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WO2007018281A1 - INHIBITEUR DE L'ACTIVATION DE L’Akt - Google Patents

INHIBITEUR DE L'ACTIVATION DE L’Akt Download PDF

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Publication number
WO2007018281A1
WO2007018281A1 PCT/JP2006/315897 JP2006315897W WO2007018281A1 WO 2007018281 A1 WO2007018281 A1 WO 2007018281A1 JP 2006315897 W JP2006315897 W JP 2006315897W WO 2007018281 A1 WO2007018281 A1 WO 2007018281A1
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WO
WIPO (PCT)
Prior art keywords
hyperinsulinemia
akt activation
leucine
activation inhibitor
cancer
Prior art date
Application number
PCT/JP2006/315897
Other languages
English (en)
Japanese (ja)
Inventor
Sonoko Ishizaki
Asami Kawakami
Original Assignee
Ajinomoto Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co., Inc. filed Critical Ajinomoto Co., Inc.
Priority to JP2007529634A priority Critical patent/JP5217436B2/ja
Publication of WO2007018281A1 publication Critical patent/WO2007018281A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a novel Akt activation inhibitor and a drug for suppressing the occurrence and Z or progression of cancer in a patient exhibiting or at risk for hyperinsulinemia.
  • Obesity is known to cause lifestyle-related diseases such as diabetes, hypertension, and hyperlipidemia.
  • visceral fat obesity tends to cause abnormal glucose tolerance and insulin resistance, and body fat mass and insulin resistance show a significant positive correlation.
  • obese model animals ob / ob mice and Zucke rfaty rats
  • severe hyperinsulinemia / serum is observed with obesity.
  • obese individuals have high blood insulin levels on an empty stomach, and insulin responses after glucose loading are also increased.
  • insulin levels in obese subjects are high at any time (Fuj.ioka S, Matsuzawa Y, Tokunaga K, et al. Contribution of intra- abdominal fat accumulation to the irapairra nt of glucose and lipid metabolism in human obesity. Metabolism 36: 54 19 87).
  • the characteristic pathology of type 2 diabetes is a decrease in insulin action, but it has been reported that an increase in blood insulin concentration during fasting and glucose loading is observed over a long period of time before the onset of diabetes (Mertin BC , Warram JH, et al. Role of glucose and insulin resistance in development of type 2 diabetes mell itus ⁇ result s of a 25-year follow-up study. Lancet 340: 925-929 1992).
  • diabetes was the number one risk factor for cancer (Na th et a ⁇ . Fasting Serum Glucose Level ana Cancer Risk in Korean Men and Women, JAMA. 2005; 293: 2210-2211) .
  • Hyperinsulinemia is envisioned as one of the mechanisms of carcinogenesis in diabetes and obesity. It is well known that insulin has a cell proliferation effect (Gupt a K, rishnaswamy G, Karnad A, Peiris AN. Insulin: A novel factor in care inogenesis. Am. J. Med. Sci 323: 140_145; 2002), the mitogenic action works via the IGF-1 and insulin receptors, but this action is more likely to occur when blood insulin levels are higher than normal. A kt has been reported as one of the molecules responsible for cell proliferation in insulin signals (La or MA and Alessi DR. PKB / Akt, a key mediator of cell proliferation, sur vival and insulin responses). J. Cell Sci. 114: 2903-2910; 2001). Disclosure of the invention
  • the present invention provides a drug that suppresses the onset or progression of cancer in a patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia by inhibiting Akt activation. Objective.
  • the present inventor has a composition containing at least one branched chain amino acid selected from isoleucine, oral isine, and parin as an active ingredient, which suppresses Akt activation. As a result, the present invention has been completed.
  • the present invention is as follows:
  • An Akt activation inhibitor comprising at least one branched chain amino acid selected from isoleucine, leucine, and valine as an active ingredient.
  • the Akt activation inhibitor according to (1) comprising at least leucine.
  • the Akt activation inhibitor according to (1) comprising three types of isoleucine, leucine, and parin.
  • a patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia 1 suffers from obesity, diabetes, non-alcoholic steatohepatitis, suppression of A kt activation according to (5) Agent.
  • Akt activation inhibitor according to any one of (5) to (7), wherein the cancer is liver cancer.
  • the patient who exhibits or is at risk for hyperinsulinemia has symptoms of insulin resistance, abnormal glucose metabolism, and abnormal Z or lipid metabolism, (1)
  • a method for inhibiting Akt activation comprising administering to a subject an effective amount of at least one branched chain amino acid selected from isoleucine, leucine, and valine.
  • a pharmaceutical composition comprising at least one branched chain amino acid selected from isoleucine, leucine, and parin and a pharmaceutically acceptable carrier, and the composition is used to inhibit Akt activation.
  • Figure 1 shows the inhibitory effect of the BCA A mixture on the proliferation of ⁇ 293 cells.
  • Figure 2 shows the inhibitory effect of leucine on Akt activation.
  • Figure 3 shows the inhibitory effect of the BCAA mixture on apoptosis inhibitor gene expression.
  • Akt serine threonine protein kinase B
  • P KB serine threonine protein kinase B
  • Akt activation refers to phosphorylation of Ak t as an index.
  • a patient who exhibits hyperinsulinemia or is at risk of hyperinsulinemia refers to a patient having symptoms such as insulin resistance, abnormal glucose metabolism, abnormal lipid metabolism, For example, patients suffering from obesity, diabetes, non-alcoholic steatohepatitis (NASH), etc. have such symptoms.
  • NASH non-alcoholic steatohepatitis
  • “Hyperinsulinemia” refers to a condition in which the amount of insulin in the blood is abnormally higher than normal. Hyperinsulinemia results in Akt activation due to excessive insulin signal, resulting in cancer (eg liver cancer, vaginal cancer, colon cancer, lung cancer, stomach cancer, gallbladder 'bile duct cancer, breast cancer, uterine cancer, etc.) There is a risk of causing.
  • cancer eg liver cancer, vaginal cancer, colon cancer, lung cancer, stomach cancer, gallbladder 'bile duct cancer, breast cancer, uterine cancer, etc.
  • cancer is a condition in which the balance between cell life and death is lost. That is, it is becoming clear that in normal cells, when damage accumulates in DNA, it induces apoptosis itself and leads to cell death. Cancer cells have acquired resistance to apoptosis and escaped cell death. This is considered one of the causes of cancer development. There are various known pathways that control apoptosis, such as death receptors such as TNF-chicken, MAP kinases such as JUNK, p 3 8, Be 1 -2 family protein, and p 53, but PI 3 K-Ak t Economics are also important.
  • B ad Bel-2 antagonist of cell death binds to B c 1 -2 and B e 1-x L and inactivates them to induce apoptosis.
  • erl 36 is phosphorylated and inactivated.
  • Ak t is an AS K 1 (apoptosis) upstream of J NK.
  • Phosphorylation of Sr83 of signal-regulating kinase 1) suppresses apoptosis induced downstream of it.
  • Akt is activated on the membrane, part of it translocates to the nucleus and phosphorylates FOXO 1, 3, and 4 to inactivate it.
  • Inactivation of FOXO by Akt leads to suppression of apoptosis because it activates transcription of factors that induce apoptosis such as mediator of cell death.
  • P 53 and p 73 are B ax
  • P It activates transcription of pro-apoptotic factors such as uma s N oxa, but Ak t is known to act in a suppressive manner on p53 and p73.
  • Akt phosphorylates MDM2 (mouse double minute 2), which controls p53 negatively, to increase its activity
  • YAP yes-associated protein
  • the transcription factor NF-KB is activated by phosphorylating the inhibitor I ⁇ B by IKK, while Akt phosphorylates IKK and activates it.
  • N F-KB suppresses apoptosis by activating IAP, A 1 and B c 1 _x L.
  • NF- ⁇ is a target of AKT in anti -apoptotic PDGF signaling.
  • Ak t is known to phosphorylate and activate Serbl 33 of CREB (c AMP-responsive element binding protein), but CR EB is an apoptosis inhibitor B c 1-2 And activate transcription of M'c 1 -1
  • the antiapoptotic gene tncl-1 is up-regulated by the phosphatidyl inositol 3 kinase / Akt signaling pathway through a transcription factor complex, containing CREB. Mol Cell Biol. 1999 Sep; 19 (9): 6195-206).
  • Akt suppresses apoptosis at many stages and various targets. Therefore, suppressing the activation of Akt will release the suppression of apoptosis, and it can be expected to lead to the suppression of cancer development and 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.
  • Isoleucine, leucine, and valine which are the active ingredients (branched chain amino acid) 'of the present invention, can be used in any of L-integral, D-isomer, and DL-isomer, respectively.
  • DL-body and more preferably L-integral.
  • 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 salts that are acceptable as pharmaceuticals for isoleucine, leucine, and parin.
  • acids that are added to isoleucine, leucine, and parin to form pharmaceutically acceptable salts include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; acetic acid, lactic acid, knnic acid, Organic acids such as tartaric acid, maleic acid, fumaric acid, and monomethyl sulfuric acid are listed. .
  • bases that are added to isoleucine, leucine, and parin to form pharmaceutically acceptable bases include, for example, hydroxides or carbonates of metals such as sodium, potassium, calcium, and ammonia.
  • inorganic bases such as ethylenediamine, propylenediamine, ethanolamine, monoalkylethanolanolamine, dianolenoethanolamine, diethanolamine, and 'triethanolanolamine.
  • the salt may be a hydrate (hydrous salt).
  • hydrates include 1 to 6 hydrates. These salts and hydrates are also included in the rights of the present invention.
  • the drug of the present invention only needs to contain one or more of isoleucine, leucine, and parin as branched chain amino acids, and may contain all three of isoleucine, leucine, and valine.
  • the agent of the present invention contains at least leucine.
  • the formulation of the present invention contains all three of isoleucine, leucine, and valine.
  • the weight ratio of isoleucine, leucine, and valine is 1: 1.5 to 2.5: 0.8 to 1.7. : 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 or parenteral, Oral dosage forms include powders, granules, capsules, tablets, liquids such as tablets, liquids such as syrups, and parenteral dosage forms include injections and sprays. Can be mentioned.
  • 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 and weight of the subject patient, or depending on the pathology, dosage form, or method of administration, etc., but the daily dose is usually isoleucine 0.5-30.
  • O g, Norin 0.5 ⁇ 30.0 g as a guide.
  • isoloicin 2.0-10.0 g, mouth isine 3.0-20.0 g, norin 2.0-0: L O. 0 g, More preferably, it is isoleucine 2.5 to 3.5 g, leucine 5.0 to 7., O g, norin 3.0 to 4.
  • O g and the total amount of amino acids is 2.0 g per day. ⁇ 50.
  • O g is preferable, and it is divided into 1 to 6 times, preferably 1 to 3 times.
  • 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.
  • the above-mentioned calculation method is determined as follows.For this purpose, for example, a branched chain amino acid that is ingested or administered for the purpose of a normal diet or for the purpose of treating another disease. 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 the normal diet from the daily dose of the active ingredient in the present invention. ..
  • Isoleucine, leucine, and valine which are the active ingredients of the present invention, may be contained alone or in any combination in the same lj, or all may be contained in one preparation. It may be contained. When separately formulated and administered, their administration route and dosage form may be the same or different. Each dose The ringing may be simultaneous or separate. These can be determined as appropriate in consideration of the types and effects of drugs used in combination.
  • the drug of the present invention when it 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, or a concomitant drug that is separately formulated and used in combination. It is possible to include all these forms. In particular, an embodiment in which all branched-chain amino acids are contained in the same preparation is preferable because it can be easily administered.
  • the “weight ratio” means the ratio of the weight of each component in the preparation.
  • each active ingredient of isoleucine, leucine and valine is contained in one preparation, it is the ratio of individual contents, and each active ingredient is used alone or in any combination in multiple preparations.
  • the weight of each amino acid is as free amino acid. .
  • the actual dose ratio is the ratio of a single dose or a daily dose of each active ingredient per subject (ie, patient).
  • the weight ratio corresponds to the dose ratio.
  • 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 are already widely used in the pharmaceutical 'food field, and safety has been established.
  • the acute toxin '14 (LD 50 ) of a formulation containing these amino acids in a ratio of 1: 2: 1.2 is greater than 10 g / Kg in oral administration to mice.
  • the drug of the present invention is formulated into a solid agent such as powder, granule, capsule, tablet, chewable agent, solution such as solution, syrup, or injection, spray, etc. by a usual method. can do.
  • Such formulations may optionally be pharmaceutically acceptable carriers such as excipients, Binder, lubricant, solvent, disintegrant, solubilizer, suspending agent, emulsifier, tonicity agent, stabilizing agent, soothing agent, preservative, antioxidant, flavoring agent, coloring agent Etc.
  • Excipients include sugars such as lactose, glucose, D-mannitol, organic excipients such as starches, celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin. . .
  • Binders include pregelatinized starch, gelatin, gum arabic, methylcellulose, canoleboxymethinoresenorelose, canolepoxymethinoresenorelose sodium, crystalline snout, D-mannito-nore, treno , .Rose, hydroxypropenoresenololose, hydroxypropylmethylcellulose, polyvinyl, nylpyrrolidone, polyvinyl alcohol, and the like.
  • lubricants include fatty acid salts such as stearic acid and stearate, talc, and silicates.
  • Examples of the solvent include purified water and physiological saline.
  • disintegrating agents include low-substituted hydroxypropylcellulose, chemically modified cellulose and starches.
  • solubilizers examples include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.
  • suspending agents or emulsifiers include sodium lauryl sulfate, gum arabic, gelatin, lecithin, glyceryl monostearate, polyvinyl alcohol, polybiolepyrrolidone, canolepoxymethinoresenorelose sodium and other senoreloses, polysorbates And polyoxyethylene hydrogenated castor oil.
  • isotonic agents include titanium chloride, potassium chloride, sugars, glycerin, urea and the like.
  • stabilizer examples include polyethylene glycol, sodium dextran sulfate, and other amino acids.
  • soothing agents include glucose, calcium dulconate, and pro-hydrochlorin hydrochloride. Can be mentioned.
  • preservatives include para-benzoic acid esters, chlorobutanol, benzenole alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. '
  • Antioxidants include sulfites and ascorbic acid.
  • flavoring agent examples include sweeteners and fragrances commonly used in the pharmaceutical and food fields. '
  • colorant examples include colorants commonly used in the pharmaceutical and food fields.
  • Akt inhibitor of the present invention examples include other drugs such as diabetic agents, hyperlipidemia therapeutic agents, hypertensive therapeutic agents, liver disease agents, anticancer agents (for example, force lupoplatin, tegafur, Paclitaxel, leuprorelin acetate, etc.) may be added.
  • drugs such as diabetic agents, hyperlipidemia therapeutic agents, hypertensive therapeutic agents, liver disease agents, anticancer agents (for example, force lupoplatin, tegafur, Paclitaxel, leuprorelin acetate, etc.) may be added.
  • phosphorylation of A kt is carried out as per protocol using Path S can Phosphd -A ktl (Ser 4 7 3) S andwich ELI SA kit (Cell Signaling Techno 1 ogy). Quantified ... The result is shown in figure 2.
  • a kt was activated in a dose-dependent manner with insulin 1 nM and 10 nM (Fig. 2 (2) and (4)), but leucine suppressed these activations (Fig. 2 ( 3) and (5.)).
  • H4 IIE cells were seeded on D-MEM + 10% FBS medium at 4 ⁇ 10 5 cells / wel 1 on 12 well plates and cultured. The next day, the medium was replaced with D-MEM FCS (-) medium and further cultured in sputum.
  • I AP-l s e n s e: c g a g g a g g a g g a g t c a g a t g (Self row number: 3)
  • the Akt activation inhibitor provided by the present invention having at least one branched chain amino acid selected from isoleucine, leucine, and valine as an active ingredient exhibits hyperinsulinemia or hyperinsulinemia Suppresses the development and / or progression of cancer in patients at risk.
  • the drug of the present invention comprises an amino acid as an active ingredient, it is highly safe and can be administered over a long period of time because it has few side effects, and it exhibits hyperinsulinemia or is at risk of hyperinsulinemia.
  • the long-term course until the patient develops cancer It can be advantageously used for prevention or treatment.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L’invention porte sur un agent permettant d’empêcher la manifestation et/ou la progression d’un cancer chez un patient souffrant d’hyperinsulinisme ou à risque d’hyperinsulinisme, en inhibant l'activation de la kinase Akt. Un inhibiteur de l’activation de l’Akt qui contient comme principe actif au moins un acide aminé ramifié sélectionné parmi l'isoleucine, la leucine et la valine.
PCT/JP2006/315897 2005-08-05 2006-08-04 INHIBITEUR DE L'ACTIVATION DE L’Akt WO2007018281A1 (fr)

Priority Applications (1)

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JP2007529634A JP5217436B2 (ja) 2005-08-05 2006-08-04 Ａｋｔ活性化抑制剤

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JP2005227780 2005-08-05
JP2005-227780 2005-08-05

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012111790A1 (fr) 2011-02-17 2012-08-23 味の素株式会社 Potentialisateur de l'activité antitumorale d'un agent chimiothérapique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06256184A (ja) * 1993-03-05 1994-09-13 Morishita Roussel Kk 癌患者用アミノ酸製剤
JP2003171271A (ja) * 2001-09-26 2003-06-17 Ajinomoto Co Inc 耐糖能異常用薬剤
JP2003238401A (ja) * 2002-02-20 2003-08-27 Ajinomoto Co Inc 疾患の治療、改善又は予防用医薬品及び飲食品
WO2004058243A1 (fr) * 2002-12-26 2004-07-15 Ajinomoto Co., Inc. Inhibiteur de l'apparition et de l'evolution du cancer du foie

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06256184A (ja) * 1993-03-05 1994-09-13 Morishita Roussel Kk 癌患者用アミノ酸製剤
JP2003171271A (ja) * 2001-09-26 2003-06-17 Ajinomoto Co Inc 耐糖能異常用薬剤
JP2003238401A (ja) * 2002-02-20 2003-08-27 Ajinomoto Co Inc 疾患の治療、改善又は予防用医薬品及び飲食品
WO2004058243A1 (fr) * 2002-12-26 2004-07-15 Ajinomoto Co., Inc. Inhibiteur de l'apparition et de l'evolution du cancer du foie

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GUPTA K. ET AL.: "Insulin: A novel factor in carcinogenesis", AM. J. MED. SCI., vol. 323, no. 3, 2002, pages 140 - 145, XP003002185 *
HINAULT C. ET AL.: "Amino acids and leucine allow insulin activation of the PKB/mTOR pathway in normal adipocytes treated with wortmannin and in adipocytes from db/db mice", FASEB JOURNAL, vol. 18, no. 15, October 2004 (2004-10-01), pages 1894 - 1896, XP003002187 *
LAWLOR M.A. ET AL.: "PKB/Akt, : a key mediator of cell proliferation, survival and insulin responses?", J. CELL SCI., vol. 114, no. 16, 2001, pages 2903 - 2910, XP003002186 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012111790A1 (fr) 2011-02-17 2012-08-23 味の素株式会社 Potentialisateur de l'activité antitumorale d'un agent chimiothérapique

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JPWO2007018281A1 (ja) 2009-02-19

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