WO2022121356A1 - 组合物及其在提高维生素c抗肿瘤效果中的用途 - Google Patents

组合物及其在提高维生素c抗肿瘤效果中的用途 Download PDF

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WO2022121356A1
WO2022121356A1 PCT/CN2021/112737 CN2021112737W WO2022121356A1 WO 2022121356 A1 WO2022121356 A1 WO 2022121356A1 CN 2021112737 W CN2021112737 W CN 2021112737W WO 2022121356 A1 WO2022121356 A1 WO 2022121356A1
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vitamin
tumor
activator
present
cancer
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French (fr)
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郑辉
李长朋
王付卉
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中国科学院广州生物医药与健康研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of medicine. Specifically, the present invention relates to a composition and its use in improving the anti-tumor effect of vitamin C.
  • NCDs Non-communicable diseases
  • colorectal cancer When abnormal growth of cells occurs in the colon or rectum, it is called colorectal cancer. Colon cancer is one of the common malignant tumors, and it is also a type of cancer with a high mortality rate. In 2018, colorectal cancer had the third highest number of new cancer cases worldwide; its mortality rate was second only to lung cancer. In my country, the incidence of colorectal cancer ranks third, after lung cancer and gastric cancer; its mortality rate is also in the forefront. In recent years, with the deepening of cancer research, the development of drugs for the treatment of malignant tumors, especially the screening of drugs with high efficacy and low toxicity, has attracted more and more attention.
  • Vitamin C is one of the essential vitamins for the human body. The idea that high doses of vitamins are beneficial to anti-tumor therapy was first put forward by Nobel Prize winner Pauling L. The reason is that normal people need vitamin C to maintain their lives, and cancer patients, especially those with end-stage tumors, have a greater demand for it. In relevant clinical trials, patients receiving high-dose intravenous vitamin C treatment generally tolerated well, but there were also certain adverse reactions. Patients with renal disease may experience renal failure when using high-dose vitamin C; for patients with hemochromatosis, using high-dose vitamin C will promote the absorption of iron in patients, thereby aggravating the disease. In addition, intravenous high-dose vitamin C also has the risk of increasing coagulation activity and promoting thrombosis in patients.
  • the present invention aims to solve at least one of the technical problems existing in the prior art at least to a certain extent.
  • the present invention proposes a composition and its use in the preparation of medicines, and a pharmaceutical composition and its use in the preparation of medicines.
  • the composition has good anti-tumor efficacy and can synergistically increase with vitamin C. At the same time, it can reduce the dosage of vitamin C, thereby avoiding the side effects caused by high-dose vitamin C, and laying the foundation for scientific research and clinical treatment of tumors.
  • the present invention proposes a composition.
  • the composition includes an O-GlcNAc glycosyltransferase inhibitor and a glycogen synthesis kinase 3 ⁇ activator.
  • O-GlcNAc glycosyltransferase inhibitor and glycogen synthesis kinase 3 ⁇ activator can play a better anti-tumor effect, and can play a synergistic effect with vitamin C, and can reduce the The dosage of vitamin C can avoid the side effects caused by high-dose vitamin C, and lay the foundation for the scientific research and clinical treatment of tumors.
  • the above-mentioned composition may also have the following additional technical features:
  • the content ratio of the O-GlcNAc glycosyltransferase inhibitor and the glycogen synthesis kinase 3 ⁇ activator is 1:(0.1-0.6).
  • the O-GlcNAc glycosyltransferase inhibitor is selected from 2-[((4-chlorophenyl)imino]tetrahydro-4-oxo-3-(2-tricyclo[ 3.3.1.13,7]Deca-1-ethyl)-2H-1,3-thiazine-6-carboxylic acid (CAS#: 442665-87-4).
  • the glycogen synthesis kinase 3 ⁇ activator is selected from 3-[[2-(4-fluorophenyl)ethyl]amino]-1-methyl-4-(2-methyl- 1H-Indol-3-yl)-1H-pyrrole-2,5-dione (CAS#: 1129669-05-1).
  • the present invention proposes the use of the aforementioned composition for the manufacture of a medicament.
  • the medicine is used to improve the anti-tumor effect of vitamin C.
  • the combined action of O-GlcNAc glycosyltransferase inhibitor and glycogen synthesis kinase 3 ⁇ activator can play a better anti-tumor effect, and can reduce the dosage of vitamin C, thereby avoiding high-dose vitamin C
  • the side effects brought by it lay the foundation for the scientific research and clinical treatment of tumors.
  • the medicament is used to reduce the dosage of vitamin C in the anti-tumor process.
  • the tumor is selected from colon cancer, rectal cancer or colorectal cancer.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises: vitamin C and the aforementioned composition.
  • O-GlcNAc glycosyltransferase inhibitor, glycogen synthesis kinase 3 ⁇ activator and vitamin C can effectively inhibit the rapid growth of tumor cells, and have significant curative effect on tumor treatment.
  • the synergistic and synergistic effect of vitamin C can reduce the amount of vitamin C, thereby avoiding the side effects caused by high-dose vitamin C.
  • the content ratio of vitamin C, O-GlcNAc glycosyltransferase inhibitor and glycogen synthesis kinase 3 ⁇ activator is (3-8):(0.5-1.5):(0.2-0.5) .
  • the concentration of the vitamin C is 3-8 ⁇ g/mL
  • the concentration of the O-GlcNAc glycosyltransferase inhibitor is 0.5-1.5 ⁇ M
  • the concentration of the glycogen synthesis kinase 3 ⁇ activator is 0.2 to 0.5 ⁇ M.
  • the pharmaceutical composition further comprises: pharmaceutically acceptable excipients.
  • the present invention proposes the use of the aforementioned pharmaceutical composition in the preparation of a medicament.
  • the drug is used for anti-tumor.
  • O-GlcNAc glycosyltransferase inhibitor, glycogen synthesis kinase 3 ⁇ activator and vitamin C can effectively inhibit the rapid growth of tumor cells and have significant curative effect on tumor treatment, and the obtained anti-tumor effect is significantly better than A single drug has significant synergistic and synergistic effects, and the dosage of vitamin C can be reduced, thereby avoiding the side effects caused by high-dose vitamin C.
  • the tumor is selected from colon cancer, rectal cancer or colorectal cancer.
  • the present invention provides an anti-tumor method.
  • the method comprises: administering the aforementioned composition or the aforementioned pharmaceutical composition to a patient.
  • a better therapeutic purpose can be achieved.
  • the tumor is selected from colon cancer, rectal cancer or colorectal cancer.
  • Figure 1 shows the results of the effect of different concentrations of O-GlcNAc glycosyltransferase inhibitor ST045849 on the viability of SW480 and SW620 cells;
  • Figure 2 shows the results of the effect of different concentrations of GSK3 ⁇ activator on the viability of SW480 and SW620 cells
  • Figure 3 shows the results of the effect of different concentrations of vitamin C on the viability of SW480 and SW620 cells
  • Figure 4 shows the result graph of the effect of the drug combination of O-GlcNAc glycosyltransferase inhibitor ST045849 and vitamin C on the viability of SW480 and SW620 cells;
  • Figure 5 shows the result graph of the effect of the drug combination of GSK3 ⁇ activator IM-12 and vitamin C on the viability of SW480 and SW620 cells;
  • Figure 6 shows a result graph of the effect of the drug combination of O-GlcNAc glycosyltransferase inhibitor ST045849, GSK3 ⁇ activator IM-12 and vitamin C on the viability of SW480 and SW620 cells.
  • the present invention proposes a composition, its use in the preparation of a medicine, a pharmaceutical composition, its use in the preparation of a medicine, and an anti-tumor method, which will be described in detail below.
  • the present invention proposes a composition.
  • the composition includes an O-GlcNAc glycosyltransferase inhibitor and a glycogen synthesis kinase 3 ⁇ activator.
  • O-GlcNAc glycosyltransferase inhibitor and glycogen synthesis kinase 3 ⁇ activator can play a better anti-tumor effect, and can play a synergistic effect with vitamin C, and can reduce the The dosage of vitamin C can avoid the side effects caused by high-dose vitamin C, and lay the foundation for the scientific research and clinical treatment of tumors.
  • O-GlcNAc glycosyltransferase (O-GlcNAc transferase, OGT) inhibitor is a key protein that mediates O-GlcNAc glycosylation of proteins. It is an important aspect of protein post-translational modification and plays a role in the regulation of cellular physiological functions. However, the role of its abnormal expression in tumors and the research on the inhibitor of this protein as an anti-tumor drug have not been reported yet.
  • Glycogen synthesis kinase 3 ⁇ activator acts on the key protein GSK3 ⁇ of the WNT pathway, inhibiting the ubiquitination and degradation of GSK3 ⁇ , thereby activating the activity of the WNT pathway. It can promote the neural cell proliferation of human neural progenitor cells in vitro, but there is no relevant report on tumor inhibition in anti-tumor.
  • the content ratio of the O-GlcNAc glycosyltransferase inhibitor and the glycogen synthesis kinase 3 ⁇ activator is 1:(0.1-0.6).
  • the O-GlcNAc glycosyltransferase inhibitor is selected from 2-[((4-chlorophenyl)imino]tetrahydro-4-oxo-3-(2-tricyclo[3.3. 1.13,7] Deca-1-ethyl)-2H-1,3-thiazine-6-carboxylic acid (CAS#: 442665-87-4).
  • the inventors found that using the above-mentioned O-GlcNAc glycosyltransferase inhibitor It can work together with glycogen synthesis kinase 3 ⁇ activator to inhibit the growth of tumor cells, and synergize with vitamin C.
  • the O-GlcNAc glycosyltransferase inhibitor is selected from ST045849 (Cat. No.) produced by Timtec or other products that inhibit the target protein.
  • the glycogen synthesis kinase 3 ⁇ activator is selected from 3-[[2-(4-fluorophenyl)ethyl]amino]-1-methyl-4-(2-methyl-1H- Indol-3-yl)-1H-pyrrole-2,5-dione (CAS#: 1129669-05-1).
  • the glycogen synthesis kinase 3 ⁇ activator is selected from 1129669-05-1 (CAS number) produced by Selleck Company or other products with the same activation target protein.
  • the present invention proposes the use of the aforementioned composition for the manufacture of a medicament.
  • the medicine is used to improve the anti-tumor effect of vitamin C.
  • the combined action of O-GlcNAc glycosyltransferase inhibitor and glycogen synthesis kinase 3 ⁇ activator can play a better anti-tumor effect, and can reduce the dosage of vitamin C, thereby avoiding high-dose vitamin C
  • the side effects brought by it lay the foundation for the scientific research and clinical treatment of tumors.
  • the medicine is used to reduce the dosage of vitamin C in the anti-tumor process.
  • O-GlcNAc glycosyltransferase inhibitor and glycogen synthase kinase 3 ⁇ activator work together, which can play a better anti-tumor effect.
  • the dosage of vitamin C can be reduced, thereby avoiding the side effects caused by high doses of vitamin C.
  • the tumor is selected from colon cancer, rectal cancer or colorectal cancer.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises: vitamin C and the aforementioned composition.
  • O-GlcNAc glycosyltransferase inhibitor, glycogen synthesis kinase 3 ⁇ activator and vitamin C can effectively inhibit the rapid growth of tumor cells, and have significant curative effect on tumor treatment.
  • the synergistic and synergistic effect of vitamin C can reduce the amount of vitamin C, thereby avoiding the side effects caused by high-dose vitamin C.
  • the content ratio of vitamin C, O-GlcNAc glycosyltransferase inhibitor and glycogen synthesis kinase 3 ⁇ activator is (3-8):(0.5-1.5):(0.2-0.5).
  • the inventors obtained the above-mentioned preferred ratio through a large number of experiments, thus, vitamin C, O-GlcNAc glycosyltransferase inhibitor and glycogen synthesis kinase 3 ⁇ activator can play a synergistic purpose and effectively inhibit the growth of tumor cells. , has a significant effect on tumor treatment.
  • the concentration of vitamin C is 3-8 ⁇ g/mL
  • the concentration of the O-GlcNAc glycosyltransferase inhibitor is 0.5-1.5 ⁇ M
  • the concentration of the glycogen synthesis kinase 3 ⁇ activator is 0.2 ⁇ 0.5 ⁇ M.
  • the pharmaceutical composition further comprises: pharmaceutically acceptable excipients.
  • the present invention proposes the use of the aforementioned pharmaceutical composition in the preparation of a medicament.
  • the drug is used for anti-tumor.
  • O-GlcNAc glycosyltransferase inhibitor, glycogen synthesis kinase 3 ⁇ activator and vitamin C can effectively inhibit the rapid growth of tumor cells and have significant curative effect on tumor treatment, and the obtained anti-tumor effect is significantly better than A single drug has significant synergistic and synergistic effects, and the dosage of vitamin C can be reduced, thereby avoiding the side effects caused by high-dose vitamin C.
  • the tumor is selected from colon cancer, rectal cancer or colorectal cancer.
  • treatment used in the present invention is used to refer to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof, and/or therapeutic in terms of partial or complete cure of the disease and/or adverse effects caused by the disease.
  • Treatment encompasses disease in mammals, particularly humans, including: (a) preventing disease symptoms in individuals susceptible to but not yet diagnosed with the disease.
  • Treatment encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, alleviate or inhibit a disease in the individual, including but not limited to administration of a drug containing a composition or pharmaceutical composition described herein individuals in need.
  • the dosage form of the pharmaceutical composition is selected from one of mixtures, injections, tablets, granules, syrups, capsules, oral liquids, aerosols and sprays. Therefore, it is convenient to adopt different dosage forms according to different administration objects.
  • tablets, granules, syrups, capsules and oral liquids can be used, and the dosage form of the drug can be adjusted according to the absorption site of the drug and the release requirement of the drug, thereby improving the bioavailability of the drug to prolong the release time of the drug.
  • injections can be used to achieve large-dose administration requirements, and to avoid the influence of gastrointestinal circulation on the active ingredients of the drug.
  • administration refers to the introduction of a predetermined amount of a substance into a patient by some suitable means.
  • the mesenchymal stem cell of the present invention can be administered by any common route as long as it can reach the intended tissue.
  • Various modes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, cortical, oral, topical, nasal, pulmonary and rectal, but the invention is not limited to these exemplified modes of administration.
  • the frequency and dosage of administration of the pharmaceutical compositions of the present invention can be determined by a number of relevant factors, including the type of disease to be treated, the route of administration, the age, sex, weight and severity of the disease of the patient as the active ingredient type of drug.
  • the daily dose may be divided into 1, 2 or more doses in suitable form to be administered 1, 2 or more times over an entire time period, so long as a therapeutically effective amount is achieved .
  • the present invention provides an anti-tumor method.
  • the method comprises: administering the aforementioned composition or the aforementioned pharmaceutical composition to a patient.
  • a better therapeutic purpose can be achieved.
  • the tumor is selected from colon cancer, rectal cancer or colorectal cancer.
  • the cells used in the experiments were commercial human colorectal cancer cell lines (SW480 and SW620).
  • the culture medium used for the human colorectal cancer cell line is MEF cell culture medium, and its formula is 10% fetal bovine serum, GlutaMax (100X), NEAA (100X).
  • Select cells with a suitable growth density operate in a biological safety cabinet, aspirate the old medium in the petri dish, add 1 mL of DPBS solution, and rinse the cells to remove residual serum.
  • An appropriate amount of 0.25% trypsin was added to the petri dish, digested at 37°C for 5 min, and an equal volume of MEF cell culture medium was added to terminate the digestion.
  • Repeatedly pipetting the cells with a pipette to form a cell suspension transfer the cell suspension to a 15ml centrifuge tube, centrifuge at 250g for 5min.
  • MEF cell culture medium to the pellet, resuspend by gently pipetting, seed the cells into a 10cm petri dish, add an appropriate amount of medium, mix well, and culture at 37°C, 5% CO 2 .
  • GSK3 ⁇ activators Different concentrations of GSK3 ⁇ activators were added to SW480 and SW620 cells seeded at appropriate densities in 96-well culture dishes. After 24 hours of treatment, the cells were counted using the CCK8 method, and the data of cell viability and drug concentration were plotted , obtain a dose-response curve, and calculate the median killing concentration. The results show that, as shown in Figure 2, the preferred concentration of GSK3 ⁇ activator is 0.38 ⁇ M.
  • O-GlcNAc glycosyltransferase inhibitor ST045849, GSK3 ⁇ activator and vitamin C were prepared at 1 ⁇ M, 0.38 ⁇ M, and 5 ⁇ g/ml, respectively, and added to SW480 and SW620 cells seeded in 6 cm dishes at appropriate density, and treated for 24 Cell counts were performed after hours.

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Abstract

一种组合物，包括O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂。O-GlcNAc糖基转移酶抑制剂选自2-[((4-氯苯基)亚氨基]四氢-4-氧代-3-(2-三环[3.3.1.13,7]癸-1-乙基)-2H-1,3-噻嗪-6-羧酸，糖原合成激酶3β激活剂选自3-[[2-(4-氟苯基)乙基]氨基]-1-甲基-4-(2-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮。该组合物具有抗肿瘤功效，可以提高维生素C的抗肿瘤效果。肿瘤选自结肠癌、直肠癌或结直肠癌。

Description

组合物及其在提高维生素C抗肿瘤效果中的用途 技术领域
本发明涉及医药领域。具体地，本发明涉及组合物及其在提高维生素C抗肿瘤效果中的用途。
背景技术
在当前社会中，癌症已成为严重威胁人类健康的主要公共卫生问题之一，它是一种以异常的细胞不受控制的分裂和存活为特征的疾病总称。2018年《临床医师癌症杂志》发表了全球癌症统计报告，该报告对185个国家和地区36种癌症的发病率和死亡率进行了推测。报告显示，2018年全球将有1810万新增癌症病例(不包括非黑素瘤皮肤癌，为1700万)和960万癌症死亡病例(不包括非黑素瘤皮肤癌，为950万)。非传染性疾病(NCDs)现在是全球死亡的主要原因，癌症预计将成为21世纪世界各国死亡的主要原因和延长预期寿命的最重要障碍。2019年1月，中国国家癌症中心发布了最新一期的全国癌症统计数据报告。报告指出，2015年全国恶性肿瘤新增病例约392.9万人，发病率为285.83/10万；死亡约233.8万人，死亡率为105.84/10万；且近十几年来恶性肿瘤的发病死亡均呈持续上升态势，防控形势严峻。
当细胞的异常生长发生在结肠或者直肠时，它便被成为结直肠癌。结肠癌是常见恶性肿瘤之一，也是致死率较高一类癌症。2018年在世界范围内，在新生癌症病例中，结直肠癌患者数目位居第三；其死亡率仅次于肺癌。在我国，结直肠癌的发病率位列第三，仅次于肺癌和胃癌；其死亡率也位居前列。近年来，随着对癌症研究的不断深入，研发用于治疗恶性肿瘤的药物，尤其是筛选出高药效低毒害的药物越来越受到关注。
维生素C是人体必需的维生素之一。大剂量服用维生素有利于抗肿瘤治疗的观点首先由诺贝尔奖得主Pauling L提出，其理由在于正常人生命的维系需要维生素C，而肿瘤患者尤其是终末期肿瘤患者对其的需求量更大。在相关临床试验中，接受大剂量静脉注射维生素C治疗的患者普遍耐受性较好，但也存在一定的不良反应。伴有肾脏疾病的患者在使用大剂量维生素C可出现肾功能衰竭；对于血色病患者使用大剂量维生素C则会促进患者铁的吸收，从而加重病情。另外，静脉注射大剂量维生素C还具有升高患者凝血活性和促进患者血栓形成的风险。
因此，目前维生素C在抗肿瘤中的应用仍有待研究。
发明内容
本发明旨在至少在一定程度上解决现有技术中存在的技术问题至少之一。为此，本发明提出了组合物及其在制备药物中的用途和药物组合物及其在制备药物中的用途，该组合物具有较好的抗肿瘤功效，并且可以与维生素C起到协同增效的作用，同时可以减少维生素C的用量，从而避免高剂量维生素C带来的副作用，为肿瘤的科学研究和临床治疗奠定基础。
在本发明的一个方面，本发明提出了一种组合物。根据本发明的实施例，所述组合物包括O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂。发明人发现，O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂共同作用，可以起到较好的抗肿瘤功效，并且可以与维生素C起到协同增效的作用，同时可以减少维生素C的用量，从而避免高剂量维生素C带来的副作用，为肿瘤的科学研究和临床治疗奠定基础。
根据本发明的实施例，上述组合物还可以具有下列附加技术特征：
根据本发明的实施例，所述O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂的含量比为1：(0.1～0.6)。
根据本发明的实施例，所述O-GlcNAc糖基转移酶抑制剂选自2-[((4-氯苯基)亚氨基]四氢-4-氧代-3-(2-三环[3.3.1.13,7]癸-1-乙基)-2H-1,3-噻嗪-6-羧酸(CAS#:442665-87-4)。
根据本发明的实施例，所述糖原合成激酶3β激活剂选自3-[[2-(4-氟苯基)乙基]氨基]-1-甲基-4-(2-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮(CAS#:1129669-05-1)。
在本发明的另一方面，本发明提出了前面所述组合物在制备药物中的用途。根据本发明的实施例，所述药物用于提高维生素C抗肿瘤效果。如前所述，O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂共同作用，可以起到较好的抗肿瘤功效，并且，可以减少维生素C的用量，从而避免高剂量维生素C带来的副作用，为肿瘤的科学研究和临床治疗奠定基础。
根据本发明的实施例，所述药物用于降低抗肿瘤过程中的维生素C用量。
根据本发明的实施例，所述肿瘤选自结肠癌、直肠癌或结直肠癌。
在本发明的又一方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包括：维生素C和前面所述组合物。O-GlcNAc糖基转移酶抑制剂、糖原合成激酶3β激活剂和维生素C能有效抑制肿瘤细胞的快速生长，对肿瘤治疗具有显著疗效，所取得的抗肿瘤作用明显优于单一用药，具有显著的协同和增效作用，并且，可以减少维生素C用量，从而避免高剂量维生素C带来的副作用。
根据本发明的实施例，所述维生素C、O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β 激活剂的含量比为(3～8)：(0.5～1.5)：(0.2～0.5)。
根据本发明的实施例，所述维生素C的浓度为3～8μg/mL，所述O-GlcNAc糖基转移酶抑制剂的浓度为0.5～1.5μM，所述糖原合成激酶3β激活剂的浓度为0.2～0.5μM。
根据本发明的实施例，所述药物组合物进一步包括：药学上可接受的辅料。
在本发明的又一方面，本发明提出了前面所述药物组合物在制备药物中的用途。根据本发明的实施例，所述药物用于抗肿瘤。如前所述，O-GlcNAc糖基转移酶抑制剂、糖原合成激酶3β激活剂和维生素C能有效抑制肿瘤细胞的快速生长，对肿瘤治疗具有显著疗效，所取得的抗肿瘤作用明显优于单一用药，具有显著的协同和增效作用，并且，可以减少维生素C用量，从而避免高剂量维生素C带来的副作用。
根据本发明的实施例，所述肿瘤选自结肠癌、直肠癌或结直肠癌。
在本发明的又一方面，本发明提出了一种抗肿瘤的方法。根据本发明的实施例，所述方法包括：向患者施加前面所述组合物或所述药物组合物。由此，可以起到较好的治疗目的。
根据本发明的实施例，所述肿瘤选自结肠癌、直肠癌或结直肠癌。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1显示了不同浓度的O-GlcNAc糖基转移酶抑制剂ST045849对SW480和SW620细胞活力影响的结果图；
图2显示了不同浓度的GSK3β激活剂对SW480和SW620细胞活力影响的结果图；
图3显示了不同浓度的维生素C对SW480和SW620细胞活力影响的结果图；
图4显示了O-GlcNAc糖基转移酶抑制剂ST045849和维生素C的药物组合对SW480和SW620细胞活力影响的结果图；
图5显示了GSK3β激活剂IM-12和维生素C的药物组合对SW480和SW620细胞活力影响的结果图；
图6显示了O-GlcNAc糖基转移酶抑制剂ST045849、GSK3β激活剂IM-12和维生素C的药物组合对SW480和SW620细胞活力影响的结果图。
具体实施方式
下面详细描述本发明的实施例。下面描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
本发明提出了组合物、其在制备药物中的用途和药物组合物及其在制备药物中的用途和抗肿瘤的方法，下面将分别对其进行详细描述。
组合物
在本发明的一个方面，本发明提出了一种组合物。根据本发明的实施例，该组合物包括O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂。发明人发现，O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂共同作用，可以起到较好的抗肿瘤功效，并且可以与维生素C起到协同增效的作用，同时可以减少维生素C的用量，从而避免高剂量维生素C带来的副作用，为肿瘤的科学研究和临床治疗奠定基础。
O-GlcNAc糖基转移酶(O-GlcNAc transferase,OGT)抑制剂是介导蛋白发生O-GlcNAc糖基化得关键蛋白，是蛋白翻译后修饰的重要方面，在细胞生理功能调节方面发挥作用。但是，其异常表达在肿瘤中的作用，以及该蛋白的抑制剂作为抗肿瘤药物的研究还未见报道。
糖原合成激酶3β激活剂(GSK3β激活剂)是作用于WNT通路关键蛋白GSK3β，抑制GSK3β的泛素化降解，从而达到激活WNT通路活性的作用。可体外促进人神经祖细胞的神经细胞增殖，但在抗肿瘤方面还未见抑制肿瘤的相关报道。
根据本发明的实施例，O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂的含量比为1：(0.1～0.6)。发明人发现，在此较佳配比下，可以较好地抑制肿瘤细胞生长，并与维生素C起到协同增效目的，同时可以减少维生素C用量，尤其适用于治疗结肠癌、直肠癌或结直肠癌。
根据本发明的实施例，O-GlcNAc糖基转移酶抑制剂选自2-[((4-氯苯基)亚氨基]四氢-4-氧代-3-(2-三环[3.3.1.13,7]癸-1-乙基)-2H-1,3-噻嗪-6-羧酸(CAS#:442665-87-4)。发明人发现，采用上述O-GlcNAc糖基转移酶抑制剂可以与糖原合成激酶3β激活剂共同作用，抑制肿瘤细胞生长，并与维生素C起到协同增效目的，同时可以减少维生素C用量，尤其适用于治疗结肠癌、直肠癌或结直肠癌。在一些实施例中，O-GlcNAc糖基转移酶抑制剂选自Timtec公司生产的ST045849(货号)或者同抑制靶蛋白其他产品。
根据本发明的实施例，糖原合成激酶3β激活剂选自3-[[2-(4-氟苯基)乙基]氨基]-1-甲基-4-(2-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮(CAS#:1129669-05-1)。发明人发现，采用上述糖原合成激酶3β激活剂可以与O-GlcNAc糖基转移酶抑制剂共同作用，抑制肿瘤 细胞生长，并与维生素C起到协同增效目的，同时可以减少维生素C用量，尤其适用于治疗结肠癌、直肠癌或结直肠癌。在一些实施例中，糖原合成激酶3β激活剂选自Selleck公司生产的1129669-05-1(CAS号)或者同激活靶蛋白其他产品。
组合物在制备药物中的用途
在本发明的另一方面，本发明提出了前面所述组合物在制备药物中的用途。根据本发明的实施例，所述药物用于提高维生素C抗肿瘤效果。如前所述，O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂共同作用，可以起到较好的抗肿瘤功效，并且，可以减少维生素C的用量，从而避免高剂量维生素C带来的副作用，为肿瘤的科学研究和临床治疗奠定基础。
根据本发明的实施例，药物用于降低抗肿瘤过程中的维生素C用量。如前所述，O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂共同作用，可以起到较好的抗肿瘤功效。同时，可以减少维生素C的用量，从而避免高剂量维生素C带来的副作用。
根据本发明的实施例，肿瘤选自结肠癌、直肠癌或结直肠癌。
需要说明的是，前面针对组合物所描述的特征和优点，同样适用于该用途，在此不再赘述。
药物组合物
在本发明的又一方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包括：维生素C和前面所述组合物。O-GlcNAc糖基转移酶抑制剂、糖原合成激酶3β激活剂和维生素C能有效抑制肿瘤细胞的快速生长，对肿瘤治疗具有显著疗效，所取得的抗肿瘤作用明显优于单一用药，具有显著的协同和增效作用，并且，可以减少维生素C用量，从而避免高剂量维生素C带来的副作用。
根据本发明的实施例，维生素C、O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂的含量比为(3～8)：(0.5～1.5)：(0.2～0.5)。发明人经过大量实验得到上述较佳配比，由此，维生素C、O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂可以起到协同增效的目的，有效地抑制肿瘤细胞生长，对肿瘤治疗具有显著疗效。
根据本发明的实施例，维生素C的浓度为3～8μg/mL，所述O-GlcNAc糖基转移酶抑制剂的浓度为0.5～1.5μM，所述糖原合成激酶3β激活剂的浓度为0.2～0.5μM。发明人经过大量实验得到上述三者的较佳浓度，由此，维生素C、O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂可以起到协同增效的目的，有效地抑制肿瘤细胞生长，对肿瘤治疗具有显 著疗效。
根据本发明的实施例，所述药物组合物进一步包括：药学上可接受的辅料。
需要说明的是，前面针对组合物所描述的特征和优点，同样适用于该药物组合物，在此不再赘述。
药物组合物在制备药物中的用途
在本发明的又一方面，本发明提出了前面所述药物组合物在制备药物中的用途。根据本发明的实施例，药物用于抗肿瘤。如前所述，O-GlcNAc糖基转移酶抑制剂、糖原合成激酶3β激活剂和维生素C能有效抑制肿瘤细胞的快速生长，对肿瘤治疗具有显著疗效，所取得的抗肿瘤作用明显优于单一用药，具有显著的协同和增效作用，并且，可以减少维生素C用量，从而避免高剂量维生素C带来的副作用。
根据本发明的实施例，肿瘤选自结肠癌、直肠癌或结直肠癌。
需要说明的是，本发明使用的术语“治疗”用于指获得期望的药理学和/或生理学效果。所述效果就完全或部分预防疾病或其症状而言可以是预防性的，和/或就部分或完全治愈疾病和/或疾病导致的不良作用而言可以是治疗性的。本文使用的“治疗”涵盖哺乳动物、特别是人的疾病，包括：(a)在容易患病但是尚未确诊得病的个体中预防疾病状。本文使用的“治疗”涵盖将药物或化合物给予个体以治疗、治愈、缓解、改善、减轻或抑制个体的疾病的任何用药，包括但不限于将含本文所述组合物或药物组合物的药物给予有需要的个体。
根据本发明的一些实施例，该药物组合物的剂型选自合剂、注射液、片剂、颗粒剂、糖浆剂、胶囊、口服液、气雾剂以及喷雾剂之一。由此，便于根据给药对象不同，采用不同的剂型。例如，为了便于给药，可以采用片剂、颗粒剂、糖浆剂、胶囊和口服液，并且，可以根据药物的吸收部位和药物的释放需求，对药物的剂型进行调整，从而提高药物的生物利用度，延长药物的释放时间。对于病情严重者，可以采用注射液，进而实现大剂量的给药需求，并且，避免胃肠循环对药物有效成分的影响。
在本发明中所使用的术语“给药”指将预定量的物质通过某种适合的方式引入病人。本发明的间充质干细胞可以通过任何常见的途径被给药，只要它可以到达预期的组织。给药的各种方式是可以预期的，包括腹膜、静脉、肌肉、皮下、皮层、口服、局部、鼻腔、肺部和直肠，但是本发明不限于这些已举例的给药方式。
本发明的药物组合物的给药频率和剂量可以通过多个相关因素被确定，该因素包括要被治疗的疾病类型、给药途径、病人年龄、性别、体重和疾病的严重程度以及作为活性成分的药物类型。根据本发明的一些实施例，日剂量可分为适宜形式的1剂、2剂或多剂， 以在整个时间段内以1次、2次或多次给药，只要达到治疗有效量即可。
抗肿瘤的方法
在本发明的又一方面，本发明提出了一种抗肿瘤的方法。根据本发明的实施例，所述方法包括：向患者施加前面所述组合物或所述药物组合物。由此，可以起到较好的治疗目的。
根据本发明的实施例，所述肿瘤选自结肠癌、直肠癌或结直肠癌。
除非另外指明，本发明的实践将使用分子生物学、微生物学、细胞生物学、免疫学和重组DNA的传统技术，其属于本领域技术范围。参见例如，Sambrook，Fritsch和Maniatis，分子克隆实验指南，第3版(2002)；CURRENT PROTOCOLS IN MOLECULAR BIOLOGY(F.M.Ausubel等人编著(1987))；丛书METHODS IN ENZYMOLOGY(Academic Press，Inc.)：PCR 2：A PRACTICAL APPROACH(M.J.MacPherson，B.D.Hames和G.R.Taylor编著，(1995))，Harlow和Lane编著，(1988)ANTIBODIES，A LABORATORY MANUAL and ANIMAL CELL CULTURE(R.I.Freshney编著，(1987))；W.French Anderson等人，HANDBOOK OF STEM CELLS，卷2。
除非另外说明，本文中所用的术语均具有本领域技术人员常规理解的含义，为了便于理解本发明，将本文中使用的一些术语进行了下述定义。
所有的数字标识，例如pH、温度、时间和浓度，包括范围，都是近似值。要了解，虽然不总是明确的叙述所有的数字标识之前都加上术语“约”。也要了解，虽然不总是明确的叙述，本文中描述的试剂仅仅是示例，其等价物是本领域已知的。
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1肿瘤细胞传代与培养
实验中所使用的细胞为市售的人类结直肠癌细胞系(SW480和SW620)。
人类结直肠癌细胞系所用培养基为MEF细胞培养基，其配方为10％胎牛血清、GlutaMax(100X)、NEAA(100X)。选择生长密度合适的细胞，在生物安全柜中操作，吸去培养皿中旧的培养基，加入1mL的DPBS溶液，漂洗细胞以除去残留的血清。向培养皿中加入适量0.25％的胰蛋白酶，37℃条件下，消化5min，加入等体积MEF细胞培养基， 终止消化。用移液管反复吹打细胞形成细胞悬液，将细胞悬液转移至15ml离心管中，250g，离心5min。弃上清，向沉淀中加入MEF细胞培养基，轻轻吹打重悬，将细胞分种到10cm培养皿中，补充适量培养基，混匀，于37℃，5％CO 2条件下培养。
实施例2探索单独使用O-GlcNAc糖基转移酶抑制剂对肿瘤细胞增殖产生影响的适宜浓度
将不同浓度的OGT抑制剂分别加入到以合适密度种于96孔培养皿的SW480和SW620细胞中，处理24小时后，使用CCK8方法对进行细胞计数，将细胞存活率与药物浓度的数据作图，得到剂量反应曲线，计算半数杀伤浓度。结果如图1所示，优选O-GlcNAc糖基转移酶抑制剂ST045849使用浓度为1μM。
实施例3探索单独使用GSK3β激活剂对肿瘤细胞增殖产生影响的适宜浓度
将不同浓度的GSK3β激活剂分别加入到以合适密度种于96孔培养皿的SW480和SW620细胞中，处理24小时后，使用CCK8方法对进行细胞计数，将细胞存活率与药物浓度的数据作图，得到剂量反应曲线，计算半数杀伤浓度。结果表明，如图2所示，优选GSK3β激活剂使用浓度为0.38μM。
实施例4探索单独使用维生素C对肿瘤细胞增殖产生影响的浓度
将不同浓度的维生素C分别加入到以合适密度种于96孔培养皿的SW480和SW620细胞中，处理24小时后，进行细胞计数，将细胞存活率与药物浓度的数据作图，得到剂量反应曲线，计算半数杀伤浓度。结果表明，如图3所示，维生素C的使用浓度为5μg/ml。
实施例5使用O-GlcNAc糖基转移酶(O-GlcNAc transferase,OGT)抑制剂ST045849、GSK3β激活剂和维生素C药物组合物对肿瘤细胞增殖的影响
将O-GlcNAc糖基转移酶抑制剂ST045849、GSK3β激活剂和维生素C分别配置成1μM、0.38μM、5μg/ml，分别加入到以合适密度种于6cm培养皿的SW480和SW620细胞中，处理24小时后进行细胞计数。结果表明，如图4所示，与单独用药相比，O-GlcNAc糖基转移酶抑制剂ST045849和维生素C药物组合物可显著抑制人类结直肠癌细胞的增殖；如图5所示，与单独用药相比，GSK3β激活剂和维生素C药物组合物可显著抑制人类结直肠癌细胞的增殖；如图6所示，与单独用药相比，O-GlcNAc糖基转移酶抑制剂ST045849、GSK3β激活剂和维生素C药物组合物可显著抑制人类结直肠癌细胞的增殖。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (15)

  1. 一种组合物，其特征在于，包括O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂。
  2. 根据权利要求1所述的组合物，其特征在于，所述O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂的含量比为1：(0.1～0.6)。
  3. 根据权利要求1所述的组合物，其特征在于，所述O-GlcNAc糖基转移酶抑制剂选自2-[((4-氯苯基)亚氨基]四氢-4-氧代-3-(2-三环[3.3.1.13,7]癸-1-乙基)-2H-1,3-噻嗪-6-羧酸。
  4. 根据权利要求1所述的组合物，其特征在于，所述糖原合成激酶3β激活剂选自3-[[2-(4-氟苯基)乙基]氨基]-1-甲基-4-(2-甲基-1H-吲哚-3-基)-1H-吡咯-2,5-二酮。
  5. 权利要求1～4任一项所述组合物在制备药物中的用途，其特征在于，所述药物用于提高维生素C抗肿瘤效果。
  6. 根据权利要求5所述的用途，其特征在于，所述药物用于降低抗肿瘤过程中的维生素C用量。
  7. 根据权利要求6所述的用途，其特征在于，所述肿瘤选自结肠癌、直肠癌或结直肠癌。
  8. 一种药物组合物，其特征在于，包括：维生素C和权利要求1～4任一项所述组合物。
  9. 根据权利要求8所述的药物组合物，其特征在于，所述维生素C、O-GlcNAc糖基转移酶抑制剂和糖原合成激酶3β激活剂的含量比为(3～8)：(0.5～1.5)：(0.2～0.5)。
  10. 根据权利要求8所述的药物组合物，其特征在于，所述维生素C的浓度为3～8μg/mL，所述O-GlcNAc糖基转移酶抑制剂的浓度为0.5～1.5μM，所述糖原合成激酶3β激活剂的浓度为0.2～0.5μM。
  11. 根据权利要求8所述的药物组合物，其特征在于，进一步包括：药学上可接受的辅料。
  12. 权利要求8～11任一项所述药物组合物在制备药物中的用途，其特征在于，所述药物用于抗肿瘤。
  13. 根据权利要求12所述的用途，其特征在于，所述肿瘤选自结肠癌、直肠癌或结直肠癌。
  14. 一种抗肿瘤的方法，其特征在于，包括：
    向患者施加权利要求1～4任一项所述组合物或权利要求8～11任一项所述药物组合物。
  15. 根据权利要求14所述的方法，其特征在于，所述肿瘤选自结肠癌、直肠癌或结直肠癌。
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