US20100184859A1 - Medicament having promoting action on hepatocyte proliferation - Google Patents

Medicament having promoting action on hepatocyte proliferation Download PDF

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Publication number
US20100184859A1
US20100184859A1 US12/665,342 US66534208A US2010184859A1 US 20100184859 A1 US20100184859 A1 US 20100184859A1 US 66534208 A US66534208 A US 66534208A US 2010184859 A1 US2010184859 A1 US 2010184859A1
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acid
medicament
proliferation
promoting
hepatocytes
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Masahiko Ogihara
Mitsutoshi Kimura
Naoto Ishibashi
Jun Kojima
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JOSAI UNIVERSITY EDUCATIONAL Corp
Kowa Co Ltd
Josai Univ Educational Corp
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Kowa Co Ltd
Josai Univ Educational Corp
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Assigned to KOWA COMPANY, LTD., JOSAI UNIVERSITY EDUCATIONAL CORPORATION reassignment KOWA COMPANY, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ISHIBASHI, NAOTO, KOJIMA, JUN, KIMURA, MITSUTOSHI, OGIHARA, MASAHIKO
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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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/745—Polymers of hydrocarbons
    • 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
    • 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 medicament comprising a polyprenyl compound having a promoting action on hepatocyte proliferation as an active ingredient and used for a liver regeneration therapy.
  • liver regeneration therapy at present, glucagon-insulin therapy has been clinically used for fulminant hepatitis.
  • effectiveness thereof is not satisfactory.
  • hepatoma resection is not applied to those with complication of chronic hepatitis or cirrhosis showing decrease of hepatic residual function, because sufficient liver regeneration cannot be expected after the resection and a problem of hepatic failure may arise.
  • it is strongly desired to develop a medicament having a promoting action on liver regeneration which is safely usable for prophylactic and/or therapeutic treatment of fulminant hepatitis or hepatic failure after hepatoma resection.
  • hepatoma is a disease associated with poor prognosis, and it is known that the disease recurs at a high rate even after treatment.
  • a substance as a medicament that induces transformation of hepatocytes or a substance having proliferation promoting action on cancer cells, even if said substance has promoting action on hepatocyte proliferation, because the substance may promote recurrence of hepatoma. Therefore, in order to improve treatment results of hepatoma and prevent recurrence thereof over a long period of time, it is an important subject to develop a medicament that suppresses oncogenesis in the liver and promotes liver regeneration.
  • retinoids such as all-trans-retinoic acid (ATRA), 9-cis-retinoic acid (9CRA), and fenretinide are reported, and among them, ATRA is reported to induce the proliferation of mouse hepatocytes.
  • ATRA is also reported to promote oncogenesis in a mouse liver carcinogenic model, and therefore safety of ATRA is questioned.
  • ATRA retinoic acid syndrome
  • retinoic acid syndrome various symptoms including pyrexia, dyspnoea, retention of pleural effusion, lung infiltration, interstitial pneumonia, pulmonary congestion, hypoxemia, hypotension, hepatic failure, renal failure, and multiple organ failure
  • leukocytosis leukocytosis
  • NIK-333 polyprenyl compounds, (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid
  • this substance may also be referred to as “NIK-333”
  • NIK-333 polyprenyl compounds, (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid
  • Non-patent documents 7 and 8 it has been reported that NIK-333 does not affect proliferation of primarily cultured mouse hepatocytes at a concentration inducing apoptosis of hepatoma cells (Non-patent documents 7 and 8), and it has also been reported that NIK-333 delays DNA synthesis of a regenerated liver in a rat partially hepatectomized model (Non-patent document 9).
  • Non-patent document 1 Biohem. Biophys. Res. Commun., 133, pp. 1042-1050, 1985
  • Non-patent document 2 Proc. Natl. Acad. Sci. USA, 86, pp. 1558-1562, 1989
  • Non-patent document 3 Cell, 18, pp.153-163, 1979
  • Non-patent document 4 Eur. J. Pharmacol., 510, pp. 167-180, 2005
  • Non-patent document 5 Kanzo (Liver, Journal of the Japan Society of Hepatology, 44, pp. 383-394, 2003
  • Non-patent document 6 N. Eng. J. Med., 334, pp. 1561-1567, 1996
  • Non-patent document 7 Biohem. Biophys. Res. Commun., 219, pp. 100-104, 1996
  • Non-patent document 8 J. Lipid Res., 45, pp. 1092-1103, 2004
  • Non-patent document 9 Kanzo, 26, pp. 605-612, 1985
  • Patent document 1 Japanese Patent Unexamined Publication (KOKAI) No. 8-67628
  • Patent document 2 Japanese Patent Unexamined Publication No. 5-229940
  • Patent document 3 Japanese Patent Unexamined Publication No. 2007-23002
  • Patent document 4 Japanese Patent Unexamined Publication No. 2007-45721
  • Patent document 5 Japanese Patent Unexamined Publication No. 2003-2522792
  • An object of the present invention is to provide a medicament for promoting liver regeneration which has a promoting action on hepatocyte proliferation and is useful for therapeutic and/or prophylactic treatment of hepatic failure, and the like.
  • a particularly preferred object of the present invention is to provide the aforementioned medicament having both of a promoting action on hepatocyte proliferation and a liver oncogenesis suppressing action as a medicament useful for prophylactic and therapeutic treatments of hepatoma.
  • the inventors of the present invention conducted various researches to find a substance having a promoting action on hepatocyte proliferation and useful as a medicament for promotion of liver regeneration.
  • polyprenyl compounds which was reported to have a liver oncogenesis suppressing action, promoted the proliferation of primarily cultured rat hepatocytes at a low concentration not affecting proliferation of hepatoma cells, and that the proliferated cells maintained cell density dependency, namely, the cells were non-transformation-induced cells (non-hepatoma cells), indicating that polyprenyl compounds selectively promoted the proliferation of normal hepatocytes.
  • the present invention was accomplished on the basis of the aforementioned findings.
  • the present invention thus provides a medicament for promoting proliferation of hepatocytes, which comprises a polyprenyl compound as an active ingredient.
  • the present invention also provides a medicament for promoting regeneration of liver, which comprises a polyprenyl compound as an active ingredient.
  • the aforementioned medicament which is used for promotion of liver regeneration in a therapeutic treatment of hepatoma
  • the aforementioned medicament which is used for promotion of liver regeneration after resection of hepatoma are provided.
  • the aforementioned medicaments wherein the polyprenyl compound is a polyprenylcarboxylic acid; the aforementioned medicaments, wherein the polyprenylcarboxylic acid is 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid; and the aforementioned medicaments, wherein the polyprenylcarboxylic acid is (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid.
  • a polyprenyl compound preferably a polyprenylcarboxylic acid, more preferably 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid, particularly preferably (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid, for manufacture of the aforementioned medicaments; a method for promoting proliferation of hepatocytes, which comprises the step of administering an effective amount of a polyprenyl compound to a mammal including human in need of promotion of proliferation of hepatocytes; and a method for promoting liver regeneration, preferably promoting liver regeneration in therapeutic treatment of hepatoma, which comprises the step of administering an effective amount of a polyprenyl compound to a mammal including human in need of regeneration of liver.
  • FIG. 1 is a graph showing action of retinoids and polyprenyl compounds for promoting proliferation of primarily cultured rat hepatocytes. Meanings of the abbreviations used in the graph are as follows: NIK-333: (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid, trans: all-trans-retinoic acid, cis: 9-cis-retinoic acid, GG: geranylgeraniol, and GGP: geranylgeranyl pyrophosphate ammonium salt, and “*” and “**” indicate that there is significant difference (P ⁇ 0.05 or P ⁇ 0.01, respectively) compared with the control group in which the solvent was added.
  • NIK-333 (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid
  • trans all
  • FIG. 2 is a graph showing cell density dependency with the action of retinoids and polyprenyl compounds for promoting proliferation of primarily cultured rat hepatocytes.
  • the abbreviations used in the graph have the same meanings as those of FIG. 1 , and “*” indicates that there is significant difference (P ⁇ 0.05) compared with the control group in which the solvent was added.
  • FIG. 3 is a graph showing that NIK-333 have no promoting action on the proliferation of a cell line derived from human hepatic cancer at a concentration showing the action of promoting proliferation of primarily cultured rat hepatocytes.
  • FIG. 4 is a graph showing effect of NIK-333 for promoting liver regeneration in a partially hepatectomized liver regeneration model animal. The values are indicated as average ⁇ standard error in the graph, and “*” indicates that there is significant difference (P ⁇ 0.05).
  • the medicament of the present invention is characterized to comprise a polyprenyl compound as an active ingredient, and to have an action of promoting proliferation of hepatocytes and an action of promoting liver regeneration.
  • polyprenyl compound as the active ingredient of the medicament of the present invention examples include, for example, 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid, geranylgeranoic acid (GGA), phytanic acid, and the like, which are polyprenylcarboxylic acid, as well as polyprenylcarboxylic acid esters, vitamin K1, vitamin K2, and the like.
  • the polyprenyl compound used as the active ingredient of the medicament of the present invention may be a cyclic or acyclic polyprenyl compound
  • the compound is preferably an acyclic polyprenyl compound.
  • the acyclic polyprenyl compound means a compound containing several straight chain isoprene units. Type of the functional group at the end of the acyclic polyprenyl compound is not particularly limited.
  • Examples include polyprenyl alcohols (polyprenols) having a primary allylic hydroxyl group at the end, compounds consisting of a polyprenol of which end hydroxyl group forms an ester with an organic acid, polyprenylcarboxylic acids having carboxyl group at the end, and the like, but not limited to these examples.
  • Polyprenylcarboxylic acids can be preferably used.
  • Preferred polyprenylcarboxylic acids include, for example, 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid, and more preferred polyprenyl carboxylic acids include (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (NIK-333).
  • the polyprenyl compounds used in the present invention can be synthesized by known methods (Japanese Patent Publication (KOKOKU) No. 63-32058, J. Chem. Soc. (C), p. 2154, 1966, and the like).
  • polyprenyl compound a physiologically acceptable salt thereof may be used.
  • Type of the salt is not particularly limited, and it may be an acid addition salt or base addition salt.
  • a hydrate or solvate of a polyprenyl compound in a free form or in the form of a salt may also be used.
  • the term “polyprenyl compound” used in this specification encompasses salts, hydrates, solvates, and the like, as well as arbitrary stereoisomers (including enantiomers and diastereoisomers), mixtures of stereoisomers, arbitrary geometrical isomers, arbitrary mixtures of geometrical isomers, and the like.
  • the medicament provided by the present invention has a promoting action on hepatocyte proliferation, and also has a promoting action on liver regeneration based on the promoting action on hepatocyte proliferation. Therefore, the medicament of the present invention can achieve, for example, promotion of the regeneration of the liver on the basis of the promotion on the proliferation of normal hepatocytes in hepatic diseases such as hepatic failure or hepatoma, and thereby therapeutic treatments of the liver diseases can be efficiently attained. Moreover, the medicament of the present invention can also be used from a preventive viewpoint, for example, for prevention of recurrence of a hepatic disease by attaining normalization of the liver on the basis of the liver regeneration.
  • the hepatic disease as a target of application of the medicament of the present invention is not particularly limited. Examples include viral or alcoholic acute or chronic hepatitis, fulminant hepatitis, cirrhosis, hepatic failure, hepatoma, and the like, but not limited to these examples.
  • Polyprenyl compounds are known to have an apoptosis inducing action for hepatoma cells, and it has been reported that NIK-333 does not affect proliferation of hepatocytes at a concentration inducing the apoptosis (Non-patent documents 7 and 8). Although it is not intended to be bound by any specific theory, the promoting action on hepatocyte proliferation of the polyprenyl compounds of the present invention is exhibited at a concentration lower than the concentration at which the apoptosis of hepatoma cells is induced.
  • polyprenyl compounds exhibit a proliferation promotion action for normal hepatocytes to selectively proliferate normal hepatocytes at a low concentration, and selectively induce apoptosis of hepatoma cells at a high concentration to exhibit an anticancer action.
  • the medicament of the present invention can induce apoptosis of hepatoma cells when a high blood concentration thereof is maintained immediately after the administration, and can exhibit a proliferation promotion action for normal hepatocytes when a low blood concentration thereof is obtained several hours after the administration, and therefore the medicament can be used as an extremely safe and effective medicament.
  • high concentration administration or low concentration administration depending on the therapeutic stage, for example, high concentration administration can be maintained immediately after resection of hepatoma to eradicate hepatoma cells, and low concentration administration can be maintained to promote liver regeneration during the following convalescence period.
  • the medicament of the present invention can usually be prepared as a pharmaceutical composition comprising a polyprenyl compound, and administered by an appropriate administration method of oral administration or parenteral administration.
  • forms of the pharmaceutical composition suitable for oral administration include, for example, tablets, granules, capsules, soft capsules, pills, powders, solutions, and the like.
  • forms of the pharmaceutical composition for parenteral administration include, for example, injections, suppositories, and the like.
  • These pharmaceutical compositions can be prepared by a conventional method using a polyprenyl compound or a pharmacologically acceptable salt thereof and one or more kinds of usual pharmaceutical carriers.
  • a desired pharmaceutical composition can be prepared by using, as pharmaceutical carriers, excipients such as lactose, glucose, corn starch and sucrose, disintegrating agents such as carboxymethylcellulose calcium and hydroxypropylcellulose, lubricants such as calcium stearate, magnesium stearate, talc, polyethylene glycol and hydrogenated oil, binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gelatin and gum arabic, and moistening agents such as glycerin and ethylene glycol, as well as surfactants, flavoring agents and the like as required.
  • excipients such as lactose, glucose, corn starch and sucrose
  • disintegrating agents such as carboxymethylcellulose calcium and hydroxypropylcellulose
  • lubricants such as calcium stearate, magnesium stearate, talc
  • polyethylene glycol and hydrogenated oil binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose,
  • medicament suitable for parenteral administration there can be used, as pharmaceutical carriers, diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oil, agar and tragacanth gum as well as dissolving aids, suspending agents, emulsifiers, stabilizers, buffers, isotonic agents, preservatives, soothing agents and the like as required.
  • diluents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oil, agar and tragacanth gum
  • dissolving aids such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oil, agar and tragacanth gum
  • suspending agents such as water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oil, agar and tragacanth gum
  • suspending agents such as water, ethanol, glycerin,
  • dose of the medicament of the present invention is not particularly limited, for example, it may be, for an adult, 50 to 1,200 mg, preferably 300 to 900 mg, per day in the case of oral administration, or 1 to 1,200 mg, preferably 5 to 900 mg, per day in the case of parenteral administration. Desired promoting effects can be expected by administering the compound at a dose within the aforementioned range 1 to 3 times per day as the whole amount or divided amounts.
  • Wistar male rats (weight: 200 to 205 g) were used, and hepatocytes were isolated by the in situ collagenase perfusion technique according to the method of Seglen et al. (Methods. Cell Biol., 13, pp. 29-83, 1975).
  • the isolated hepatocytes were suspended in the Williams' medium E (containing 0.1 ⁇ g/mL aprotinin, 100 U/mL of penicillin G, 0.1 mg/mL of streptomycin, and 0.1 nmol/L of dexamethasone) containing 5% bovine neonate serum 3 times for washing, and then inoculated on a collagen coated culture dish (35 mm ⁇ ) at a cell density of 3.3 ⁇ 10 4 cells/cm 2 .
  • the cells were adhered to the culture dish by culturing them at 37° C. for 3 hours in the presence of 5% CO 2 to prepare a primarily cultured hepatocyte cell line. Survival rate of the isolated hepatocytes was obtained by the trypan blue exclusion method, and those showing a survival rate not lower than 93% were used for the following experiments.
  • the medium of the isolated hepatocytes was replaced with serum-free Williams' medium E (containing 0.1 ⁇ g/mL of aprotinin, 100 U/mL of penicillin G, 0.1 mg/mL of streptomycin), and (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (NIK-333), all-trans retinoic acid (trans), 9-cis-retinoic acid (cis), geranylgeraniol (GG) and geranylgeranyl pyrophosphate ammonium salt (GGP) were each added at final concentrations of 10 ⁇ 11 , 10 ⁇ 10 , 10 ⁇ 9 , 10 ⁇ 8 , 10 ⁇ 7 , and 10 ⁇ 6 mol/L.
  • serum-free Williams' medium E containing 0.1 ⁇ g/mL of aprotinin, 100 U/mL of penicillin G, 0.1 mg
  • a phosphate buffer (PBS, pH 7.4) containing 0.01% DMSO was used as the solvent.
  • number of nuclei was measured as follows. The hepatocytes were washed with PBS, and then added with 0.25 mL of a 0.1 mol/L citric acid solution containing 0.1% Triton X-100. The cells were incubated at 37° C. for 30 minutes to solubilize the cell membranes and thereby obtain naked nuclei. The same volume of a PBS solution containing 0.3% trypan blue was further added, and number of the stained nuclei was measured with a hemacytometer. As shown in FIG. 1 , significant effect of promoting proliferation of the primarily cultured rat hepatocytes was observed for NIK-333, trans, and GGP, and NIK-333 gave the strongest effect.
  • NIK-333 (10 ⁇ 9 mol/L), trans (10 ⁇ 7 mol/L), cis (10 ⁇ 6 mol/L), GG (10 ⁇ 7 mol/L), and GGP (10 ⁇ 6 mol/L) were each added to the hepatocytes pre-cultured in the same manner as that of Example 1.
  • number of nuclei was measured by the same method as that of Example 1.
  • trans gave the cell proliferation promoting action even when the cell density was increased, and thus action of inducing transformation of hepatocytes was suggested.
  • the cell proliferation promoting action of NIK-333 and GGP was decreased with the increase of the cell density, and it was suggested that the cells were maintained to be in normal forms.
  • Cells of cell lines derived from human hepatoma were cultured by using a minimum essential medium (MEM) (100 U/mL of penicillin G, 0.1 mg/mL of streptomycin) containing 5% bovine neonate serum.
  • MEM minimum essential medium
  • the cells were inoculated on a 96-well plate at a cell density of 1 ⁇ 10 4 cells/mL, and cultured overnight at 37° C. in the presence of 5% CO 2 .
  • the medium was exchanged for a 1% serum containing MEM (100 U/mL of penicillin G, 0.1 mg/mL of streptomycin), and NIK-333 was added at final concentrations of 10 ⁇ 11 , 10 ⁇ 10 , 10 ⁇ 9 , 10 ⁇ 8 , and 10 ⁇ 7 mol/L.
  • As the solvent DMSO was used.
  • the cells were cultured overnight at 37° C. in the presence of 5% CO 2 , and live cell count was measured. The live cell count was measured by using Cell Counting Kit (Wako Pure Chemical Industries). A WST-1 solution was added to each well in a volume of 10 ⁇ L, and the culture was incubated at 37° C. for 3 hours in the presence of 5% CO 2 .
  • NIK-333 gave no proliferation promotion action for any of the four kinds of cell strains derived from human hepatoma.
  • Hepatocyte proliferation promoting effect of NIK-333 was examined by using a 70% partially hepatectomized rat (partial hepatectomy: PH rat) as an in vivo experiment system.
  • Wistar male rats (weight: 130 to 170 g) were subjected to 70% partial hepatectomy according to the method of Higgins G. M. et al. (Arch. Pathol., 12, pp.186-202, 1931) to prepare PH rats.
  • NIK-333 solvent was soybean oil, 0.4 mg/kg/day
  • the model animals fed for 1 to 14 days after the hepatectomy were subjected to abdominal section under diethyl ether anesthesia, and the remaining livers were extracted.
  • the remaining livers were separated into normal hepatic tissues and necrotizing hepatic tissues (liver tissues which were not excisable by the partial hepatectomy and remained), and weight of each was measured (wet weight). The examination was performed for three animals for each group, and the results are indicated as average ⁇ standard error. Student t-test was performed between a solvent administered group (soybean oil, 4 mL/kg, p.o.) as a control group and the NIK-333 administered group. The significance level of the test was set at 5% and 1% on both sides.
  • the liver weight of the control group was 2.5 g liver weight/100 g body weight (LW/BW) (increase rate was about 70%)
  • the liver weight of the NIK-333 administered group was 3.0 g LW/BW (increase rate was 85%), and thus significant difference was observed between both the groups.
  • the results are shown in FIG. 4 (the values in the graph are indicated as average ⁇ standard error, and * indicates that there is significant difference with P ⁇ 0.05).
  • NIK-333 exhibited an action of promoting proliferation of normal hepatocytes as shown by the in vitro experiment system (primarily cultured hepatocyte system) at an early stage, and also promoted liver regeneration without resulting hyperproliferation.
  • the medicament provided by the present invention has promoting action on liver regeneration based on promoting action on hepatocyte proliferation, and can selectively proliferate normal hepatocytes. Therefore, the medicament is useful for liver regeneration, for example, in therapeutic treatment of hepatoma, and the like.

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CA3071363A1 (en) 2017-07-28 2019-01-31 Nissan Chemical Corporation Additive composition for culture medium, additive compound for culture medium, and method for culture of cells or tissue using same
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JP5352459B2 (ja) 2013-11-27
US20120220659A1 (en) 2012-08-30
EP2168577A4 (en) 2010-10-27
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KR20100040725A (ko) 2010-04-20
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