WO2005107731A1 - Remèdes contenant de la vitamine k2 comme ingrédient actif - Google Patents

Remèdes contenant de la vitamine k2 comme ingrédient actif Download PDF

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WO2005107731A1
WO2005107731A1 PCT/JP2005/009112 JP2005009112W WO2005107731A1 WO 2005107731 A1 WO2005107731 A1 WO 2005107731A1 JP 2005009112 W JP2005009112 W JP 2005009112W WO 2005107731 A1 WO2005107731 A1 WO 2005107731A1
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vitamin
hydrate
menatetrenone
agent
cancer
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PCT/JP2005/009112
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English (en)
Japanese (ja)
Inventor
Iwata Ozaki
Hao Zhang
Toshihiko Mizuta
Kyosuke Yamamoto
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Eisai R & D Management Co., Ltd.
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Priority to JP2006513064A priority Critical patent/JPWO2005107731A1/ja
Publication of WO2005107731A1 publication Critical patent/WO2005107731A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a cyclin D1 expression inhibitor, an NF- ⁇ B activation inhibitor, and an I ⁇ B phosphorylation inhibitor containing vitamin K 2 (eg, menatetrenone) or a hydrate thereof as an active ingredient.
  • the present invention also relates to a cancer cell growth inhibitor and a cancer therapeutic containing these inhibitors as an active ingredient.
  • the present invention provides an anti-inflammatory agent, an anti-rheumatic agent, an immunosuppressant, an anti-allergic agent, a transplant rejection inhibitor, a therapeutic agent for psoriasis, comprising vitamin K 2 (for example, menatetolenone) or a hydrate thereof as an active ingredient.
  • the present invention relates to an antiviral agent, a therapeutic agent for arteriosclerosis, a therapeutic agent for ischemic reperfusion injury, a therapeutic agent for diabetes, and a therapeutic agent for renal failure.
  • Vitamin K is a coenzyme of ⁇ -daltamyl carboxylase, an enzyme that converts the glutamate residue at the N-terminus of vitamin-dependent protein into bioactive y-carboxyglutamic acid (GLA).
  • Vitamin ⁇ is an essential vitamin for the biosynthesis of vitamin ⁇ -dependent proteins such as blood coagulation factor II (prothrombin), VII, IX and X.
  • Vitamin IV family 1 is composed of natural K 1 (phytonadione), ⁇ 2 (menatetolenone) and synthetic ⁇ 3 (menadione). Vitamin 2, especially menatetrenone, is marketed as a treatment for osteoporosis.
  • Vitamin kappa 2 e.g. menatetrenone has been reported to inhibit the proliferation of hepatoma cell lines (Hep3B, Hep40) (1 _ 3). Moreover, menatetrenone, in leukemia cells (Primary, HL-60, etc.), are known to induce apoptosis and differentiation (4 _ 7). Furthermore, it has been reported that geranylgeraniol, a side chain of menatetrenone, induces apoptosis in tumor cell lines (HL-60, K562, Molt3, Colo320DM) ( 8) , as well as menaquinone-3 and menaquinone-4.
  • Vitamin K 2 power such as menaquinone 1-5 It has been reported to induce apoptosis in primary cultured leukemia cells ( 4) . In recent years, it has been known that menatetrenone suppresses recurrence of liver cancer in patients after liver cancer treatment and increases the survival rate ( 9) . However, the molecular mechanism by which vitamin K2 suppresses cancer cell growth is not fully understood.
  • the present invention has been made in view of such a situation, and the problem to be solved is to determine the molecular mechanism by which vitamin K2 represented by menatetrenone suppresses cancer cell growth. It is an object of the present invention to provide a highly effective and safe drug and treatment method for cancer patients.
  • Another object of the present invention is to elucidate the molecular mechanism of vitamin K2 and to provide a new therapeutic agent and method for a disease.
  • menatetrenone inhibits the expression of cyclin D1 in liver cancer cells, inhibits NF- / B, and inhibits ⁇ . It was found to inhibit phosphorylation.
  • menatetrenone inhibits cyclin D1 expression, inhibits NF- / cB, and inhibits I / cB phosphorylation, so that menatetrenone is useful in suppressing cancer cell growth and treating cancer Furthermore, they found that the antitumor effect of menatetrenone was enhanced by combining it with an antitumor agent.
  • menatetrenone inhibits NF- ⁇ B activation, anti-inflammatory drugs, anti-rheumatic drugs, immunosuppressants, anti-allergic drugs, transplant rejection suppressants, psoriasis treatment drugs, antiviral drugs, and atherosclerosis treatment
  • the present invention was found to be useful as an agent, a therapeutic agent for ischemic reperfusion injury, a therapeutic agent for diabetes or a therapeutic agent for renal failure, and completed the present invention.
  • the present invention relates to the following.
  • An NF- ⁇ B activation inhibitor comprising vitamin K2 or a hydrate thereof as an active ingredient.
  • a ⁇ phosphoric acid inhibitor comprising vitamin K2 or a hydrate thereof as an active ingredient.
  • Anti-inflammatory, anti-rheumatic, immunosuppressant, anti-allergic, transplant rejection suppressant, psoriasis treatment, anti-viral, arteriosclerosis treatment containing vitamin ⁇ 2 or its hydrate as an active ingredient At least one agent selected from the group consisting of a therapeutic agent for ischemic reperfusion injury, a therapeutic agent for diabetes, and a therapeutic agent for renal failure.
  • a cyclin D1 expression inhibitor comprising vitamin II or a hydrate thereof as an active ingredient.
  • a method for inhibiting NF- / C ⁇ activation which comprises administering vitamin ⁇ 2 or a hydrate thereof to a living body.
  • a method for inhibiting ⁇ phosphorylation which comprises administering vitamin ⁇ 2 or a hydrate thereof to a living body.
  • Inflammation, rheumatism, immunosuppression, allergy, transplant rejection, psoriasis, viral diseases characterized by administering to a patient an effective amount of an agent containing vitamin ⁇ 2 or a hydrate thereof as an active ingredient.
  • the agent described in (4) is administered to a patient in an effective amount, which is characterized by inflammation, rheumatism, immunosuppression, allergy, transplant rejection, psoriasis, viral disease, arteriosclerosis, ischemic relapse.
  • a method for inhibiting expression of citalin D1 comprising administering vitamin ⁇ ⁇ 2 or a hydrate thereof to a living body.
  • a cancer treatment agent comprising a combination of vitamin 2 or a hydrate thereof and an antitumor substance.
  • a cancer therapeutic agent comprising a combination of vitamin ⁇ 2 or a hydrate thereof and 5-FU.
  • the cancer therapeutic agent according to any one of (19) to (21), wherein the cancer is liver cancer. Further, the present invention relates to the following.
  • a cancer cell growth inhibitor comprising the inhibitor according to any one of (1), (2) and (5) as an active ingredient.
  • a therapeutic agent for cancer comprising as an active ingredient the inhibitor according to any one of (1), (2) and (5).
  • a method for treating cancer comprising administering an effective amount of the inhibitor according to any one of (1), (2) and (5) to a patient.
  • vitamin ⁇ 2 for example, menatetrenone
  • an antitumor agent enhances the antitumor effect of vitamin ⁇ 2. This has made it possible to greatly improve the quality of life of cancer patients.
  • Vitamin ⁇ 2 inhibits the activation of NF- ⁇ and the phosphorylation of ⁇ ⁇ , and that vitamin K2 activates NF- ⁇ B or phosphorylates I ⁇ B.
  • Vitamin K2 is an effective anti-inflammatory, anti-rheumatic, immunosuppressant, anti-allergic, transplant rejection inhibitor, psoriasis treatment, anti-will It has become possible to use it as an active ingredient in medicines, arteriosclerosis treatment, ischemic reperfusion injury treatment, diabetes treatment or renal failure treatment.
  • Figure 1 shows the results of analysis of changes in cyclin D1 due to treatment with menatetrenone by Western blotting (A), RT-PCR (B), and luciferase reporter Atsusei (C). .
  • FIG. 2 shows the results of an examination of the effect of menatetrenone on the DNA binding activity of NF-cB by gel shift assay.
  • FIG. 3 shows the results of examining the effect of menatetrenone on the transcriptional activity of NF- ⁇ using the NF- / cB luciferase reporter plasmid. 4, in order to investigate the role of transcription factor AP-1 and NF-? Kappa B in cyclin D1 promoter active '1 1 production regulation by menatetrenone, in hepatoma cells, wild-type AP-1 and NF-?
  • Figure 5 shows that NF- ⁇ B dependence of cyclin D1 promoter activity by menatetrenone was confirmed by introducing p65 / RelA, a subunit of NF- / cB, into hepatoma cells and overexpressing the cyclin D1 promoter by menatetrenone. It is a result of examining whether or not the suppression of the activity is released.
  • Figure 6 shows that the subunit of p65 / RelA or cyclin D1 gene was introduced into hepatocellular carcinoma cells HepG2 in order to examine whether the inhibition of hepatoma cell growth was dependent on NF- / cB or cyclin D1. This figure shows the results of examining whether or not reproductive suppression by menatetrenone changes.
  • Figure 7 shows that the NF- ⁇ subunit p65 / RelA or the cyclin D1 gene was added to the hepatoma cell Hep3B in order to examine whether the suppression of hepatoma cell growth was dependent on NF-KB or cytaline D1. Introduced growth suppression by menatetrenone It shows the result of examining whether the system will change.
  • Fig. 8 shows the results of examining the effects of low-concentration 5-FU (5 ⁇ g / ml) and menatetrenone, which do not cause abotosis on hepatoma cells HepG2, Hep3B, and Huh7, on hepatoma cells and the effect on cell proliferation. It is shown.
  • FIG. 9 shows the results of Western blot analysis of the phosphorylation of I ⁇ B, the expression level of I ⁇ ; B protein, and the transfer of ⁇ 65 subunit to the nucleus.
  • FIG. 10 shows the results of examining the effect of menatetrenone on the activation of NF- ⁇ induced by TPA, TNF-a, and IL-1 using a luciferase reporter atsey.
  • FIG. 11 shows the results of an examination of the effect of menatetrenone on the DNA binding activity of NF- ⁇ B induced by TPA, TNF-a, and IL-1 by gel shift assay.
  • Figure 12 shows the results of Western blot analysis of the effects of menatetrenone on I ⁇ phosphorylation and I ⁇ protein levels under TPA, TNF-a, and IL-1 ⁇ stimulation. .
  • Figure 13 shows the results of in vitro kinase assay analysis of the effect of menatetrenone on the kinase activity of the IKK complex under the stimulation of TPA and TNF-aIL_1] 3.
  • Vitamin K2 is known to have the effect of suppressing the growth of cancer cells.
  • the present inventors have elucidated the molecular mechanism of this cancer cell growth inhibitory action, and surprisingly found that vitamin ⁇ 2 inhibits the expression of cyclin D1, a factor that plays an important role in cell growth.
  • This inhibition of cyclin D1 expression was caused by the inhibition of phosphorylation of ⁇ , a transcription factor of the cyclin D1 promoter, by vitamin ⁇ 2, thereby inhibiting the activation of NF-zcB.
  • vitamin K2 inhibits the activation of ⁇ by inhibiting ⁇ phosphoric acid, resulting in the inhibition of the expression of cytaline D1, which uses NF- ⁇ as a transcription factor.
  • the present invention provides a cyclin D1 expression inhibitor, an NF- ⁇ activation inhibitor, an I / cB phosphoric acid inhibitor, and an inhibitor comprising these inhibitors, which contain vitamin K2 or a hydrate thereof as an active ingredient.
  • Cancer cell proliferation inhibitor, cancer therapeutic agent, and cyclin D1 expression inhibiting method using vitamin K2 or a hydrate thereof, NF- ⁇ activation inhibiting method, I / cB phosphorylation inhibiting method Provided are a method for suppressing cancer cell growth using an inhibitor and a method for treating cancer.
  • the present invention also provides a therapeutic agent for cancer comprising a combination of vitamin II or a hydrate thereof and an antitumor substance for cancer patients.
  • vitamin ⁇ 2 inhibits activation of NF- ⁇ and inhibits phosphorylation of ⁇ ⁇ ⁇ ⁇ ⁇
  • vitamin ⁇ ⁇ ⁇ ⁇ 2 is useful for the treatment of diseases caused by activation of ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ or phosphorylation of ⁇ . It is. Therefore, the present invention provides an anti-inflammatory agent, an anti-rheumatic agent, an immunosuppressant, an anti-allergy agent, a transplant rejection inhibitor, a psoriasis treatment agent, an antiviral agent, which contains vitamin ⁇ 2 or a hydrate thereof as an active ingredient.
  • the present invention also provides a therapeutic agent for arteriosclerosis, a therapeutic agent for ischemic reperfusion injury, a therapeutic agent for diabetes or renal failure, and a therapeutic method using the same.
  • vitamin 2 or a hydrate thereof may be used as an active ingredient for all or two or more of the above-mentioned agents, or may be used as an active ingredient for one of the above-mentioned agents. it can.
  • vitamin K2 inhibits the activation of NF- ⁇ ⁇ ⁇ ⁇ ⁇ and the phosphorylation of ⁇ ⁇ ⁇ ⁇ ⁇ in liver cancer cells. Therefore, vitamin ⁇ 2 can be used as an active ingredient of an activation inhibitor of and a phosphorylation inhibitor of ⁇ .
  • NF- ⁇ is one of the transcription factors, forms a complex with I ⁇ B, and is known to exist in the inactive state in the cytoplasm (Baeuerle, PA and Baltimore, D. Science 242). Beg, AA et al. Genes Dev. 7, 2064-2070, 1993; Finco, TS et al. Proc. Natl. Acad. Sci. USA 91, 11883-11888, 1994 ⁇ ).
  • the complex in the inactivated state is activated through phosphorylation of serine (Serine-32) and serine (Serine-36) of the second and third amino acids of I ⁇ B.
  • Activated NF- ⁇ translocates into the nucleus (Finco, TS et al. Proc. Natl. Acad.
  • Vitamin K 2 in order to inhibit the phosphorylation of I kappa B, complex inactivated state active activatable Sarezu, resulting in the this Vitamin K2 NF-? / Activation of B is inhibited Become.
  • an agent for inhibiting the activation of NF- ⁇ B containing vitamin K2 or hydrate thereof, or vitamin K2 or hydrate thereof, and an agent for inhibiting phosphorylation of I ⁇ B are NF -It is possible to suppress an increase in the expression levels of cytokines, chemopotins, adhesion molecules, cyclins, etc., through inhibition of ⁇ activation and inhibition of I / c B phosphorylation. That is, the NF- ⁇ activity inhibitor and the ⁇ phosphate inhibitor are useful for treating diseases caused by these physiologically active substances.
  • the agent is, for example, an anti-inflammatory agent, an anti-rheumatic agent, an immunosuppressant, an anti-allergic agent, a transplant rejection inhibitor, a therapeutic agent for psoriasis, an antiviral agent, a therapeutic agent for atherosclerosis, ischemic reperfusion injury
  • an anti-inflammatory agent for example, an anti-inflammatory agent, an anti-rheumatic agent, an immunosuppressant, an anti-allergic agent, a transplant rejection inhibitor, a therapeutic agent for psoriasis, an antiviral agent, a therapeutic agent for atherosclerosis, ischemic reperfusion injury
  • a therapeutic agent for diabetes or a therapeutic agent for renal failure It also inhibits NF- ⁇ NF activation.
  • Harmful agents and ⁇ phosphorylation inhibitors are also useful as cyclin D1 expression inhibitors. This cyclin D1 is known to play an important role in cell proliferation. That is, the NF- ⁇ activation inhibitor or the ⁇ phosphorylation inhibitor is useful
  • cancer is not particularly limited, and examples thereof include brain tumor, cervical cancer, esophageal cancer, thyroid cancer, tongue cancer, lung cancer, breast cancer, spleen cancer, stomach cancer, liver cancer, biliary tract cancer, spleen cancer, colon cancer, At least one selected from the group consisting of small intestine and duodenum cancer, colon cancer, rectal cancer, bladder cancer, kidney cancer, prostate cancer, uterine cancer, ovarian cancer, testicular cancer, sarcoma and melanoma can be mentioned.
  • it is liver cancer.
  • vitamin 2 is preferably menatetrenone
  • the target for cell growth suppression and the target for cancer treatment are preferably liver cancer cells and liver cancer.
  • ⁇ phosphorylation inhibitor means an agent having an action of inhibiting the phosphorylation of ⁇ ⁇ required for dissociation from NF- / cB in a living body or a part of the living body.
  • IKK I ⁇ B kinase
  • IKK I ⁇ B kinase
  • NF- ⁇ B activation inhibitor means an agent having an action of inhibiting the function of transcription factor NF- ⁇ B.
  • an agent that inhibits release of NF- / cB from a complex with I ⁇ B in an organism or a part of an organism, an agent that inhibits NF- ⁇ B translocation to the nucleus, NF- ⁇ B examples include an agent that inhibits the DNA binding activity of B, and an agent that inhibits the transcriptional activity of NF- ⁇ ⁇ ⁇ .
  • the inhibition of the activation of NF- ⁇ or the inhibition of the phosphorylation of I ⁇ can be carried out by administering vitamin 2 or its hydrate to a living body or a part thereof.
  • the dosage and administration method for humans can be referred to the description of the dosage of the pharmaceutical composition containing vitamin 2 described below.
  • the "part of a living body” is a cancer cell line
  • vitamins kappa 2 to 10 '8 to 10, 2 Micromax, preferably 10 ⁇ 7 to 10 ⁇ 3 Micromax, more preferably 10.6 - In a medium containing L0 ' 4 M at a concentration of 12 to 96 hours, preferably
  • the NF- ⁇ B activation inhibitory action and I ⁇ B phosphorylation inhibitory action can also be examined by using the transcriptional activity of NF- ⁇ as an index.For example, they can be examined by the method described in Example 2 or 3. Can be.
  • the “living body” is a living body of a mammal, and in the present invention, the “living body” is preferably a living body of a mammal having cancer, more preferably a living body of a mammal having liver cancer. .
  • “part of a living body” includes each organ, tissue, body fluid (including blood, cerebrospinal fluid, lymph, saliva, etc.) or cells derived from mammals.
  • the “part of the living body” is preferably each organ, tissue or cancer cell that has developed cancer, more preferably liver or liver cancer cell that has developed cancer.
  • the cancer cells may be primary cultured cells or cell lines.
  • a mammal refers to a human or non-human mammal (eg, mouse, rat, hamster, guinea pig, egret, stag, dog, canine, magpie, monkey, etc.).
  • the mammal is preferably a human.
  • vitamin II inhibits cyclin D1 expression in liver cancer cells. Therefore, vitamin II can be used as an active ingredient of a cyclin D1 expression inhibitor.
  • cyclin D1 is known as a protein that regulates the cell cycle.
  • Rb Retinoblastoma protein
  • E2F the transcription factor E2F is released from the E2F-Rb complex, which promotes the transition from the G1 phase to the S phase of the cell cycle and activates cell proliferation (Sherr, CJ Science 274). , 1672-1677, 1996.).
  • vitamin K2 which inhibits the expression of cyclin D1 is useful as a cell-proliferation inhibitor and a therapeutic agent for cancer.
  • vitamin K2 is preferably menatetrenone
  • the subject for suppressing cell growth and the subject for treating cancer are preferably liver cancer cells and liver cancer.
  • the “cyclin D1 expression inhibitor” refers to an agent having an action of decreasing the expression level of cyclin D1 or stopping the expression of cyclin D1 in a living body or a part of the living body.
  • vitamin 2 or a hydrate thereof may be administered to a living body or a part thereof. That is, the activity of the administered vitamin II or a hydrate thereof suppresses the activity of the cyclin D1 promoter and inhibits the expression of cyclin D1.
  • the dosage and administration method for humans can be referred to the description of the dosage of the pharmaceutical composition containing vitamin 2 described below.
  • the "part of a living body” is a cancer cell
  • a vitamin ⁇ 2 10- 8 ⁇ 10- 2 ⁇ preferably 10 - 7 ⁇ : 10 ⁇ 3 Micromax, more preferably 10.6 -
  • the expression of cyclin D1 can be inhibited.
  • the expression level of cyclin D1 can be examined, for example, by measuring the amount of cyclin D1 mRNA by RT "PCR, or by measuring the amount of cyclin D1 protein by dust blotting. It can also be examined, for example, by the method described in Example 1.
  • cancer cell growth inhibitor refers to an agent that has the effect of suppressing the growth of cancer cells, preferably liver cancer cells, or the function of stopping the growth of cancer cells, preferably liver cancer cells.
  • the cyclin D1 expression inhibitor, the NF- ⁇ activation inhibitor, and the B phosphorylation inhibitor are effective in suppressing the growth of cancer cells, preferably liver cancer cells. Therefore, when these inhibitors are administered to a living body or a part thereof, cancer cells, preferably CYCIN D1 expression inhibition, NF- ⁇ B activation inhibition, and / or I / cB phosphorylation inhibition are inhibited. It can suppress the growth of liver cancer cells.
  • the dosage and administration method for Reference can be made to the description of the dosage of the pharmaceutical composition containing Tamine K2.
  • the previous SL "part of a living body" is a cancer cell line
  • vitamins kappa 2 to 10 ⁇ 8 to 10-2 Micromax favored properly is 10 ⁇ 7 ⁇ 10 ⁇ 3 ⁇ , more preferably 10 ' Cell culture can be suppressed by culturing for 12 to 96 hours, preferably 24 to 72 hours, more preferably 48 hours in a medium containing a concentration of 6 to 10 4 ⁇ .
  • Cell growth inhibitory effects can be measured, for example, by measuring nucleic acid uptake (tritiated thymidine method), mitochondrial activity measurement ( ⁇ method, Alamar Blue method, etc.), DNA amount measurement method, glucose A method for measuring consumption, a method for measuring cell number or cell area by image analysis, a method for measuring fluorescence intensity (a method using fluorescently labeled cells), etc., or the method described in Example 4 or 5. , You can also check.
  • cancer treatment refers to suppressing cancer progression in a patient suffering from cancer, eliminating cancer tumors, suppressing tumor growth, preventing the onset of cancer, or recurring cancer. Means to prevent.
  • the “cancer therapeutic agent” refers to an agent used for the above treatment or an agent having a therapeutic effect.
  • the therapeutic agent for cancer of the present invention is administered to a patient, inhibition of cyclin D1 expression, inhibition of NF- ⁇ activation, and / or I / c B phosphate Cancer treatment can be performed through the inhibition of the dagger.
  • the carcinoma to be treated is preferably liver cancer.
  • the effectiveness of cancer treatment can be determined by radiographic findings, CT, MRI, PET, etc., by histopathological diagnosis of biopsy, or by the value of tumor markers.
  • the stage of the cancer is not particularly limited. For example, each stage (stage I, II, III, II, IIIA, III, IV) classified by the TNM classification is included.
  • the cyclin D1 expression inhibitor, NF- ⁇ activation inhibitor, I / c ⁇ phosphorylation inhibitor, anti-inflammatory agent, anti-cyclin D1 expression inhibitor of the present invention comprising vitamin ⁇ 2 or a hydrate thereof as an active ingredient.
  • Rheumatism, immunosuppressant, antiallergic, transplant rejection suppressant, psoriasis treatment, antiviral, arteriosclerosis treatment, ischemic reperfusion injury treatment, renal failure treatment The agent for suppressing cancer cell proliferation, the agent for treating diabetes, or the agent for treating cancer is hereinafter sometimes collectively referred to as “the pharmaceutical composition of the present invention”.
  • vitamin K 2 used in the present invention is synthesized by intestinal bacteria in a living body, so that various homologs having similar structures exist.
  • the structural formula of menaquinone is shown in the following formula (I).
  • n an integer of 1 to 7.
  • Menatetrenone used in the present invention is a chemical compound represented by the chemical name 2-methyl-3-tetrapreninole-1,4-afphtoquinone (2-methl-3-tetraprenyl-1,4-nahthoqumone), and is a typical vitamin K 2 It is. Its structural formula is shown in the following formula (II).
  • Menatetrenone is a yellow crystalline or oily substance that has no odor and is easily decomposed by light. It is hardly soluble in water. Menatetrenone is also referred to as vitamin II-II and VK-II.
  • vitamin II such as menatetrenone
  • blood coagulation factors prothrombin, VII, IX, and X
  • ⁇ -potency glutamate which has biological activity.
  • the pharmacological action of vitamin K2 such as menatetrenone promotes hepatic synthesis of normal oral thrombin and the like, activates the hemostatic mechanism of the living body, and exerts a physiological hemostatic action.
  • Vitamin-2 preferably menatetrenone, which is an active ingredient of the pharmaceutical composition of the present invention, may be an anhydride or may form a hydrate. Menatetrenone may have a polymorphism, but is not limited to a particular crystal form. Any one of the crystal forms may be single or a mixture of crystal forms. Furthermore, the present invention also encompasses metabolites generated by decomposing vitamin ⁇ 2, preferably menatetrenone, or a hydrate thereof used in the present invention in a living body.
  • the vitamin 2 or a hydrate thereof used in the present invention can be produced by a known method, and a typical example is disclosed in JP-A-49-55650. It can be easily manufactured by the method. It can also be obtained as a commercial product from a synthesis manufacturer.
  • Menatetrenone or a hydrate thereof used in the present invention can also be produced by a known method, and a typical example is a method disclosed in Japanese Patent Application Laid-Open No. 49-55650. According to the method, it can be easily manufactured and can be easily obtained from a synthesis manufacturer. Menatetrenone is available in capsules (for example, "K2 Capsule” and “Darakei Capsule” (both from Eisai Co., Ltd.)), injections (for example, "K2 ⁇ ⁇ Note” (Eisai Co., Ltd.)), syrups (For example, “K2SILOP” (manufactured by Eisai Co., Ltd.)).
  • capsules for example, "K2 Capsule” and “Darakei Capsule” (both from Eisai Co., Ltd.)
  • injections for example, "K2 ⁇ ⁇ Note” (Eisai Co., Ltd.)
  • syrups for example, “K2SILOP”
  • vitamin V2 used in the present invention a substance which is metabolized in the body to vitamin V2, preferably menatetrenone, may be used.
  • the substance which is metabolized into menatetrenone in the body is not particularly limited, but examples include vitamin Kl and phytonadione. Phytonadion can be obtained as K-One Capsule (trade name) (Eza Co., Ltd.), K-One Tablet (trade name) (Eisa Co., Ltd.) or Kane-san (trade name) (Eisa Co., Ltd.). it can.
  • the vitamin ⁇ 2 of the present invention preferably menatetrenone or its hydrate, is Although a pharmaceutical composition containing the same as a component can be used as it is, usually, a pharmaceutical composition prepared by mixing appropriate additives is used.
  • additives examples include excipients, binders, lubricants, disintegrants, coloring agents, flavoring agents, emulsifiers, surfactants, solubilizing agents, suspending agents, which are generally used in medicine.
  • examples include isotonic dandruffs, buffers, preservatives, antioxidants, stabilizers, absorption promoters, and the like. If desired, these can be used in appropriate combination.
  • the following are examples of the above additives.
  • Excipients lactose, sucrose, glucose, cornstarch, mannitol, sorbitol Le, starch, alpha starch, dextrin, crystalline cellulose, light anhydrous Kei acid, aluminum Kei, calcium Kei acid, magnesium aluminometasilicate, hydrogen phosphate calcium
  • Binders for example, polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, syrup, hydroxypropylmethyl cenorellose, hydroxypropinoresenolerose, canolepoxymethinoresenolerose sodium, polybierpyrrolidone, Macro goal
  • Lubricants magnesium stearate, calcium stearate, sodium stearyl fumarate, tanolek, polyethylene glycol, colloidal silica
  • Disintegrators crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropyl cerenolose, canoleboximetinolecellulose, phenolic methylcellulose Cros canolemelose sodium, canolepox methinolestarch, canolepoxy methyl starch sodium
  • Coloring agents Iron sesquioxide, yellow sesquioxide, carmine, caramel, beta-potassin, titanium oxide, tanolek, sodium riboflavin phosphate, yellow aluminum lake, etc., which are permitted to be added to pharmaceutical products
  • Flavoring agent cocoa powder, heart-shaped brain, fragrance powder, heart-shaped oil, dragon brain, cinnamon powder emulsifier or surfactant: stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, dariseri monostearate Sucrose fatty acid ester, glycerin fatty acid ester
  • Solubilizers polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium taenoate, polysorbate 80, nicotinic acid amide
  • Suspending agent In addition to the above surfactants, hydrophilic polymers such as, for example, polybutyl alcohol, polybutylpyrrolidone, methinoresenorelose, hydroxymethinoresenorelose, hydroxyshethyl cellulose, and hydroxypropyl cellulose.
  • hydrophilic polymers such as, for example, polybutyl alcohol, polybutylpyrrolidone, methinoresenorelose, hydroxymethinoresenorelose, hydroxyshethyl cellulose, and hydroxypropyl cellulose.
  • Isotonizing agents include glucose, sodium salt, mannitol, sorbitol, and buffering agents: buffers such as phosphate, acetate, carbonate, and citrate.
  • Preservatives methyl paraben, propyl paraben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid
  • Antioxidants sulfate, ascorbic acid, ⁇ -tocopherol
  • Stabilizer commonly used in medicine
  • Absorption enhancers those commonly used in medicine
  • components such as vitamins and amino acids may be added.
  • the above preparations include tablets, powders, granules, fine granules, capsules, syrups, troches, inhalants, etc .; suppositories, ointments, eye ointments, tapes, eye drops Agents, nasal drops, ear drops, cataplasms, lotions and the like, or external preparations and injections.
  • the oral preparation can be formulated by appropriately combining the above additives. In addition, you may coat these surfaces as needed.
  • the above-mentioned external preparations are, among the above-mentioned additives, particularly excipients, binders, flavoring agents, emulsifiers, surfactants, solubilizing agents, suspending agents, isotonic agents, preservatives, antioxidants, It can be formulated by appropriately combining a stabilizer or an absorption enhancer.
  • the above-mentioned injection includes, among the above-mentioned additives, particularly an emulsifier, a surfactant, a solubilizer, a suspending agent, a tonicity agent, a buffer, a preservative, an antioxidant, a stabilizer, or an absorption enhancer. They can be formulated in appropriate combinations.
  • Menatetrenone capsules are available under the brand name K2 Capsule (Eisai Co., Ltd.) Shike Co., Ltd.), Graquet Capsule (Eisai Co., Ltd.), Syrup as K2 Syrup (Eisai Co., Ltd.), and Injection as K2N Note (Eisai Co., Ltd.) Can be obtained.
  • vitamin K2 used in the present invention a substance which is metabolized in the body to form vitamin K2, preferably menatetrenone (for example, vitamin K1, phytonadione, etc.) can also be used.
  • menatetrenone for example, vitamin K1, phytonadione, etc.
  • the capsenole of Huitonadione is sold under the trade name K-One Capsule (manufactured by Eisai Co., Ltd.), and the tablets are manufactured under the trade name K-One Tablet (manufactured by Eisai Co., Ltd.).
  • K-One Capsule manufactured by Eisai Co., Ltd.
  • K-One Tablet manufactured by Eisai Co., Ltd.
  • the pharmaceutical composition of the present invention containing vitamin ⁇ 2 comprises cyclin D1 expression inhibition, NF- ⁇ activation inhibition, I / c ⁇ phosphorylation inhibition, cancer cells, preferably liver cancer cells, Or it is useful for treating cancer, preferably liver cancer.
  • the preferred dose (effective amount) of vitamin ⁇ 2, preferably menatetrenone, or a hydrate thereof is generally 10 to 20 Omg / day per adult (body weight 6 Okg). Yes, preferably 15-; 135 mg / day, more preferably 30-6 Omg / day (eg 45 mg / day).
  • the administration period is not particularly limited, and is, for example, 1 to 100 days, preferably 7 to 300 days.
  • the dose and the administration period can be appropriately set in consideration of the therapeutic effect of cancer and the condition of the patient (for example, performance status).
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered to a patient suffering from cancer, it is possible to obtain a therapeutic effect on cancer without causing side effects (there is only a slight degree that does not affect patients even if side effects occur). is there.
  • the pharmaceutical composition containing vitamin K2 is useful for inflammation, rheumatism, immunosuppression, allergy, transplant rejection, psoriasis, viral disease, arteriosclerosis, ischemic reperfusion injury, diabetes, or renal failure It is.
  • the preferred dose (effective amount) of vitamin K2, preferably menatetrenone, or a hydrate thereof is generally 10 to 200 mg per adult (body weight 6 Okg).
  • the administration period is not particularly limited, and is, for example, 1 to 100 days, preferably 7 to 300 days.
  • the dose and the administration period can be appropriately set in consideration of the therapeutic effect of cancer and the condition of the patient.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered to a patient, it does not cause side effects (there is a slight degree that does not affect the patient even if side effects occur), inflammation, rheumatism, immunosuppression, allergies, transplant rejection , Psoriasis, viral diseases, arteriosclerosis, ischemic reperfusion injury, diabetes or renal failure, and the pharmaceutical composition of the present invention comprises all or a combination of two or more of the above diseases It can be treated or one of the above diseases can be treated. Furthermore, the present invention includes the use of vitamin K2 or a hydrate thereof for producing the pharmaceutical composition of the present invention.
  • the pharmaceutical composition of the present invention comprises, as described above, a pharmaceutical composition comprising vitamin K2 or a hydrate thereof as an active ingredient, and a NF- ⁇ B activation inhibitor or I of the present invention.
  • vitamin K2 is preferably menatetrenone.
  • the present invention provides administering to a patient the pharmaceutical composition of the present invention containing vitamin K2 or a hydrate thereof as an active ingredient, inflammation, rheumatism, immunosuppression, allergy, transplant rejection.
  • vitamin K2 is preferably menatetrenone.
  • a pharmaceutical composition containing vitamin K2 or a hydrate thereof as an active ingredient, or the NF- ⁇ B activation inhibitor or the ⁇ phosphorylation inhibitor of the present invention as an active ingredient The administration route and administration method of the pharmaceutical composition containing the composition are not particularly limited, and the description of the pharmaceutical composition of the present invention can be referred to. 3.
  • the combination of an agent containing vitamin K2 and an antitumor agent of the present invention is useful for treating cancer, preferably liver cancer. That is, the present invention relates to a cancer therapeutic agent comprising vitamin K2 or a hydrate thereof and an antitumor substance (hereinafter, also referred to as “combination pharmaceutical composition of the present invention”), preferably a liver cancer therapeutic agent. provide.
  • the combined pharmaceutical composition of the present invention can be used for treating cancer, preferably for treating liver cancer.
  • the preferred dose (effective amount) of vitamin K2, preferably menatetrenone, or a hydrate thereof is usually 10 to 200 mg / day, preferably 15 to 20 mg / day for an adult (body weight of 6 O kg). 1135 mg / day, more preferably 30-6 O mg Z day (for example, 45 mg Z day).
  • the administration period is not particularly limited, and is, for example, 1 to 100 days, preferably 7 to 300 days. The dose and the administration period can be appropriately set in consideration of the therapeutic effect of cancer and the condition of the patient (for example, performance status).
  • an antitumor substance is a substance having an antitumor action such as an action of suppressing tumor growth, an action of slowing down the growth rate of a tumor, an action of reducing a tumor, or an action of eliminating a tumor.
  • anti-JB ulcer substances include fluorouracil (5-FU, trade name 5-FU), CPT-11 (irinotecan, trade name topotecin, campto), mitomycin C (mytomycin C, trade name mitomycin), and cisplatin (cisplatin).
  • the dose of the antitumor substance is preferably in accordance with a normal clinical dose, and can be increased or decreased as appropriate.
  • “combined” means a combination for use in combination with a compound, in which separate substances are used in combination at the time of administration, and as a mixture. Including both forms.
  • vitamin K 2 or a hydrate thereof, or a formulated antitumor substance can be used.
  • the present invention includes the use of vitamin K2 or a hydrate thereof for producing a pharmaceutical composition in combination with an antitumor substance.
  • vitamin K2 is preferably menatetrenone.
  • the above pharmaceutical composition is useful as an agent for treating cancer.
  • the present invention also includes a method for treating cancer, which comprises administering an effective amount of vitamin K2 or a hydrate thereof and an antitumor substance to a patient simultaneously or separately.
  • vitamin K2 is preferably menatetrenone.
  • the route of administration and the method of administration of vitamin K2 or a hydrate thereof and an antitumor substance are not particularly limited, and the description of the pharmaceutical composition of the present invention can be referred to. .
  • the present invention will be described with reference to specific examples, but the present invention is not limited thereto.
  • menatetrenone was used as vitamin K2 (the title in the figure was “vitamine K2").
  • Example 1 Effect of Menatetrenone on Cyclin D1 Expression
  • menatetrenone suppresses proliferation of liver cancer cells in a concentration-dependent manner, and that the mechanism is that the cell cycle is arrested in G1 phase.
  • the effect of menatetrenone on the expression of the cytaline D1 gene was examined.
  • the cyclin D1 promoter luciferase plasmid The effect on non-cyclin Dl promoter activity was examined.
  • the plasmid used was -1745CD1LUC described in Reference Journal of Biological Chemistry. 270 (40), 23589-23597, 1995.
  • luciferase was used. The activity is sometimes shown as a relative value (relative luciferase activity) when the value in the control is taken as 100).
  • cyclin D1 in liver cancer cells was suppressed by menatetrenone in a concentration-dependent manner at both the protein level and the mRNA level (FIGS. 1A, B;).
  • menatetrenone inhibited the activity of cytaline D1 promoter in liver cancer cells in a concentration-dependent manner (Fig. 1C).
  • cyclin D1 has transcription factor AP-1 and NF- / cB binding regions in its promoter region, and its activity is regulated by these transcription factors.
  • the effect of menatetrenone on the DNA binding activity of NF- ⁇ was examined by gel shift assay according to a conventional method.
  • the effect of menatetrenone on the transcriptional activity of NF-zcB was examined using NF- / cB luciferase reporter plasmid (Clontech).
  • menatetrenone suppressed the DNA binding activity of NF- ⁇ B in moon-dehydrated cancer cells Hep3B and Huh7 in a concentration-dependent manner (Fig. 2).
  • the DNA binding activity of NF- / B was inhibited by NF- ⁇ non-radioactive competitor, but was not suppressed by mutant NF- ⁇ B having no DNA binding activity.
  • a shift in the binding band of NF-KB was observed with antibodies against p65 and p5'0, which are NF-KB subunits.
  • menatetrenone suppressed the luciferase activity of the NF- / cB reporter plasmid in a concentration-dependent manner (Fig. 3).
  • Luciferase reporter assembly was performed using the mutant AP-1 having no binding activity and the cyclin D1 promoter having an NF- ⁇ B binding site, and the effects of the transcription factors AP-1 and NF-zcB were examined.
  • Menatetrenone was allowed to act on liver cancer cells at concentrations of 0, 10-6, 10-5, and 10-4 M for 48 hours, followed by luciferase reporter accession.
  • p65 / RelA a subunit of NF-cB
  • Menatetrenone 12 hours after the introduction into p65 / RelA bra plasmid of (pcDNA3.1 / p65) HepG2, 0 , 10- 6, was added at a concentration of 10- 5, 1CH M, was allowed to act for 48 hours.
  • p65 / RelA is a subunit of NF- ⁇ B
  • its overexpression in cells increases the expression level of NF- ⁇ . Therefore, when menatetrenone inhibits NF- ⁇ B activation and thereby suppresses cyclin D1 promoter activity, if the expression level of NF- ⁇ B increases, menatetrenone inhibits cyclin D1 promoter activity. The effect is expected to be suppressed.
  • menatetrenone was shown to be wild-type The luciferase activity of the Clin Dl promoter was suppressed (Fig. 4, top 1 and 2). Similar to the wild-type cyclin D1 promoter, the activity of the cyclin D1 promoter (-964AP-lmtCD1LUC) having the mutant AP-1 binding site was suppressed by menatetrenone in a concentration-dependent manner (Fig. 4, top 3). ). However, whereas the cyclin D1 promoter containing the wild-type NF- / cB binding site was repressed by menatetrenone in a concentration-dependent manner (the second row from the bottom in Fig. 4), the mutant NF- ⁇ In the cyclin D1 promoter (_66NF-KBmutCD1LUC), the suppression of promoter activity by menatetrenone was not observed (the first row from the bottom in FIG. 4).
  • menatetrenone exhibits an inhibitory effect on the cyclin D1 promoter activity by suppressing NF-zcB activation.
  • Example 4 Examination of NF- / cB and Citalin D1 Dependence of Hepatoma Cell Proliferation Inhibition by Menatetrenone
  • menatetrenone was reduced to 0, 10 using liver cancer cell HepG2 transfected with luciferase plasmid having a consensus sequence for NF- ⁇ in the promoter region as a reporter gene.
  • the effect of menatetrenone on the DNA binding activity of NF- / cB was examined using HepG2 cells without stimulation and under stimulation with TPA, TNF- ⁇ , and IL-lj3 by the gel shift assay using the usual method. did.
  • menatetrenone When menatetrenone was added to HepG2 cells and the activity of NF-zcB was measured using a luciferase reporter assay, menatetrenone inhibited NF- ⁇ activity in a concentration-dependent manner (FIG. 10). Furthermore, ⁇ 20 nM, respective concentrations of TNF- a 10 nM, IL-1 ⁇ 1 nM was added to NF-? Kappa 0 menatetrenone the B in the state of being activated, 10 ⁇ 6, 10 ⁇ 5 , 10 ⁇ 4 M In all cases, the induced NF- / cB activity was suppressed in a concentration-dependent manner (FIG. 10).
  • the phosphorylation reaction by the kinase activity is performed by adding ⁇ -32 ⁇ - ⁇ to a solution containing the substrate GST-IK Bo; (1-54) and adding a certain amount of ⁇ complex to the solution at 37 ° C. minutes reacted, after electrophoresis anti ⁇ product in SDS-PAGE gels and detected phosphorylation of Iotakappabeta alpha by autoradiography scratch.
  • menatetrenone was not stimulated in various liver cancer cells and in various NF- / In the presence of the c B stimulus signal, it was found to have a concentration-dependent inhibitory effect on the activity of NF- ⁇ B.
  • NF- ⁇ p50 / p65 dimer
  • menatetrenone is NF- ⁇ (p50 / p65 dimer) suppresses the translocation to the nucleus and suppresses the phosphorylation of Ba ⁇ Ba, which is stagnated in the cytoplasm, and phosphorylates ⁇ . It shows that the effect is exhibited by suppressing It was.
  • cyclin D1 inhibits the expression of cyclin D1, inhibit NF- ⁇ , and inhibit ⁇ phosphoric acid in cancer cells, preferably in liver cancer cells, by using vitamin ⁇ 2.
  • these inhibitory effects suppress the growth of cancer cells, preferably liver cancer cells, it has become possible to select and treat patients who can expect a more therapeutic effect.
  • the antitumor effect of menatetrenone is enhanced by using menatetrenone in combination with an antitumor substance. It has made it possible to greatly improve the quality of life of cancer patients.
  • vitamin ⁇ 2 activates NF- ⁇ and I ⁇ Vitamin K2 is an anti-inflammatory, anti-rheumatic, immunosuppressant, antiallergic, transplant rejection inhibitor, psoriasis treatment, antiviral, arteriosclerosis treatment, ischemic It can be used as an active ingredient in therapeutic agents for perfusion injury, diabetes and renal failure.

Abstract

Inhibiteurs de l'activation de NF-κB et inhibiteurs de la phosphorylation de IκB, contenant de la vitamine K2 ou des hydrates de celle-ci comme ingrédient actif. L'invention amène non seulement l'efficacité de la vitamine K2 comme remède pour un patient souffrant d'un cancer du foie mais également une sûreté extrêmement élevée dans une administration à long terme de vitamine K2, ce qui permet le traitement à long terme avec de la vitamine K2 et contribue à une grande amélioration de la qualité de vie d'un patient souffrant d'un cancer du foie.
PCT/JP2005/009112 2004-05-12 2005-05-12 Remèdes contenant de la vitamine k2 comme ingrédient actif WO2005107731A1 (fr)

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WO2011031602A1 (fr) * 2009-09-14 2011-03-17 Nestec S.A. Compositions nutritionnelles destinees a moduler l'inflammation, contenant de la vitamine k2 exogene
EP2671574A1 (fr) * 2012-06-04 2013-12-11 VitaK B.V. Utilisation de la vitamine K pour réduire la défaillance d'allogreffon et mortalité de patient après une transplantation d'organe

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JP2003040792A (ja) * 2001-07-23 2003-02-13 West Park Kk リグニンの新規用途

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011031602A1 (fr) * 2009-09-14 2011-03-17 Nestec S.A. Compositions nutritionnelles destinees a moduler l'inflammation, contenant de la vitamine k2 exogene
WO2011031601A3 (fr) * 2009-09-14 2011-06-03 Nestec S.A. Compositions nutritionnelles comprenant de la vitamine k2 exogène
JP2013504571A (ja) * 2009-09-14 2013-02-07 ネステク ソシエテ アノニム 外因性ビタミンｋ２を含む栄養組成物
JP2013504572A (ja) * 2009-09-14 2013-02-07 ネステク ソシエテ アノニム 外因性ビタミンｋ２を含む炎症調節用栄養組成物
AU2010292440B2 (en) * 2009-09-14 2015-06-18 Société des Produits Nestlé S.A. Nutritional compositions for modulating inflammation including exogenous vitamin K2
JP2016041705A (ja) * 2009-09-14 2016-03-31 ネステク ソシエテ アノニム 外因性ビタミンｋ２を含む炎症調節用栄養組成物
EP2671574A1 (fr) * 2012-06-04 2013-12-11 VitaK B.V. Utilisation de la vitamine K pour réduire la défaillance d'allogreffon et mortalité de patient après une transplantation d'organe
WO2013182578A1 (fr) 2012-06-04 2013-12-12 Vitak B.V. Utilisation de vitamine k pour réduire l'échec d'allogreffe et la mortalité de patients après une transplantation d'organe

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