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| JPH06256184A (en) * | 1993-03-05 | 1994-09-13 | Morishita Roussel Kk | Amino acid preparation for cancer patient |
| JP2003171271A (en) * | 2001-09-26 | 2003-06-17 | Ajinomoto Co Inc | Medicine for glucose tolerance disorder |
| JP2003238401A (en) * | 2002-02-20 | 2003-08-27 | Ajinomoto Co Inc | Medicine and food and beverage for treating, curing or preventing disease |
| WO2004058243A1 (en) * | 2002-12-26 | 2004-07-15 | Ajinomoto Co., Inc. | Inhibitor for liver cancer onset and progress |
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2006
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06256184A (en) * | 1993-03-05 | 1994-09-13 | Morishita Roussel Kk | Amino acid preparation for cancer patient |
| JP2003171271A (en) * | 2001-09-26 | 2003-06-17 | Ajinomoto Co Inc | Medicine for glucose tolerance disorder |
| JP2003238401A (en) * | 2002-02-20 | 2003-08-27 | Ajinomoto Co Inc | Medicine and food and beverage for treating, curing or preventing disease |
| WO2004058243A1 (en) * | 2002-12-26 | 2004-07-15 | Ajinomoto Co., Inc. | Inhibitor for liver cancer onset and progress |
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| Title |
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| JPN6012027272; ＮＡＩＲ，Ｋ．Ｓ． ｅｔ ａｌ: 'Ｈｏｒｍｏｎａｌ ａｎｄ ｓｉｇｎａｌｉｎｇ ｒｏｌｅ ｏｆ ｂｒａｎｃｈｅｄ-ｃｈａｉｎ ａｍｉｎｏ ａｃｉｄｓ' Ｊ Ｎｕｔｒ Ｖｏｌ．１３５， Ｎｏ．６ Ｓｕｐｐｌ, 2005, ｐ．１５４７Ｓ-５２Ｓ * |
| JPN6012027276; ＪＯＵＶＥＴ，Ｐ． ｅｔ ａｌ: 'Ｂｒａｎｃｈｅｄ ｃｈａｉｎ ａｍｉｎｏ ａｃｉｄｓ ｉｎｄｕｃｅ ａｐｏｐｔｏｓｉｓ ｉｎ ｎｅｕｒａｌ ｃｅｌｌｓ ｗｉｔｈｏｕｔ ｍｉｔｏｃｈｏｎｄｒｉａｌ ｍｅｍｂｒａｎｅ ｄｅｐｏｌａｒｉｚ' Ｍｏｌ Ｂｉｏｌ Ｃｅｌｌ Ｖｏｌ．１１， Ｎｏ．５, 2000, ｐ．１９１９-３２ * |
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