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WO2004056351A1 - Regulateur d'activite pka - Google Patents

Regulateur d'activite pka Download PDF

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Publication number
WO2004056351A1
WO2004056351A1 PCT/JP2003/016386 JP0316386W WO2004056351A1 WO 2004056351 A1 WO2004056351 A1 WO 2004056351A1 JP 0316386 W JP0316386 W JP 0316386W WO 2004056351 A1 WO2004056351 A1 WO 2004056351A1
Authority
WO
WIPO (PCT)
Prior art keywords
pka
salt
menatetrenone
vitamin
active ingredient
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2003/016386
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English (en)
Japanese (ja)
Inventor
Motoyuki Otsuka
Masao Omata
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eisai Co Ltd
Original Assignee
Eisai Co Ltd
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 Eisai Co Ltd filed Critical Eisai Co Ltd
Priority to AU2003289467A priority Critical patent/AU2003289467A1/en
Priority to JP2004562064A priority patent/JPWO2004056351A1/ja
Publication of WO2004056351A1 publication Critical patent/WO2004056351A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a cAMP dependent protein kinase A (hereinafter, simply referred to as “PKA”) activity regulator or the like, which contains menatetrenone or a salt thereof as an active ingredient.
  • PKA cAMP dependent protein kinase A
  • HCC hepatocellular carcinoma
  • PVI portal venous invasion
  • DCP Des- ⁇ -Carboxy Prothrombin
  • VK vitamin
  • VK when administered to patients with high DCP-level HC C, serum DCP levels decrease (for example, see Non-Patent Document 2), and VK-II is administered to DCP-producing HC C cell line in vitro. It has been reported that cell growth suppresses cell proliferation (for example, see Non-Patent Document 3).
  • liver cancer includes the prevention of recurrence of liver cancer by acyclic retinoid (for example, see Non-Patent Document 4), ACE inhibitor (for example, see Non-Patent Document 5) and COX2 inhibitor (for example, see Non-Patent Document 6) Inhibition of hepatocarcinogenesis by liver ⁇ It is known to inhibit liver cancer cell proliferation and promote apoptosis.
  • vitamin K2 is found in leukemia cells and MDS cells (for example, see Non-Patent Document 7), breast cancer cells (for example, see Non-Patent Document 8), and fibroblasts (for example, see Non-Patent Document 9). It has been reported to suppress the growth of cancer cells.
  • Non-Patent Document 1 Koike Y. Cancer 2001; 91: 561-9
  • Non-Patent Document 8 Kar S, J Cell Physiol 2000; 185: 386-93
  • Non-Patent Document 9 Li N, J Cell Physiol 1998; 175: 359-69 Disclosure of the Invention
  • an object of the present invention is to provide a PKA activity regulator useful for treating a cancer disease.
  • the present inventors have conducted intensive studies on PKA activity regulators, and found that vitamin K 2 (menatetrenone or a salt thereof) regulates PKA, that vitamin K2 activates PKA, Activation of transcription factors CRE / CREB, USF-1 and AP-2 by activation of PKA by vitamin K2, proliferation of liver cancer cells by activation of PKA by vitamin K2 It has been found that an inhibitory effect and an infiltration inhibitory effect are brought about. In other words, PKA activity is a mechanism of hepatocellular carcinoma cell growth suppression and invasion suppression. The inventor has found that intermediation is involved and completed the present invention.
  • a PKA activity modulator comprising menatetrenone or a salt thereof as an active ingredient
  • a PKA activator comprising menatetrenone or a salt thereof as an active ingredient
  • a prophylactic or therapeutic agent for a cancer disease comprising a PKA activator comprising menatetrenone or a salt thereof as an active ingredient;
  • a cancer cell growth inhibitor comprising a PKA activator comprising menatetrenone or a salt thereof as an active ingredient
  • a cancer cell invasion inhibitor comprising a PKA activator comprising menatetrenone or a salt thereof as an active ingredient
  • an activator of AP-2, CREB and USF-1 including a PK A activator comprising menatetrenone or a salt thereof as an active ingredient;
  • a preventive or therapeutic agent for a disease derived from a change in PKA activity comprising menatetrenone or a salt thereof as an active ingredient;
  • a method of modulating PKA activity which comprises administering an effective amount of menatetrenone or a salt thereof to a subject;
  • FIG. 1 is a graph showing the effect of the addition of vitamin K 2 on the suppression of the growth of liver cancer cells.
  • Figure 2 is a chart showing the effect of adding vitamin K2 on the cell cycle.
  • FIG. 3 is a gel photograph showing the effect of vitamin K2 on cell invasion ability.
  • Figure 4 shows (a) Daraf and (b) analysis chart photographs showing the changes in gene expression due to the addition of vitamin K2.
  • FIG. 5 is an RT-PCR analysis chart photograph showing the change in gene expression level due to the addition of vitamin K2.
  • FIG. 6 is a graph showing the time course of gene expression due to the addition of vitamin K2.
  • FIG. 7 is a diagram showing a gene network.
  • FIG. 8 shows (a) an analysis photograph and (b) a graph showing changes in protein expression caused by addition of vitamin K2.
  • FIG. 9 is an analysis photograph showing activation of a signal transduction pathway by addition of vitamin K2.
  • FIG. 10 is an analysis photograph showing activation of the signal transduction pathway (AP-2) by addition of vitamin K2.
  • FIG. 11 is an analysis photograph showing activation of a signal transduction pathway (CREB) by addition of vitamin K2.
  • CREB signal transduction pathway
  • FIG. 12 is an analysis photograph showing activation of PKA by addition of vitamin K2.
  • FIG. 13 is a graph showing the inhibition of the cell growth inhibitory effect of vitamin K2 by a PKA inhibitor.
  • Figure 14 shows an analysis of the inhibition of Rho activation by the addition of vitamin K2. Is true.
  • the menatetrenone used in the date of the present invention is preferably menaquinone — 1 to 14, more preferably menaquinone 4 to 8, and even more preferably menaquinone-14.
  • examples of the cancer disease include liver cancer.
  • Hepatoma develops at a high rate from chronic hepatitis and cirrhosis, and recurs more frequently once it develops.
  • hepatitis C or hepatitis B may cause cirrhosis and recur after tumor resection.
  • the prognosis after such treatment for liver cancer can be extremely effectively improved (prevention or treatment of recurrence).
  • the occurrence of PVI which is one of the recurrent forms of liver cancer with a poor prognosis, can be extremely effectively suppressed.
  • examples of the disease derived from a change in PKA activity include leukemia, knee cancer, and ovarian cancer.
  • PKA cAMP dependent protein kinase A
  • cAMP cAMP dependent protein kinase A
  • Activated PKA activates downstream signal molecules to exert various effects on cells, but from the perspective of cell proliferation, activated PKA is promoted in cell growth
  • van Oirschot BA J Biol Chem 2001; 276: 33854-60 other
  • PKA phosphorylates CHE Binding Protein (CREB), a transcription factor that binds to cAMP Responseve Element (CRE) when activated, although various transcription factors work in cells to contribute to gene expression. It is known that the activation of this gene activates transcription and regulates downstream gene expression. Transcription factors regulated by PKA include USF-l (Xiao Q, Am J Physiol Heart Circ Physiol 2002; 283: H213.9), AP-2 (Garcia MA, FEBS Lett 1999; 444: 27-31), etc. Many others have been reported, and the regulation of the downstream signaling system is considered to be extremely complex.
  • CREB CHE Binding Protein
  • CRE cAMP Responseve Element
  • Menate trenone is also referred to as vitamin K2 and is also referred to as menaquinone-n (M K-n) due to the number n of isoprenyl groups.
  • M K-n menaquinone-n
  • Substances with an isoprenyl group at the 3-position of the 2-methyl-1,4-naphthoquinone ring are collectively referred to as vitamin K2 (VitaminK2).
  • Vitamin K2 has homologs due to the different numbers of isoprenyl groups.
  • the structural formula of menatetrenone is shown below.
  • n is preferably from 1 to 14, more preferably from 4 to 8.
  • 2-methyl-3-tetraprenyl-1,4-naphthoquinone where n is 4 (2-methl-3-tetraprenyl-l, 4-naplithoquinone; MK-4) Is preferred.
  • Menatetrenone is a yellow crystalline or oily substance that has no smell and taste and is easily decomposed by light. It is hardly soluble in water.
  • the pharmacological action of menatetrenonone is the ability of lutepoxyl to convert glutamic acid residues into bioactive ⁇ -carboxyglutamic acid during the protein synthesis process of blood coagulation factors (prothrombin, VII, IX, X). It promotes hepatic synthesis of normal prontrobin and the like, activates the hemostatic mechanism of the living body, and exerts a physiological hemostatic action.
  • Menatetrenone which is an active ingredient of the medicament of the present invention, may form a salt.
  • a salt include hydrohalides (eg, hydrofluoric acid, hydrochloride, hydrogen bromide) Acid salt, hydroiodide, etc.), inorganic acid salt (eg, sulfate, nitrate, perchlorate, phosphate, carbonate, bicarbonate, etc.) Organic carboxylate (eg, acetate) , Trifluoroacetate, oxalate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonates (eg methanesulfonate, trifluoromethanesulfonate, ethanesulfone) Acid salt, benzenesnolephonate, tonorenensorenoate, camphorsulfonate, etc., amino acid salt (eg, aspartate, glutamate, etc.), quaternary amine salt, alkal
  • Menatetrenone or a salt thereof which is an active ingredient of the medicament according to the present invention, may be an anhydride or may form a hydrate. Menate trenone or a salt thereof may have a polymorphism in some cases, but is not limited thereto. Any one of the crystal forms may be single or a mixture of crystal forms. Furthermore, metabolites generated by decomposing menatetrenone or a salt thereof used in the present invention in a living body are also included in the claims of the present invention. Menatetrenone used in the present invention can be produced by a known method.As a typical example, menatetrenone can be easily produced by the method disclosed in JP-A-49-155650. Besides, it can be easily obtained from a synthesis manufacturer, or can be converted into a salt according to a known method. Menatetrenone is also available as capsules and injections.
  • menatetrenone may be used as it is, or a known pharmaceutically acceptable carrier or the like (eg, excipient, binder, disintegrant, lubricant, coloring agent, Flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH regulators, preservatives, antioxidants, etc.) and ingredients commonly used as raw materials for pharmaceutical preparations Formulation may be made by any method. If necessary, components such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, a vitamin, an amino acid, a humectant, a keratolytic agent, and the like may be added.
  • a known pharmaceutically acceptable carrier or the like eg, excipient, binder, disintegrant, lubricant, coloring agent, Flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH regulators, preservatives, antioxidants, etc.
  • Formulation dosage forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, freeze-dried preparations, ointments, eye ointments Preparations, eye drops, nasal drops, ear drops, cataplasms, lotions and the like.
  • menatetrenone is not particularly limited, but it is preferable to administer orally.
  • Menatetrenone capsules are available under the trade name K2 Capsules (Eisai Co., Ltd.), and syrups are available under the trade name K2 Syrup (Eisai Co., Ltd.).
  • the drug containing menatetrenone according to the present invention is useful for the treatment and prevention of liver diseases in mammals (eg, humans, mice, rats, guinea pigs, rabbits, dogs, dogs, monkeys, etc.), and particularly useful in humans. It is useful for the treatment of liver disease.
  • the preferred dosage of menatetolenone is usually between 10 and 100 mg Z days, More preferably, it is 30 to 6 OmgZ days.
  • the system using HepG2 is a typical hepatoma cell line, MK-4 (vitamin K 2) the 2X10- 5, 6X10- 5, 8X10- 5 , 10 X 10- 5 to become the concentration of M After addition, the degree of cell proliferation was measured over time by an MT T assay (MTT assay).
  • MK-4 vitamin K 2
  • FIG. 1 is a graph showing the effect of the addition of vitamin K 2 on the suppression of the growth of liver cancer cells. As shown in Fig. 1, no significant change was observed in the degree of cell proliferation on the first and second days after the addition of vitamin K2, but on the third and fifth days, it depends on the vitamin K2 concentration. As a result, the number of living cells was suppressed. Further, from the results shown in FIG. 1, HepG2 cell growth 50% suppression concentration of vitamin K 2 it is thought to be about 5X10_ 5 M.
  • liver cancer cell growth inhibitory action to investigate whether is effective at any stage of the cell cycle, elapses between 5 S was added so that MK-4 to a concentration of 5X10- 5 M HepG2 cells were subjected to nuclear staining, and the cell cycle was measured using a FACS (fluorescence-activated cell sorter). As shown in the chart in FIG. 2, it was found that the cell fraction in the G1 and G2 / M phases increased, and the cell fraction in the S phase (DNA synthesis phase) decreased relatively. From this, it was found that arrest of the cell cycle was mainly linked to suppression of cell proliferation.
  • vitamin K 2 has an effect not only on the proliferation of hepatoma cells but also on suppressing the invasion ability of the cells.
  • cDNA microarray The effect of vitamin K2 on cell gene expression was examined using a cDNA microarray (cDNA microarray).
  • the gene expression profile was analyzed using an in-house cDNA microarray equipped with about 4300 types of cDNA extracted from liver and stomach tissues (Fig. 4 (b)).
  • Fig. 4 (a) is a gene expression profile obtained by scatterplotting cells without vitamin K2 (control) on the horizontal axis and cells with MK-4 on the vertical axis.
  • both the vertical and horizontal axes indicate the signal intensity (log scale), and the red point (R in Fig. 4 (a)) is more than twice or less than 0.5 times.
  • the genes showing the expression change are shown.
  • a gene expression level change of 2 times or more or 0.5 times or less was observed. The gene was found in less than about 10%.
  • FIG. 6 shows about 4300 genes examined in the vertical direction, and genes that are down regulated compared to non-supplemented cells are green (part G in Fig. 6) and up regulation (up (Regulated) genes are drawn in red (R in Fig. 6). As shown in FIG. 6, it became clear that the expression of the gene changed over time.
  • FIG. 7 shows a diagram depicting a gene network based on the above-mentioned temporal changes in gene expression. These genes shown in FIG. 7 are also associated with changes in expression, and it is considered that the regulation of gene expression is similar.
  • MK_4 had an effect on gene expression. It was added to HepG2 cells MK-4 and so that the 5 X 10- 5 M, extract proteins cells were harvested after 4 days, after two-dimensional electrophoresis, silver staining was carried out. As shown in FIG. 8, it was confirmed that there was a difference in gene expression even at the protein level between cells to which MK-4 was added and cells to which MK-4 was not added. From the above results, it became clear that MK-4 affected gene expression in cells. In other words, it was found that changes in the expression of these genes are related to the mechanism of the inhibitory effect of MK-4 on cancer cell proliferation and invasion.
  • the nuclear extracts before (0 hour) and 2, 6, 12, 24, 48 hours after the addition of MK-4 were subjected to gel shift assay using an AP-2 consensus probe. As shown in FIG. 10, the results show that after the addition, protein binding to DNA was increased as compared to before the addition of MK-4. Similarly, gel shift assay was performed on CREB and USF-1, and it was found that the binding between DNA and protein increased 2 to 6 hours after the addition of MK-4 compared to before the addition. (Data not shown).
  • CREB CREB
  • pEGFP-CREB Clontech
  • vitamin K 2 activates each of the transcription factors AP-2, CREB and USF-1.
  • the lysate of the cells was mixed with a PKA substrate peptide and electrophoresed.
  • the results are shown in FIG.
  • the PKA substrate peptide is originally positively charged (+), and the intracellular PKA is activated by mixing the fluorescently labeled PKA substrate peptide with the cell lysate.
  • phosphorylation of the substrate peptide results in the substrate being negatively charged and moving to the + pole. That is, when phosphorylated (ie, when PKA is activated), it goes to the positive pole, and when it is not phosphorylated (ie, when PKA is not activated), it goes to the unipolar side. Will be moved to.
  • liver cancer cell growth inhibitory effect by the addition of vitamin K2 is at least partially mediated by the activation of PKA.
  • Rho When activated, the Ro protein becomes GTP-Rho with GTP bound, and this activated Rho is known to bind to Rhotekin and the EIio Binding Domain (RBD) of the protein with high affinity.
  • Rhotekin and the EIio Binding Domain (RBD) of the protein with high affinity.
  • Rho is a low molecular weight G protein that is thought to play an important role in invasive metastasis of cancer (Clark EA, Nature 2000; 406: 532-5).
  • Rho activation was suppressed depending on MK-4 concentration, and this effect was canceled by H89.
  • PKA controls Rho activation (Faucheux N, Biomaterials 2002; 23--2295-30i; Manganello JM, J Biol Chem 2002), suggesting that vitamin K2 activates Rho. It was found that the action was mediated by PKA.
  • vitamin K 2 activates ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ in a concentration range several times higher than that which functions as a coenzyme of vitamin K-dependent ⁇ -glutamyl calpoxylase, thereby suppressing the growth of liver cancer cells and infiltrating ability. It has been found that it has an effect on production and controls various gene expressions. Industrial applicability
  • the activity modulator of the present invention is useful for the prevention or treatment of cancer disease treatment.
  • the activator according to the present invention is useful for inhibiting cancer cell proliferation and inhibiting cancer cell invasion.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un régulateur d'activité PKA contenant, en tant que principe actif, du ménatétrénone ou son sel. Ce régulateur d'activité PKA est utile dans la production d'une substance prophylactique ou d'un remède contre des maladies cancéreuses, dans un inhibiteur de prolifération de cellules cancéreuses, dans un inhibiteur d'infiltration de cellules cancéreuses et dans des activateurs AP-2, CREB et USF-1. En outre, cette invention est sensée fournir un procédé permettant de réguler l'activité PKA caractérisé en ce qu'il consiste à administrer une dose efficace de ménatétrénone ou de son sel à un sujet.
PCT/JP2003/016386 2002-12-20 2003-12-19 Regulateur d'activite pka Ceased WO2004056351A1 (fr)

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AU2003289467A AU2003289467A1 (en) 2002-12-20 2003-12-19 Pka activity regulator
JP2004562064A JPWO2004056351A1 (ja) 2002-12-20 2003-12-19 Ｐｋａ活性調節剤

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004093858A1 (fr) * 2003-04-23 2004-11-04 Eisai Co., Ltd. Inhibiteur d'expression de metalloproteinase matricielle

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06305955A (ja) * 1993-04-27 1994-11-01 Eisai Co Ltd キノン系細胞分化誘導剤
WO2000064260A1 (fr) * 1999-04-23 2000-11-02 Bristol-Myers Squibb Company Compositions et procedes pour traiter des maladies hyperproliferatives
US20020165153A1 (en) * 1998-04-06 2002-11-07 Peter Angel Transcription factors and their use
WO2003063850A1 (fr) * 2002-01-31 2003-08-07 Hisamitsu Pharmaceutical Co., Inc. Compositions medicamenteuses contenant de la vitamine k comme renforçateur du facteur de croissance neuronal et utilisation correspondante

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002037729A (ja) * 2000-05-19 2002-02-06 Eisai Co Ltd メナテトレノンを含有する医薬

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06305955A (ja) * 1993-04-27 1994-11-01 Eisai Co Ltd キノン系細胞分化誘導剤
US20020165153A1 (en) * 1998-04-06 2002-11-07 Peter Angel Transcription factors and their use
WO2000064260A1 (fr) * 1999-04-23 2000-11-02 Bristol-Myers Squibb Company Compositions et procedes pour traiter des maladies hyperproliferatives
WO2003063850A1 (fr) * 2002-01-31 2003-08-07 Hisamitsu Pharmaceutical Co., Inc. Compositions medicamenteuses contenant de la vitamine k comme renforçateur du facteur de croissance neuronal et utilisation correspondante

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GARCIA, M. A. ET AL.: "Transcription factor AP-2 activity is modulated by protein kinase A-mediated phosphorylation", FEBS LETTERS, vol. 444, no. 1, 1999, pages 27 - 31, XP002974877 *
TSANG, C. K. ET AL.: "Novel effect of vitamin K1 (phylloquin one) and vitamin K2 (menaquinone) on promoting nerve growth factor-mediated neurite outgrowth from PC12D cells", NEUROSCIENCE LETTERS, vol. 323, no. 1, 2002, pages 9 - 12, XP002964325 *
VAN OIRSCHOT, B. A. ET AL.: "Protein Kinase A Regulates Expression of p27kip1 and Cyclin D3 to Suppress Proliferation of Leukemic T Cell Lines", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 276, no. 36, 2001, pages 33854 - 33860, XP002974876 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004093858A1 (fr) * 2003-04-23 2004-11-04 Eisai Co., Ltd. Inhibiteur d'expression de metalloproteinase matricielle

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