WO2015093588A1 - 抗癌剤 - Google Patents
抗癌剤 Download PDFInfo
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- WO2015093588A1 WO2015093588A1 PCT/JP2014/083657 JP2014083657W WO2015093588A1 WO 2015093588 A1 WO2015093588 A1 WO 2015093588A1 JP 2014083657 W JP2014083657 W JP 2014083657W WO 2015093588 A1 WO2015093588 A1 WO 2015093588A1
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- cancer
- malignant
- glycero
- phosphoethanolamine
- dipalmitoleoyl
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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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- 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 an anticancer agent containing a phospholipid compound having a cancer cell growth inhibitory action, particularly diacylphosphatidylethanolamine as an active ingredient.
- a liposome preparation is a preparation in which a drug is encapsulated in particles having a bilayer structure formed by phospholipids, and detailed analysis of targeting to cancer cells is being conducted.
- Phospholipids are the main lipids constituting the biological membrane system, and are classified into glycerophospholipids having a glycerol skeleton and sphingophospholipids having a sphingosine skeleton. Furthermore, glycerophospholipids are classified into phospholipid classes such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cardiolipin, and phosphatidic acid depending on the type of hydrophilic moiety.
- inositol phospholipids are known to play a role in intracellular signal transduction pathways by phospholipase C and as anchors to the membrane of proteins.
- Phosphatidylserine which regulates the activity of lipids, blood coagulation proteins, protein kinase C, etc., sphingomyelin pathway involved in the regulation of protein kinase C activity and apoptosis of cells, retention of inflammatory mediator arachidonic acid and phospholipase D
- the phosphatidylcholine pathway involved in signal transduction pathways, platelet activation factors such as platelet activation, vascular permeability, leukocyte migration activity, and platelet activation factors, etc. have been reported. .
- 1,2-dilinoleoyl-sn-glycero-3-phosphocholine or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine is a spatial learning and memory disorder or mild cognitive impairment induced by scopolamine And improving dementia (Non-Patent Documents 1 and 2).
- phosphatidylethanolamine is a phospholipid that is one of the main components of biological membranes and is marketed as a health food along with phosphatidylserine and the like.
- phosphatidylethanolamines in particular, dilinoleoyl phosphatidylethanolamine (as fatty acids) (Including two linoleic acids) have cell death induction inhibitory activity, particularly endoplasmic reticulum stress inhibitory activity. Due to this activity, dilinoleoyl phosphatidylethanolamine is used for pharmaceutical use, particularly for prevention and / or treatment of neurodegenerative diseases. (Patent Document 1).
- An object of the present invention is to provide an anticancer agent having a novel action mechanism.
- phosphatidylethanolamine has excellent protein phosphatase 2A (PP2A) activation enhancing action and protein tyrosine phosphatase 1B (PTP1B) activation enhancing action. It was. Furthermore, the excellent anticancer action of phosphatidylethanolamine having palmitic acid as a fatty acid was confirmed and the present invention was completed. That is, the present invention is as follows. [1] An anticancer agent containing 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine as an active ingredient.
- Cancers to be treated are glioblastoma, medulloblastoma, tongue cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer , Adrenal cancer, bladder cancer, prostate cancer, penile cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, breast cancer, thyroid cancer, lung cancer, malignant pleural mesothelioma, skin cancer, malignant melanoma, malignant bone tumor, soft part
- the anticancer agent according to the above [1] which is at least one selected from the group consisting of sarcoma, malignant lymphoma, leukemia, and multiple myeloma.
- cancer to be treated is at least one selected from the group consisting of lung cancer, malignant pleural mesothelioma, stomach cancer, colon cancer and breast cancer.
- Cancer cells are glioblastoma, medulloblastoma, tongue cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer, adrenal cancer , Bladder cancer, prostate cancer, penile cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, breast cancer, thyroid cancer, lung cancer, malignant pleural mesothelioma, skin cancer, malignant melanoma, malignant bone tumor, soft tissue sarcoma, malignant
- the agent of the above-mentioned [3] which is at least one cancer cell selected from the group consisting of lymphoma, leukemia, and multiple myeloma.
- cancer cells are at least one cancer cell selected from the group consisting of lung cancer, malignant pleural mesothelioma, gastric cancer, colon cancer and breast cancer.
- a protein tyrosine phosphatase 1B activation enhancer comprising 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine as an active ingredient.
- Cancer is glioblastoma, medulloblastoma, tongue cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer, adrenal cancer, Bladder cancer, prostate cancer, penile cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, breast cancer, thyroid cancer, lung cancer, malignant pleural mesothelioma, skin cancer, malignant melanoma, malignant bone tumor, soft tissue sarcoma, malignant lymphoma
- the method is at least one selected from the group consisting of leukemia and multiple myeloma.
- cancer is at least one selected from the group consisting of lung cancer, malignant pleural mesothelioma, stomach cancer, colon cancer and breast cancer.
- a method for inducing cell death of cancer cells comprising treating cancer cells with 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine.
- the cancer cells are glioblastoma, medulloblastoma, tongue cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer, adrenal cancer.
- the cell is at least one cancer cell selected from the group consisting of lymphoma, leukemia, and multiple myeloma.
- the cancer cells are cells of at least one cancer selected from the group consisting of lung cancer, malignant pleural mesothelioma, stomach cancer, colon cancer and breast cancer.
- Cancer is glioblastoma, medulloblastoma, tongue cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer, adrenal cancer, Bladder cancer, prostate cancer, penile cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, breast cancer, thyroid cancer, lung cancer, malignant pleural mesothelioma, skin cancer, malignant melanoma, malignant bone tumor, soft tissue sarcoma, malignant lymphoma 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine according to [13] above, which is at least one selected from the group consisting of leukemia, leukemia, and multiple
- Phosphatidylethanolamine particularly phosphatidylethanolamine having palmitic acid as a constituent fatty acid has an excellent cancer cell death-inducing action.
- phospholipid compounds such as phosphatidylethanolamine are naturally present in living bodies. Therefore, this invention can provide the anticancer agent which was excellent in safety
- FIG. 1 is a graph showing the effect of various phosphatidylethanolamines on the activity of protein phosphatase 2A (PP2A) and protein tyrosine phosphatase 1B (PTP1B).
- A shows the result of PP2A
- B shows the result of PTP1B.
- the vertical axis shows the activity of each phosphatase.
- DAPE 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine
- DLPE 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine
- DOPE 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
- DPPE 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine
- Oka A okadaic acid.
- FIG. 2 is a scheme schematically showing the action sites of PP2A and PTP1B in cell proliferation.
- RTK receptor tyrosine kinase
- MAPK mitogen-activated protein kinase
- MAPKK mitogen-activated protein kinase kinase
- MAPKKK mitogen-activatedaseprotein kinase kinase kinase
- GDP guanosine diphosphate
- GTP guanosine triphosphate
- FIG. 3 is a graph showing that 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine (DPPE) induces human malignant pleural mesothelioma cell death in a concentration-dependent manner.
- DPPE 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine
- A shows the result of Met5A which is a human non-malignant mesothelioma cell
- B shows the result of NCI-H28 which is a human malignant mesothelioma cell.
- ⁇ indicates the results of 24 hours of treatment
- ⁇ indicates the results of 48 hours of treatment.
- the vertical axis represents cell viability
- the horizontal axis represents DPPE concentration.
- FIG. 4 is a graph showing that DPPE induces apoptosis of human malignant pleural mesothelioma cells.
- the vertical axis represents the proportion of TUNEL-stained cells in all cells, and the horizontal axis represents the concentration of DPPE.
- the present invention uses phosphatidylethanolamine as an active ingredient.
- phosphatidylethanolamines used as an active ingredient in the present invention, 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine (DPPE) is preferred, and an anticancer agent containing the phosphatidylethanolamine as an active ingredient I will provide a.
- DPPE is also called dipalmitoleoyl phosphatidylethanolamine.
- phospholipids There are roughly two types of phospholipids: glycerophospholipids with a glycerin skeleton and sphingophospholipids with a sphingosine skeleton. It has a structure in which two fatty acids and phosphoric acid are combined with glycerin or sphingosine as a central skeleton, and alcohol is ester-bonded to phosphoric acid.
- DPPE is a glycerophospholipid, in which two fatty acids bonded to glycerin as a central skeleton are palmitic acid, and an alcohol esterified to phosphoric acid is ethanolamine.
- DPPE may contain one or more stereoisomers (eg, optical isomers, geometric isomers) resulting from asymmetric carbon atoms or double bonds. All of the bodies and mixtures thereof are within the scope of the present invention.
- DPPE can be produced according to the usual synthesis method of phosphatidylethanolamine. DPPE is preferred because it is commercially available and can be used conveniently.
- DPPE may also be used as its salt.
- a salt is not particularly limited, but is preferably a pharmaceutically or food acceptable salt, for example, an inorganic base (eg, alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; aluminum and ammonium), organic Base (eg, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine), inorganic acid (eg, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphorus) Acid), organic acid (eg, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene
- DPPE has (1) protein phosphatase 2A (PP2A) activation enhancing action and (2) protein tyrosine phosphatase 1B (PTP1B) activation enhancing action, as shown by data in Examples. These excellent pharmacological actions induce cancer cell growth inhibitory action and can be provided as pharmaceuticals such as anticancer agents.
- FIG. 2 shows points of action of PP2A and PTP1B in the cell proliferation pathway.
- PP2A activation enhancing action Protein phosphatase 2A
- PP2A is a kind of serine / threonine phosphatase, and plays an important role in in vivo signal transduction related to intracellular processing such as cell cycle, proliferation and differentiation.
- PP2A has an effect of dephosphorylating p53, c-Myc, and b-Catenin in addition to Akt, MEK, and ERK, and is known to act as a cell growth, signal transduction, and apoptosis regulator.
- Protein tyrosine phosphatase (PTP) 1B is a cytoplasmic tyrosine phosphatase, and is involved in the regulation of tyrosine kinase by controlling the phosphorylation state of tyrosine kinase.
- PTP1B is known to have a function of regulating cell proliferation, differentiation, apoptosis, and cell migration (chemotaxis).
- DPPE has an action of inducing cell death and suppressing cell proliferation for cancer cells, as shown in the data in the Examples.
- a pharmacological action is that DPPE is useful as a cancer cell death inducer (hereinafter sometimes simply referred to as the agent of the present invention), an anticancer agent (hereinafter also referred to as the pharmaceutical of the present invention), and cancer prevention / This suggests that it is also useful as a research reagent that can be a useful tool for the development of therapeutic drugs.
- the present invention can provide a method for inducing cell death of cancer cells, and a method for preventing and / or treating cancer (hereinafter also simply referred to as the method of the present invention).
- a subject can be a mammal.
- mammals include primates (eg, humans, monkeys, chimpanzees), rodents (eg, mice, rats, guinea pigs), pets (eg, dogs, cats, rabbits), working animals or livestock.
- rodents eg, mice, rats, guinea pigs
- pets eg, dogs, cats, rabbits
- working animals or livestock eg, cows, horses, pigs, sheep, goats
- cows, horses, pigs, sheep, goats are preferred.
- the cancer (cancer cell) to which the agent, medicine and method of the present invention are applied is not particularly limited. Specifically, glioblastoma, medulloblastoma, tongue cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, Gastric cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer, adrenal cancer, bladder cancer, prostate cancer, penile cancer, uterine cancer, ovarian cancer, vulvar cancer, vaginal cancer, breast cancer, thyroid cancer, lung cancer Malignant pleural mesothelioma, skin cancer, malignant melanoma, malignant bone tumor, soft tissue sarcoma, malignant lymphoma, leukemia, multiple myeloma, etc., preferably malignant pleural mesothelioma, lung cancer, stomach cancer, colon cancer and Applies to breast cancer.
- cancer cells to be treated with DPPE are various cancer cells to which the above-mentioned pharmaceuticals of the present invention are applied, specifically glioblastoma, medulla Blastoma, tongue cancer, pharyngeal cancer, laryngeal cancer, esophageal cancer, stomach cancer, colon cancer, liver cancer, gallbladder cancer, bile duct cancer, pancreatic cancer, kidney cancer, adrenal cancer, bladder cancer, prostate cancer, penile cancer, uterine cancer, Ovarian cancer, vulvar cancer, vaginal cancer, breast cancer, thyroid cancer, lung cancer, malignant pleural mesothelioma, skin cancer, malignant melanoma, malignant bone tumor, soft tissue sarcoma, malignant lymphoma, leukemia, multiple myeloma, etc.
- treatment refers to bringing the above-mentioned cells into contact with DPPE for a necessary and sufficient time, and the time varies depending on the desired effect and the type of cells used, but usually 0.5 to 76 hours, preferably Is about 0.5 to 48 hours.
- the treatment may be performed for a shorter time, for example, about 0.5 to 24 hours, preferably about 0.5 to 12 hours. Conveniently, it is carried out by culturing in a culture solution containing DPPE.
- the medicament of the present invention varies depending on the type of cancer to be administered, its severity, the animal species to be administered, the drug acceptability of the administration target, body weight, age, etc., but usually by the oral or parenteral route, In the case of oral administration per day for adults, 0.1 to 10 g, preferably 1 to 4 g, is administered to the subject in the amount of DPPE as an active ingredient, and 0.01 to 1 g, preferably 0, in parenteral administration. .1-0.4 g is administered to the subject.
- the medicament of the present invention can contain any additive such as a pharmaceutically acceptable carrier in addition to DPPE which is an active ingredient.
- pharmaceutically acceptable carriers include sucrose, starch, mannitol, sorbit, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate and other excipients, cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone.
- the medicament of the present invention can be formulated as a preparation suitable for oral administration.
- Preparations suitable for oral administration include solutions in which an effective amount of a substance is dissolved in a diluent such as water or physiological saline, capsules, granules, powders or tablets containing the effective amount of the substance as solids or granules.
- a diluent such as water or physiological saline
- capsules such as water or physiological saline
- granules, powders or tablets containing the effective amount of the substance as solids or granules.
- a suspension in which an effective amount of a substance is suspended in an appropriate dispersion medium an emulsion in which a solution in which an effective amount of a substance is dissolved is dispersed in an appropriate dispersion medium, and the like.
- the medicament of the present invention can be formulated as a preparation suitable for parenteral administration.
- Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which include antioxidants, Buffers, antibacterial agents, isotonic agents and the like may be included.
- Aqueous and non-aqueous sterile suspensions are also included, which may contain suspending agents, solubilizers, thickeners, stabilizers, preservatives and the like.
- the preparation can be enclosed in a container in unit doses or multiple doses like ampoules and vials.
- the active ingredient and a pharmaceutically acceptable carrier can be lyophilized and stored in a state that may be dissolved or suspended in a suitable sterile vehicle immediately before use.
- the medicament of the present invention may be one in which the unit intake of the medicament or a divided amount thereof is individually packaged or filled, or a plurality of unit intake or the divided amounts thereof are comprehensively packaged or filled.
- the unit intake or its divided amount can be converted into a normal package (for example, PTP (press through packing) sheet, paper container, film ( Examples include plastic packages), glass containers, plastic containers) that are packaged or filled separately.
- a normal package for example, PTP (press through packing) sheet, paper container, film ( Examples include plastic packages), glass containers, plastic containers) that are packaged or filled separately.
- Such individually packaged or filled medicines are further combined and packaged or filled together in one container (eg, paper container, film (eg, plastic film) container, glass container, plastic container). It may be.
- Examples of a medicine in which a large number of unit intakes or divided amounts thereof are comprehensively packaged or filled include, for example, a single container (for example, a paper container, a film (eg, plastic) without being divided into a large number of tablets or capsules.
- the medicament of the present invention may also contain a unit intake or its divided amount in a sufficient number for long-term intake.
- a unit intake or its divided amount in a sufficient number for long-term intake.
- it is 3 days or more, preferably 7 days, 10 days, 14 days.
- it may be included in a number sufficient for ingestion for 21 days or more, or 1 month, 2 months, 3 months or more.
- the medicament of the present invention may contain one or more other anticancer agents.
- other anticancer agents include antimetabolites (eg, methotrexate, 5-fluorouracil, etc.), alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), platinum anticancer agents (eg, cisplatin, carboplatin, etc.), topoisomerase, etc.
- Inhibitors eg, etoposide, etc.
- anticancer antibiotics eg, mitomycin, adriamycin, etc.
- plant-derived anticancer agents eg, vincristine, vindesine, taxol, etc.
- tyrosine kinase inhibitors eg, gefitinib, imatinib, etc.
- humanized antibodies eg, Herceptin
- Example 1 PP2A activation enhancing action and PTP1B activation enhancing action (method) 1.
- Assay of PP2A and PTP1B activity under cell-free conditions The measurement of PP2A and PTP1B under cell-free conditions is in accordance with the method described in the previous report (Kanno T et al., Cell Physiol Biochem 2012; 30: 1014-1022.). went. Human recombinant PP2A was purchased from Millipore (Billerica, MA, USA). Human PTP1B was cloned into a pGEX-6P-3 vector having a GST tag at the NH 2 terminus and competent E. coli suitable for transformation and protein expression. It was expressed in E. coli BL21 (DE3).
- GST-fused PTP1B was affinity purified using glutathione sepharose 4B (GE Healthcare Bio-Science KK, Tokyo, Japan). Each phosphatase activity was measured by reacting with p-nitrophenyl phosphate (p-NPP) (Sigma, St. Louis, MO, USA) as a substrate.
- p-NPP p-nitrophenyl phosphate
- PP2A 0.2 U / well
- PTP1B (1 mg / well) in reaction medium at 37 ° C. for 30 minutes
- phosphatase inhibitor okadaic acid; 2 nM, sodium vanadate; 1 ⁇ M
- DAPE phosphatidylethanolamine
- DOPE DOPE
- DPPE phosphatidylethanolamine
- Reaction medium for PP2A 50 mM Tris-HCl, 0.1 mM EGTA, 0.1% (v / v) 2-mercaptoethanol, pH 7.0
- Reaction medium for PTP1B 50 mM HEPES, 1 mM EDTA, 50 mM NaCl, 1 mM dithiothreitol, pH 7.2
- p-NPP 0.5 mM for PP2A, 10 mM for PTP1B
- Dephosphorylated p-NPP, ie p-NP was quantified using SpectraMax PLUS384 (Molecular Devices, Sunnyvale, CA, USA) at an absorbance of 405 nm.
- Example 2 Cancer cell death inducing action (materials and methods) 1.
- NCI-H28 a cell line of cell culture human malignant pleural mesothelioma
- Met5A a cell line of human non-malignant mesothelioma
- RPMI Roswell Park Memorial Institute
- the medium was supplemented with 10% (v / v) heat-inactivated bovine serum, penicillin (final concentration, 100 U / ml) and streptomycin (final concentration, 0.1 mg / ml), 5% CO 2 and 95% Incubate at 37 ° C. in a humid atmosphere of air.
- Cell viability was determined by using 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) and reported previously (Nogi Y, et al., Cell Physiol Biochem 2012; 30: 61-74.). Measurement was performed using Met5A, which is a human non-malignant mesothelioma cell, and NCI-H28, which is a human malignant mesothelioma cell. The DPPE concentration was changed to 0, 1 ⁇ M, 10 ⁇ M and 100 ⁇ M, and treatment was performed for 24 hours or 48 hours went.
- MTT 3- (4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide
- TUNEL Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining
- TUNEL staining was performed using In Situ Apoptosis Detection Kit (Takara Bio; Otsu, Japan) .
- Fixed and membrane permeabilized cells were incubated with terminal deoxynucleotidyl transferase and fluorescein isothiocyanate (FITC) -deoxyuridine triphosphate at 37 ° C. for 90 minutes.
- FITC signals were visualized with a confocal laser microscope (LSM 510; Carl Zeiss Co., Ltd., Oberkochen, Germany).
- the cells used were Met5A, which is a human non-malignant mesothelioma cell, and NCI-H28, which is a human malignant mesothelioma cell.
- the DPPE concentrations were changed to 0, 30 ⁇ M and 100 ⁇ M and treated for 48 hours.
- the cell viability assay results are shown in FIG. 3, and the results of TUNEL staining are shown in FIG.
- the results in FIG. 3 show that DPPE has little effect on non-malignant mesothelioma cells, but induces concentration-dependent cell death on malignant mesothelioma cells.
- the results of FIG. 4 indicate that DPPE induces apoptosis of malignant mesothelioma cells but does not induce apoptosis in non-malignant mesothelioma cells.
- DPPE has a strong PP2A activation enhancing action and PTP1B activation enhancing action, and further has an excellent cancer cell death inducing action, so that it can be expected to be used as an anticancer agent. Moreover, since the phospholipid compound is originally present in the living body, the present invention can provide an anticancer agent with better safety.
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Abstract
Description
[1]1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する抗癌剤。
[2]治療対象となる癌が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種である、上記[1]記載の抗癌剤。
[2-1]治療対象となる癌が、肺癌、悪性胸膜中皮腫、胃癌、大腸癌及び乳癌からなる群から選択される少なくとも1種である、上記[1]記載の抗癌剤。
[3]1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する癌細胞死誘導剤。
[4]癌細胞が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種の癌の細胞である、上記[3]記載の剤。
[4-1]癌細胞が、肺癌、悪性胸膜中皮腫、胃癌、大腸癌及び乳癌からなる群から選択される少なくとも1種の癌の細胞である、上記[3]記載の剤。
[5]1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する、プロテインホスファターゼ2A活性化増強剤。
[6]1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する、プロテインチロシンホスファターゼ1B活性化増強剤。
[7]抗癌剤である、上記[5]又は[6]記載の剤。
[8]研究用試薬である、上記[5]又は[6]記載の剤。
[9]有効量の1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを、それを必要とする対象に投与することを含む、癌の予防及び/又は治療方法。
[10]癌が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種である、上記[9]記載の方法。
[10-1]癌が、肺癌、悪性胸膜中皮腫、胃癌、大腸癌及び乳癌からなる群から選択される少なくとも1種である、上記[10]記載の方法。
[11]1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンで癌細胞を処理することを特徴とする、癌細胞の細胞死を誘導する方法。
[12]癌細胞が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種の癌の細胞である、上記[11]記載の方法。
[12-1]癌細胞が、肺癌、悪性胸膜中皮腫、胃癌、大腸癌及び乳癌からなる群から選択される少なくとも1種の癌の細胞である、上記[11]記載の方法。
[13]癌の予防及び/又は治療に使用する1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミン。
[14]癌が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種である、上記[13]記載の1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミン。
[14-1]癌が、肺癌、悪性胸膜中皮腫、胃癌、大腸癌及び乳癌からなる群から選択される少なくとも1種である、上記[13]記載の1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミン。
本発明は有効成分としてホスファチジルエタノールアミンを用いる。本発明で有効成分として用いるホスファチジルエタノールアミンのうち、好ましくは1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミン(DPPE)であり、該ホスファチジルエタノールアミンを有効成分として含有する抗癌剤を提供する。DPPEは、ジパルミトレオイル・ホスファチジルエタノールアミンともいう。
(1)PP2A活性化増強作用
プロテインホスファターゼ2A(PP2A)は、セリン/スレオニンホスファターゼの1種であり、細胞周期、増殖、分化などの細胞内プロセシングに関わる生体内シグナル伝達に重要な役割を果たしている。
PP2AはAkt、MEK、ERK以外にp53、c-Myc、b-Cateninを脱リン酸化する作用があり、細胞増殖、シグナルトランスダクション、アポトーシス調節因子としても働くことが知られている。
参考文献:P. Seshacharyulu P et al., Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett 2013;335:9-18.
従って、PP2A活性化増強剤は種々の医薬用途への可能性を有している。
(2)PTP1B活性化増強作用
プロテインチロシンホスファターゼ(PTP)1Bは、細胞質型のチロシンホスファターゼであり、チロシンキナーゼのリン酸化状態をコントロールすることによって、チロシンキナーゼの調整に関与している。
PTP1Bは細胞増殖、分化、アポトーシス、細胞移動(ケモタキシス)を調節する働きを有することが知られている。
参考文献:Haj FG et al., Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J Biol Chem 2003;278:739-744.
従って、PTP1B活性化増強剤は種々の医薬用途への可能性を有している。
また、DPPEのかかる薬理作用により、本発明は、癌細胞の細胞死を誘導する方法、並びに癌の予防及び/又は治療方法(以下、単に本発明の方法とも称する)を提供することができる。
ここで「処理」とは、上記細胞とDPPEとを必要十分な時間接触させることであり、その時間は所望される効果や用いる細胞の種類によっても異なるが、通常0.5~76時間、好ましくは0.5~48時間程度である。又、より短い時間、例えば0.5~24時間、好ましくは0.5~12時間程度の処理であってもよい。簡便には、DPPEを含有する培養液中で培養することによって実施される。
(方法)
1.無細胞条件化でのPP2A及びPTP1B活性のアッセイ
無細胞条件下でのPP2A及びPTP1Bの測定は既報(Kanno T et al., Cell Physiol Biochem 2012;30:1014-1022.)に記載された方法に従って行った。ヒトリコンビナントPP2AはMillipore (Billerica, MA, USA)から購入した。ヒトPTP1BをNH2末端にGSTタグを有するpGEX-6P-3ベクターにクローニングし、形質転換及び蛋白質発現に適したコンピテントE.coli BL21(DE3)中で発現させた。GST融合PTP1Bをグルタチオンセファロース4B(GE Healthcare Bio-Science KK, Tokyo, Japan)を用いてアフィニティー精製した。基質としてp-ニトロフェニルホスフェート(p-NPP)(Sigma, St. Louis, MO, USA)と反応させて各ホスファターゼ活性を測定した。PP2A(0.2 U/well)又はPTP1B(1 mg/well)を反応メディウム中37℃で30分間、ホスファターゼインヒビター(オカダ酸;2 nM、バナジン酸ナトリウム;1 μM)、ホスファチジルエタノールアミン(DAPE、DLPE、DOPE、DPPE;100 μM、いずれもAvanti Polar Lipids, Inc.( Alabaster, AL, USA)より入手)存在下及び非存在下でプレインキュベートした。
PP2A用の反応メディウム:50 mM Tris-HCl, 0.1 mM EGTA, 0.1% (v/v) 2-mercaptoethanol, pH 7.0
PTP1B用の反応メディウム:50 mM HEPES, 1 mM EDTA, 50 mM NaCl, 1 mM dithiothreitol, pH 7.2
次いで、p-NPP(PP2Aの場合には0.5 mM、PTP1Bの場合には10 mM)を反応メディウムに添加して60分間インキュベートした。反応は0.1N NaOHを添加することにより停止させた。脱リン酸化されたp-NPP、即ちp-NPをSpectraMax PLUS384 (Molecular Devices, Sunnyvale, CA, USA)を用い405nmの吸光度で定量した。
結果を図1に示す。この結果は、DPPEが強力なPP2A活性化増強作用及びPTP1B活性化増強作用を有することを示している。DPPEのかかる作用は図2の細胞増殖のシグナル経路に照らし合わせると、細胞増殖を抑制することを示唆している。
(材料と方法)
1.細胞培養
ヒト悪性胸膜中皮腫の細胞株であるNCI-H28及びヒト非悪性中皮腫の細胞株であるMet5Aを用いた。これらの細胞はAmerican Type Culture Collection (Manassas, VA, USA)から購入した。0.003%(w/v)L-グルタミンを添加したRoswell Park Memorial Institute (RPMI)-1640培地で細胞を培養した。培地には10%(v/v)の熱非働化したウシ血清、ペニシリン(最終濃度, 100 U/ml)及びストレプトマイシン(最終濃度, 0.1 mg/ml)を添加し、5%CO2及び95%空気の湿雰囲気下、37℃でインキュベートした。
細胞生存度は3-(4,5-ジメチル-2-チアゾリル)-2,5-ジフェニル-2H-テトラゾリウムブロミド(MTT)を用い、既報(Nogi Y, et al., Cell Physiol Biochem 2012;30: 61-74.)に従って測定した。測定は、ヒト非悪性中皮腫細胞であるMet5A及びヒト悪性中皮腫細胞であるNCI-H28を用い、DPPEの濃度を0、1μM、10μM及び100μMと変え、24時間あるいは48時間処理にて行った。
アポトーシスの指標となるin situ DNA断片化を検出するために、In Situ Apoptosis Detection Kit (Takara Bio; Otsu, Japan)を用いてTUNEL染色を行った。固定し膜透過性にした細胞をターミナルデオキシヌクレオチジルトランスフェラーゼ及びフルオレセインイソチオシアネート(FITC)-デオキシウリジントリホスフェートと37℃で90分間インキュベートした。FITCシグナルを共焦点レーザー顕微鏡(LSM 510; Carl Zeiss Co., Ltd., Oberkochen, Germany)で可視化した。
細胞は、ヒト非悪性中皮腫細胞であるMet5A及びヒト悪性中皮腫細胞であるNCI-H28を用い、DPPEの濃度を0、30μM及び100μMと変え、48時間処理したものを用いた。
細胞生存度のアッセイ結果を図3に、TUNEL染色の結果を図4に示す。図3の結果より、DPPEが非悪性中皮腫細胞に対してはほとんど影響がないが、悪性中皮腫細胞に対しては濃度依存性細胞死を誘導することがわかる。さらに図4の結果よりDPPEが悪性中皮腫細胞のアポトーシスは誘導するが非悪性中皮腫細胞においてはアポトーシスを誘導しないことがわかった。
Claims (14)
- 1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する抗癌剤。
- 治療対象となる癌が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種である、請求項1に記載の抗癌剤。
- 1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する癌細胞死誘導剤。
- 癌細胞が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種の癌の細胞である、請求項3記載の剤。
- 1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する、プロテインホスファターゼ2A活性化増強剤。
- 1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを有効成分として含有する、プロテインチロシンホスファターゼ1B活性化増強剤。
- 抗癌剤である、請求項5又は6記載の剤。
- 研究用試薬である、請求項5又は6記載の剤。
- 有効量の1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンを、それを必要とする対象に投与することを含む、癌の予防及び/又は治療方法。
- 癌が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種である、請求項9記載の方法。
- 1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミンで癌細胞を処理することを特徴とする、癌細胞の細胞死を誘導する方法。
- 癌細胞が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種の癌の細胞である、請求項11記載の方法。
- 癌の予防及び/又は治療に使用する1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミン。
- 癌が、神経膠芽腫、髄芽腫、舌癌、咽頭癌、喉頭癌、食道癌、胃癌、大腸癌、肝臓癌、胆嚢癌、胆管癌、膵臓癌、腎臓癌、副腎癌、膀胱癌、前立腺癌、陰茎癌、子宮癌、卵巣癌、外陰癌、膣癌、乳癌、甲状腺癌、肺癌、悪性胸膜中皮腫、皮膚癌、悪性黒色腫、悪性骨腫瘍、軟部肉腫、悪性リンパ腫、白血病、及び多発性骨髄腫からなる群から選択される少なくとも1種である、請求項13記載の1,2-ジパルミトレオイル-sn-グリセロ-3-ホスホエタノールアミン。
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