WO2022033459A1 - Use of double non-oncology drug in preparation of pharmaceutical composition for treating cancers - Google Patents

Use of double non-oncology drug in preparation of pharmaceutical composition for treating cancers Download PDF

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WO2022033459A1
WO2022033459A1 PCT/CN2021/111714 CN2021111714W WO2022033459A1 WO 2022033459 A1 WO2022033459 A1 WO 2022033459A1 CN 2021111714 W CN2021111714 W CN 2021111714W WO 2022033459 A1 WO2022033459 A1 WO 2022033459A1
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cancer
pharmaceutical composition
dual non
drug
drugs
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WO2022033459A9 (en
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萧乃文
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萧乃文
石贵中
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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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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 invention provides a new application, which is used to achieve the effect of treating cancer by combining dual non-cancer drugs with synergistic effect.
  • Cancer is a disease that is suitable for combined drug therapy. Cancer cells exhibit various characteristics during the process of proliferation. They can resist programmed cell apoptosis and resist the attack of the human immune system. In addition, cancer cells have the ability to metastasize and drug resistance. It increases the difficulty of treatment. If a single drug is used to treat cancer, the treatment effect may be poor due to a single therapeutic effect. Therefore, the use of combined drug therapy can inhibit the growth of cancer cells at multiple targets and improve the success rate of cancer treatment. .
  • the advantage of the old drug for cancer is that the old drug has passed many toxicity and other tests and clinical trial data to improve the safety, and the risk of failure is also greatly reduced.
  • non-cancer old drugs significantly reduce adverse side effects, which means that old drugs are more suitable for patients with poor tolerance to chemotherapy side effects.
  • Most of the non-cancer old drugs have been on the market for a long time, and the patent period of the drugs has expired, so the prices are usually relatively cheap.
  • the combination of non-cancer drugs can improve the effect of treatment. It is hoped to provide important information on the use of old drugs for cancer in clinical practice to help doctors find the best combination of old drugs to treat cancer patients, which not only reduces the cost of treatment, but also reduces the amount of treatment. The side effects of the drug improve safety and can benefit more cancer patients.
  • the present invention provides the use of two non-cancer drugs for preparing a pharmaceutical composition for treating cancer (Two non-cancer drugs pharmaceutical composition use of cancer treatment).
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating pancreatic cancer
  • the dual non-cancer drug is selected from Pyrvinium, Niclosamide, Zidovudine ), Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate ( Any two drugs in the group consisting of Clodronate), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.325 and the synergy value is above 1.33.
  • the non-cancer drug refers to a drug not used for cancer (eg, niclosamide is an eelicide (Iampricide)).
  • the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating ovarian cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexame Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram ) or any two drugs in the group consisting of bisphosphonates such as Clodronate, the pharmaceutical composition can inhibit the cancer cell survival rate below 0.17 and the synergy value above 1.6.
  • the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating triple-negative breast cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium ), Niclosamide, Zidovudine, Albendazole, Carbimazole, Dexamethasone, Flubendazole, Lobendazole Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate
  • the pharmaceutical composition can inhibit the cancer cell survival rate below 0.485 and the synergy value above 1.305.
  • the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating breast cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Any two drugs from the group consisting of Niclosamide, Zidovudine, Auranofin, and Disulfiram, a pharmaceutical composition that inhibits cancer cell survival
  • the ratio is below 0.47 and the synergy value is above 1.335.
  • the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating liver cancer
  • the dual non-cancer drug is selected from Pyrvinium, Niclosamide , Zidovudine, Albendazole, Auranofin, Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine ( Pyrimethamine), Amlodipine besylate (Amlodipine besylate) or any two drugs in the group consisting of Disulfiram (Disulfiram), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.451 and the synergy value of 1.334 above.
  • the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating non-small cell lung cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium ), Niclosamide, Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram (Disulfiram), Fasudil (Fasudil) or any two drugs in the group consisting of bisphosphonates such as clodronate (Clodronate), the pharmaceutical composition can inhibit cancer cell survival rate to less than 0.5 And the synergy value is above 1.456.
  • the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for the treatment of colorectal cancer
  • the dual non-cancer drug is selected from niclosamide, alendronic acid ( Any two drugs in the group consisting of Alendronic Acid), Auranofin (Auranofin) or Disulfiram (Disulfiram)
  • the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.493 and the synergy value is above 1.321.
  • the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating lung cancer
  • the dual non-cancer drug is selected from the group consisting of Paroxetine, Pyrvinium, Chloride Niclosamide, Carbimazole, Dexamethasone, Pyrimethamine, Azelnidipine, Disulfiram, Fasudil Or any two drugs in the group consisting of bisphosphonates such as Clodronate
  • the pharmaceutical composition can inhibit the cancer cell survival rate below 0.493 and the synergy value above 1.343.
  • SFB is the survival rate of cells under the action of drug B
  • SF(A+B) is the survival rate of cells under the action of combined A and B drugs.
  • Antagonism is the worst effect of drug interactions, which means that the therapeutic effect of combination drugs is worse than that of single drug. Additive effect means that the effect of combined drug treatment is not much different from that of single drug.
  • Synergy is the effect of drug interaction.
  • the best effect means that the combination drug can significantly increase the therapeutic effect compared with the single drug, which not only reduces the individual dosage of the combination drug, but also reduces the harm caused by the side effects, including nausea, vomiting, abdominal pain, gastrointestinal discomfort, Hypercalcemia and granular leukopenia.
  • ⁇ >1 means that the combined drug has a synergistic effect
  • ⁇ >1.3 means that it has a significant synergistic effect
  • the dual non-cancer pharmaceutical composition of the present invention has a synergistic value greater than 1.3, and even some drug groups have a synergistic effect.
  • the value ⁇ is greater than 3, so it has a very significant synergistic effect.
  • the therapeutic effect of the drug can be improved, and the dose can be reduced, which has less burden on the human body and lessens the harm of side effects.
  • Figures 1A-1C are the effects of inhibiting cell survival of all the two-drug combinations of the present invention on pancreatic cancer cells (BxPC-3), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 1D-1F are the synergistic effects of all two-drug combinations of the present invention on pancreatic cancer cells (BxPC-3), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 2A-2C are the effects of inhibiting cell survival of all two-drug combinations of the present invention on ovarian cancer cells (TOV-21G), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 2D-2F show the synergistic effect of all dual-drug combinations of the present invention on ovarian cancer cells (TOV-21G), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 3A-3C are the effects of inhibiting cell survival of all double-drug combinations of the present invention on triple-negative breast cancer cell lines (MDA-MB-231), wherein the drugs used in each combination code are shown in Table 3;
  • FIGS 3D-3F show the synergistic effect of all dual-drug combinations of the present invention on triple-negative breast cancer cell lines (MDA-MB-231), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 4A-4C are the effects of inhibiting cell survival of all two-drug combinations of the present invention on breast cancer cells (MCF-7), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 4D-4F are the synergistic effects of all two-drug combinations of the present invention on breast cancer cells (MCF-7), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 5A-5C are the effects of inhibiting the cell survival rate of all two-drug combinations of the present invention on hepatoma cells (HepG2), wherein the drugs used in each combination code are shown in Table 3;
  • FIGS 5D-5F show the synergistic effect of all two-drug combinations of the present invention on liver cancer cells (HepG2), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 6A-6C are the effects of inhibiting cell survival of all two-drug combinations of the present invention on non-small cell lung cancer cells (H460), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 6D-6F are the synergistic effects of all two-drug combinations of the present invention on non-small cell lung cancer cells (H460), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 7A-7C are the effects of inhibiting cell survival of all the two-drug combinations of the present invention on colorectal cancer cells (HCT116), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 7D-7F are the synergistic effects of all two-drug combinations of the present invention on colorectal cancer cells (HCT116), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 8A-8C are the effects of inhibiting cell survival of all the two-drug combinations of the present invention on lung cancer cells (A549), wherein the drugs used in each combination code are shown in Table 3;
  • Figures 8D-8F are the synergistic effects of all two-drug combinations of the present invention on lung cancer cells (A549), wherein the drugs used in each combination code are shown in Table 3;
  • the concentration of the non-cancer drug of the present invention is 100 nM, and if it is *0.5, the drug concentration is 50 nM.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating pancreatic cancer
  • the dual non-cancer drug is selected from Pyrvinium, Niclosamide, Zidovudine ), Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate ( Any two drugs in the group consisting of Clodronate), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.325 and the synergy value is above 1.33.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating ovarian cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendron Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram or bisphosphonates such as chloramphenicol
  • the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.17 and the synergy value is above 1.6.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating triple-negative breast cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide ), Zidovudine, Albendazole, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Ethylamine Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as Clodronate ), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.485 and the synergy value is above 1.305.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating breast cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Any two drugs in the group consisting of Zidovudine, Auranofin or Disulfiram, the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.47 and the synergy value reaches 0.47 1.335 or more.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating liver cancer.
  • the dual non-cancer drug is selected from Pyrvinium, Niclosamide and Zidovudine. , Albendazole (Auranofin), Dexamethasone (Dexamethasone), Flubendazole (Flubendazole), Lovastatin (Lovastatin), Pyrimethamine (Pyrimethamine), Ammonium Besylate Any two drugs in the group consisting of Amlodipine besylate or Disulfiram, the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.451 and the synergy value is above 1.334.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating non-small cell lung cancer.
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide ), Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Fluorine Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil (Fasudil) or any two drugs in the group consisting of bisphosphonates such as clodronate (Clodronate), the pharmaceutical composition can inhibit the cancer cell survival rate below 0.5 and the synergy value above 1.456.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating colorectal cancer
  • the dual non-cancer drug is selected from niclosamide, alendronic acid, auranofin (Niclosamide) Any two drugs in the group consisting of Auranofin) or Disulfiram (Disulfiram), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.493 and the synergy value is above 1.321.
  • the invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating lung cancer
  • the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Cardiovascular Carbimazole, Dexamethasone, Pyrimethamine, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate
  • the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.493 and the synergy value is above 1.343.
  • the present invention picks out the most likely non-cancer drugs according to more than 10,000 kinds of drugs known in medicine at present, and conducts cancer cell poisoning experiments with the non-cancer drugs through a paired double-drug combination, and finds out the applicable drugs. Combinations of non-cancer drugs for cancer treatment.
  • Lung cancer cells A549), breast cancer cells (MCF-7), liver cancer cells (HepG2), non-small cell lung cancer cells (H460), pancreatic cancer cells (BxPC-3), colorectal cancer cells (HCT116), ovarian cancer cells (TOV-21G) and triple negative breast cancer cell line (MDA-MB-231), cultured in 10% (v/v) fetal bovine serum (Fetal Bovine Serum, Penicillin-Streptomycin Solution) (100X) (ACE Biolabs, CC1009) and Dulbecco's Modified Eagle's Medium (DMEM) (Invitrogen Carlsbad, CA, USA) containing Glutamine (Invitrogen Carlsbad, CA, USA) medium, then individual cell lines were placed in a 5% CO 2 , 37°C incubator (Astec- SCA-165DS).
  • DMEM Dulbecco's Modified Eagle's Medium
  • SFB indicates the survival rate of cells under the action of drug B
  • SF(A+B) is the survival rate of cells under the action of combined A and B drugs.
  • Table 4 Summary of the cell survival rate and synergistic effect of each dual-drug combination on ovarian cancer cell line (TOV-21G)
  • the results show that the drug combination proposed by the present invention will have different results for different cancer types, and the most effective groups for each cancer type are different. Therefore, the dual-drug pharmaceutical composition of the present invention has cancer specificity, specificity.

Abstract

Provided is the use of a double non-oncology drug in the preparation of a pharmaceutical composition for treating cancers. The double non-oncology drug involves any two drugs selected from the group consisting of Paroxetine, Pyrvinium, Niclosamide, Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine, Amlodipin besylate, Azelnidipine, Disulfiram, Fasudil, or a diphosphonate such as Clodronate. The pharmaceutical composition effectively inhibits the cancer cell survival rate to 0.5 or less and the combined drug has a synergistic value of 1.3 or more.

Description

双非癌药物用于制备治疗癌症的医药组合物的用途Use of dual non-cancer drugs for preparing pharmaceutical compositions for treating cancer 【技术领域】【Technical field】
本发明提供一种新用途，由具有协同作用的双非癌药物组合用以达到治疗癌症的效果。The invention provides a new application, which is used to achieve the effect of treating cancer by combining dual non-cancer drugs with synergistic effect.
【背景技术】【Background technique】
目前全球在癌症药物研发上的经费越来越昂贵且成功率降低，根据美国知名的医药产业分析公司Biomedtracker，数据数据库的统计分析，抗癌药物的开发从第一期的临床试验，到通过新药审查核准，进入市场的成功率约为5.1％，在各类疾病的新药开发中抗癌药物的成功率最低。研发成功上市的药物，在专利的保护下价格不便宜，并不是每位癌症患者都负担的起治疗的费用。At present, the global funding for cancer drug research and development is becoming more and more expensive and the success rate is decreasing. According to the statistical analysis of the data database of Biomedtracker, a well-known pharmaceutical industry analysis company in the United States, the development of anti-cancer drugs from the first phase of clinical trials to the approval of new drugs After review and approval, the success rate of entering the market is about 5.1%, and the success rate of anticancer drugs in the development of new drugs for various diseases is the lowest. Drugs that are successfully developed and marketed are not cheap under the protection of patents, and not every cancer patient can afford the cost of treatment.
目前癌症的治疗费用，无论是标靶或是免疫治疗都是相当昂贵，尽管化疗的部分有健保给付，费用相较标靶或免疫治疗便宜，缺点就是化疗毒性强，有许多老人或小孩之类的患者，对于化疗副作用的耐受程度较差。At present, the cost of cancer treatment, whether it is targeted or immunotherapy, is quite expensive. Although the chemotherapy part is covered by health insurance, the cost is cheaper than targeted or immunotherapy. The disadvantage is that chemotherapy is highly toxic, and there are many elderly people or children. patients with poor tolerance to chemotherapy side effects.
癌症是一种适用联合药物治疗的疾病，癌细胞在增殖过程中表现出多样的特性，可以抵抗程序性的细胞凋亡，也能够抵御人体免疫系统攻击，此外癌细胞具有转移能力以及抗药性，而增加治疗的困难度，若以单一药物治疗癌症，可能因为单一疗效而造成治疗效果不佳，因此使用联合药物治疗的方式，可以多靶点的抑制癌细胞的生长，提高癌症治疗的成功率。Cancer is a disease that is suitable for combined drug therapy. Cancer cells exhibit various characteristics during the process of proliferation. They can resist programmed cell apoptosis and resist the attack of the human immune system. In addition, cancer cells have the ability to metastasize and drug resistance. It increases the difficulty of treatment. If a single drug is used to treat cancer, the treatment effect may be poor due to a single therapeutic effect. Therefore, the use of combined drug therapy can inhibit the growth of cancer cells at multiple targets and improve the success rate of cancer treatment. .
老药癌用相较于传统癌症药物开发的优势，在于老药已经通过了许 多的毒性和其他测试及临床试验数据完整提高安全性，失败的风险也大幅度的下降。非癌老药比起化疗药物显著的降低不良的副作用，这代表老药更加适合对于化疗副作用耐受程度较差的患者。大部分的非癌老药上市许久，药物的专利期已经失效，所以价格通常都比较便宜。Compared with traditional cancer drug development, the advantage of the old drug for cancer is that the old drug has passed many toxicity and other tests and clinical trial data to improve the safety, and the risk of failure is also greatly reduced. Compared with chemotherapy drugs, non-cancer old drugs significantly reduce adverse side effects, which means that old drugs are more suitable for patients with poor tolerance to chemotherapy side effects. Most of the non-cancer old drugs have been on the market for a long time, and the patent period of the drugs has expired, so the prices are usually relatively cheap.
因此将非癌药物搭配组合以提高治疗的效果，希望在临床上提供老药癌用的重要信息帮助医生找到最佳的老药组合来治疗癌症患者，不但降低了治疗的费用，也减少了治疗的副作用提升了安全性，可以使更多的癌症患者受惠。Therefore, the combination of non-cancer drugs can improve the effect of treatment. It is hoped to provide important information on the use of old drugs for cancer in clinical practice to help doctors find the best combination of old drugs to treat cancer patients, which not only reduces the cost of treatment, but also reduces the amount of treatment. The side effects of the drug improve safety and can benefit more cancer patients.
【发明内容】[Content of the invention]
为了解决上述问题，本发明提供双非癌药物用于制备治疗癌症的医药组合物的用途(Two non-cancer drugs pharmaceutical composition use of cancer treatment)。In order to solve the above-mentioned problems, the present invention provides the use of two non-cancer drugs for preparing a pharmaceutical composition for treating cancer (Two non-cancer drugs pharmaceutical composition use of cancer treatment).
本发明提供一种双非癌药物用于制备治疗胰腺癌的医药组合物的用途，该双非癌药物选自吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可以抑制癌症细胞存活率至0.325以下且协同值达1.33以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating pancreatic cancer, the dual non-cancer drug is selected from Pyrvinium, Niclosamide, Zidovudine ), Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate ( Any two drugs in the group consisting of Clodronate), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.325 and the synergy value is above 1.33.
其中所述非癌药物是指非用于癌症上的药物(如氯硝柳胺(niclosamide)是一种杀鳗剂(Iampricide))。Wherein, the non-cancer drug refers to a drug not used for cancer (eg, niclosamide is an eelicide (Iampricide)).
在本发明一实施例中，本发明提供一种双非癌药物用于制备治疗卵巢癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑 (Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可以抑制癌症细胞存活率至0.17以下且协同值达1.6以上。In one embodiment of the present invention, the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating ovarian cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexame Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram ) or any two drugs in the group consisting of bisphosphonates such as Clodronate, the pharmaceutical composition can inhibit the cancer cell survival rate below 0.17 and the synergy value above 1.6.
在本发明一实施例中，本发明提供一种双非癌药物用于制备治疗三阴性乳腺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.485以下且协同值达1.305以上。In one embodiment of the present invention, the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating triple-negative breast cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium ), Niclosamide, Zidovudine, Albendazole, Carbimazole, Dexamethasone, Flubendazole, Lobendazole Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate Any two drugs in the group consisting of clodronate (Clodronate), the pharmaceutical composition can inhibit the cancer cell survival rate below 0.485 and the synergy value above 1.305.
在本发明一实施例中，本发明提供一种双非癌药物用于制备治疗乳腺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、金诺芬(Auranofin)和双硫仑(Disulfiram)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.47以下且协同值达1.335以上。In one embodiment of the present invention, the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating breast cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Any two drugs from the group consisting of Niclosamide, Zidovudine, Auranofin, and Disulfiram, a pharmaceutical composition that inhibits cancer cell survival The ratio is below 0.47 and the synergy value is above 1.335.
在本发明一实施例中，本发明提供一种双非癌药物用于制备治疗肝癌的医药组合物的用途，该双非癌药物选自吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、金诺芬(Auranofin)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)或双硫仑(Disulfiram)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.451以下且协同值达1.334以上。In one embodiment of the present invention, the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating liver cancer, the dual non-cancer drug is selected from Pyrvinium, Niclosamide , Zidovudine, Albendazole, Auranofin, Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine ( Pyrimethamine), Amlodipine besylate (Amlodipine besylate) or any two drugs in the group consisting of Disulfiram (Disulfiram), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.451 and the synergy value of 1.334 above.
在本发明一实施例中，本发明提供一种双非癌药物用于制备治疗非 小细胞肺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.5以下且协同值达1.456以上。In one embodiment of the present invention, the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating non-small cell lung cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium ), Niclosamide, Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram (Disulfiram), Fasudil (Fasudil) or any two drugs in the group consisting of bisphosphonates such as clodronate (Clodronate), the pharmaceutical composition can inhibit cancer cell survival rate to less than 0.5 And the synergy value is above 1.456.
在本发明一实施例中，本发明提供一种双非癌药物用于制备治疗大肠癌的医药组合物的用途，该双非癌药物选自氯硝柳胺(Niclosamide)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)或双硫仑(Disulfiram)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.493以下且协同值达1.321以上。In one embodiment of the present invention, the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for the treatment of colorectal cancer, the dual non-cancer drug is selected from niclosamide, alendronic acid ( Any two drugs in the group consisting of Alendronic Acid), Auranofin (Auranofin) or Disulfiram (Disulfiram), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.493 and the synergy value is above 1.321.
在本发明一实施例中，本发明提供一种双非癌药物用于制备治疗肺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、乙胺嘧啶(Pyrimethamine)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.493以下且协同值达1.343以上。In one embodiment of the present invention, the present invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating lung cancer, the dual non-cancer drug is selected from the group consisting of Paroxetine, Pyrvinium, Chloride Niclosamide, Carbimazole, Dexamethasone, Pyrimethamine, Azelnidipine, Disulfiram, Fasudil Or any two drugs in the group consisting of bisphosphonates such as Clodronate, the pharmaceutical composition can inhibit the cancer cell survival rate below 0.493 and the synergy value above 1.343.
协同值α算式用于评估联合药物的相互作用，对于癌细胞的毒杀效果是加成、协同或拮抗：α＝SFA×SFB/SF(A+B)，其中SFA表示A药物的作用下细胞的存活率，SFB表示B药物作用下细胞的存活率，及SF(A+B)是联合A与B药物作用下细胞的存活率。α＝1，>1，<1分别表示加成，协同增效和拮抗作用。拮抗作用是药物相互作用中效果最差的，表示联合药物的治疗效果比单一用药的成效差，加成作用是联合药物治疗的效 果相比单一用药的成效差异不大，协同是药物相互作用中效果最好的，表示联合药物比起单一用药更显著的增加治疗效果，不单减低了组合药物个别的使用剂量，同时也减少副作用带来的伤害，其中副作用包含恶心、呕吐、腹痛、肠胃不适、高血钙以及颗粒性白血球减少症。The synergy value α formula is used to evaluate the interaction of combined drugs, and the poisoning effect on cancer cells is additive, synergistic or antagonistic: α=SFA×SFB/SF(A+B), where SFA represents the cells under the action of drug A The survival rate of , SFB is the survival rate of cells under the action of drug B, and SF(A+B) is the survival rate of cells under the action of combined A and B drugs. α=1, >1, <1 represent additive, synergistic and antagonistic effects, respectively. Antagonism is the worst effect of drug interactions, which means that the therapeutic effect of combination drugs is worse than that of single drug. Additive effect means that the effect of combined drug treatment is not much different from that of single drug. Synergy is the effect of drug interaction. The best effect means that the combination drug can significantly increase the therapeutic effect compared with the single drug, which not only reduces the individual dosage of the combination drug, but also reduces the harm caused by the side effects, including nausea, vomiting, abdominal pain, gastrointestinal discomfort, Hypercalcemia and granular leukopenia.
在医学上α>1即表示组合药物具有协同作用，而α>1.3则表示具有显著的协同作用，本发明的双非癌药物医药组合物因其协同值大于1.3，甚至有些药物组别的协同值α大于3以上，因此具有非常显著的协同效应，相较于单独用药的情况，可以提高药物的治疗效果，并且可以降低剂量，对人体负担较小且减轻副作用的伤害。In medicine, α>1 means that the combined drug has a synergistic effect, while α>1.3 means that it has a significant synergistic effect. The dual non-cancer pharmaceutical composition of the present invention has a synergistic value greater than 1.3, and even some drug groups have a synergistic effect. The value α is greater than 3, so it has a very significant synergistic effect. Compared with the case of single drug use, the therapeutic effect of the drug can be improved, and the dose can be reduced, which has less burden on the human body and lessens the harm of side effects.
为达到上述及其它目的，以下对本发明一或多个具体实施例进行说明。本发明的其它特征或优点以实施例及请求项详细描述。To achieve the above and other objects, one or more specific embodiments of the present invention are described below. Other features or advantages of the present invention are described in detail in the embodiments and claims.
【图式简单说明】[Simple description of the diagram]
图1A-1C为本发明所有双药组合对胰腺癌细胞(BxPC-3)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 1A-1C are the effects of inhibiting cell survival of all the two-drug combinations of the present invention on pancreatic cancer cells (BxPC-3), wherein the drugs used in each combination code are shown in Table 3;
图1D-1F为本发明所有双药组合对胰腺癌细胞(BxPC-3)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 1D-1F are the synergistic effects of all two-drug combinations of the present invention on pancreatic cancer cells (BxPC-3), wherein the drugs used in each combination code are shown in Table 3;
图2A-2C为本发明所有双药组合对卵巢癌细胞(TOV-21G)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 2A-2C are the effects of inhibiting cell survival of all two-drug combinations of the present invention on ovarian cancer cells (TOV-21G), wherein the drugs used in each combination code are shown in Table 3;
图2D-2F为本发明所有双药组合对卵巢癌细胞(TOV-21G)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 2D-2F show the synergistic effect of all dual-drug combinations of the present invention on ovarian cancer cells (TOV-21G), wherein the drugs used in each combination code are shown in Table 3;
图3A-3C为本发明所有双药组合对三阴性乳腺癌细胞株(MDA-MB-231)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 3A-3C are the effects of inhibiting cell survival of all double-drug combinations of the present invention on triple-negative breast cancer cell lines (MDA-MB-231), wherein the drugs used in each combination code are shown in Table 3;
图3D-3F为本发明所有双药组合对三阴性乳腺癌细胞株(MDA-MB-231)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 3D-3F show the synergistic effect of all dual-drug combinations of the present invention on triple-negative breast cancer cell lines (MDA-MB-231), wherein the drugs used in each combination code are shown in Table 3;
图4A-4C为本发明所有双药组合对乳腺癌细胞(MCF-7)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 4A-4C are the effects of inhibiting cell survival of all two-drug combinations of the present invention on breast cancer cells (MCF-7), wherein the drugs used in each combination code are shown in Table 3;
图4D-4F为本发明所有双药组合对乳腺癌细胞(MCF-7)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 4D-4F are the synergistic effects of all two-drug combinations of the present invention on breast cancer cells (MCF-7), wherein the drugs used in each combination code are shown in Table 3;
图5A-5C为本发明所有双药组合对肝癌细胞(HepG2)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 5A-5C are the effects of inhibiting the cell survival rate of all two-drug combinations of the present invention on hepatoma cells (HepG2), wherein the drugs used in each combination code are shown in Table 3;
图5D-5F为本发明所有双药组合对肝癌细胞(HepG2)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 5D-5F show the synergistic effect of all two-drug combinations of the present invention on liver cancer cells (HepG2), wherein the drugs used in each combination code are shown in Table 3;
图6A-6C为本发明所有双药组合对非小细胞肺癌细胞(H460)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 6A-6C are the effects of inhibiting cell survival of all two-drug combinations of the present invention on non-small cell lung cancer cells (H460), wherein the drugs used in each combination code are shown in Table 3;
图6D-6F为本发明所有双药组合对非小细胞肺癌细胞(H460)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 6D-6F are the synergistic effects of all two-drug combinations of the present invention on non-small cell lung cancer cells (H460), wherein the drugs used in each combination code are shown in Table 3;
图7A-7C为本发明所有双药组合对大肠癌细胞(HCT116)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 7A-7C are the effects of inhibiting cell survival of all the two-drug combinations of the present invention on colorectal cancer cells (HCT116), wherein the drugs used in each combination code are shown in Table 3;
图7D-7F为本发明所有双药组合对大肠癌细胞(HCT116)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 7D-7F are the synergistic effects of all two-drug combinations of the present invention on colorectal cancer cells (HCT116), wherein the drugs used in each combination code are shown in Table 3;
图8A-8C为本发明所有双药组合对肺癌细胞(A549)的抑制细胞存活率效果，其中各组合代号所使用的药物如表三；Figures 8A-8C are the effects of inhibiting cell survival of all the two-drug combinations of the present invention on lung cancer cells (A549), wherein the drugs used in each combination code are shown in Table 3;
图8D-8F为本发明所有双药组合对肺癌细胞(A549)的协同作用效果，其中各组合代号所使用的药物如表三；Figures 8D-8F are the synergistic effects of all two-drug combinations of the present invention on lung cancer cells (A549), wherein the drugs used in each combination code are shown in Table 3;
【实施方式】[implementation]
本发明的非癌药物的浓度若无特别说明则为100nM，若为*0.5则表示该药物浓度为50nM。Unless otherwise specified, the concentration of the non-cancer drug of the present invention is 100 nM, and if it is *0.5, the drug concentration is 50 nM.
本发明提供一种双非癌药物用于制备治疗胰腺癌的医药组合物的用途，该双非癌药物选自吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、苯磺酸胺氯地平(Amlodipine  besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可以抑制癌症细胞存活率至0.325以下且协同值达1.33以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating pancreatic cancer, the dual non-cancer drug is selected from Pyrvinium, Niclosamide, Zidovudine ), Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate ( Any two drugs in the group consisting of Clodronate), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.325 and the synergy value is above 1.33.
本发明提供一种双非癌药物用于制备治疗卵巢癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可以抑制癌症细胞存活率至0.17以下且协同值达1.6以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating ovarian cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendron Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram or bisphosphonates such as chloramphenicol Any two drugs in the group composed of drodronate (Clodronate), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.17 and the synergy value is above 1.6.
本发明提供一种双非癌药物用于制备治疗三阴性乳腺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.485以下且协同值达1.305以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating triple-negative breast cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide ), Zidovudine, Albendazole, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Ethylamine Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as Clodronate ), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.485 and the synergy value is above 1.305.
本发明提供一种双非癌药物用于制备治疗乳腺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、金诺芬(Auranofin)或双硫仑(Disulfiram)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.47以下且协同值达1.335以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating breast cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Any two drugs in the group consisting of Zidovudine, Auranofin or Disulfiram, the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.47 and the synergy value reaches 0.47 1.335 or more.
本发明提供一种双非癌药物用于制备治疗肝癌的医药组合物的用 途，该双非癌药物选自吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、金诺芬(Auranofin)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)或双硫仑(Disulfiram)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.451以下且协同值达1.334以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating liver cancer. The dual non-cancer drug is selected from Pyrvinium, Niclosamide and Zidovudine. , Albendazole (Auranofin), Dexamethasone (Dexamethasone), Flubendazole (Flubendazole), Lovastatin (Lovastatin), Pyrimethamine (Pyrimethamine), Ammonium Besylate Any two drugs in the group consisting of Amlodipine besylate or Disulfiram, the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.451 and the synergy value is above 1.334.
本发明提供一种双非癌药物用于制备治疗非小细胞肺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.5以下且协同值达1.456以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating non-small cell lung cancer. The dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide ), Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Fluorine Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil (Fasudil) or any two drugs in the group consisting of bisphosphonates such as clodronate (Clodronate), the pharmaceutical composition can inhibit the cancer cell survival rate below 0.5 and the synergy value above 1.456.
本发明提供一种双非癌药物用于制备治疗大肠癌的医药组合物的用途，该双非癌药物选自氯硝柳胺(Niclosamide)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)或双硫仑(Disulfiram)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.493以下且协同值达1.321以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating colorectal cancer, the dual non-cancer drug is selected from niclosamide, alendronic acid, auranofin (Niclosamide) Any two drugs in the group consisting of Auranofin) or Disulfiram (Disulfiram), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.493 and the synergy value is above 1.321.
本发明提供一种双非癌药物用于制备治疗肺癌的医药组合物的用途，该双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、乙胺嘧啶(Pyrimethamine)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，该医药组合物可抑制癌症细胞存活率至0.493以下且协同值达1.343以上。The invention provides the use of a dual non-cancer drug for preparing a pharmaceutical composition for treating lung cancer, the dual non-cancer drug is selected from Paroxetine, Pyrvinium, Niclosamide, Cardiovascular Carbimazole, Dexamethasone, Pyrimethamine, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate Any two drugs in the group consisting of phosphonates (Clodronate), the pharmaceutical composition can inhibit the survival rate of cancer cells to below 0.493 and the synergy value is above 1.343.
本发明针对目前医学上已知的一万多种药物挑出认为最有可能的非癌药物，并将非癌药物透过两两搭配的双药组合进行癌细胞毒杀实验，找出可适用于癌症治疗上的非癌药物的组合药物。The present invention picks out the most likely non-cancer drugs according to more than 10,000 kinds of drugs known in medicine at present, and conducts cancer cell poisoning experiments with the non-cancer drugs through a paired double-drug combination, and finds out the applicable drugs. Combinations of non-cancer drugs for cancer treatment.
表一、本发明癌症测试的细胞株Table 1. Cell lines for cancer testing of the present invention
癌症类型cancer type 细胞株cell line 培养液culture medium
肺腺癌Lung adenocarcinoma A549A549 DMEMDMEM
乳腺癌breast cancer MCF-7MCF-7 DMEMDMEM
肝癌liver cancer HepG2HepG2 DMEMDMEM
非小细胞肺癌non-small cell lung cancer H460H460 DMEMDMEM
胰腺癌Pancreatic cancer BxPC-3BxPC-3 DMEMDMEM
大肠癌colorectal cancer HCT116HCT116 DMEMDMEM
卵巢细胞癌ovarian cell carcinoma TOV-21GTOV-21G DMEMDMEM
三阴性乳腺癌triple negative breast cancer MDA-MB-231MDA-MB-231 DMEMDMEM
表二、本发明双药测试的种类Table 2, the kind of double drug test of the present invention
代号code 中文药名Chinese medicine name 英文药名English drug name
C1C1 帕罗西汀paroxetine ParoxetineParoxetine
C3C3 吡维铵piraverium PyrviniumPyrvinium
C4C4 氯硝柳胺Niclosamide NiclosamideNiclosamide
C7C7 齐多夫定Zidovudine ZidovudineZidovudine
C9C9 阿苯达唑albendazole AlbendazoleAlbendazole
C10C10 阿仑膦酸alendronate Alendronic AcidAlendronic Acid
C11C11 金诺芬Auranofin AuranofinAuranofin
C13C13 卡比马唑Carbimazole CarbimazoleCarbimazole
C14C14 地塞米松Dexamethasone DexamethasoneDexamethasone
C18C18 氟苯达唑Flubendazole FlubendazoleFlubendazole
C19C19 洛伐他汀lovastatin LovastatinLovastatin
C21C21 乙胺嘧啶pyrimethamine PyrimethaminePyrimethamine
C22C22 苯磺酸胺氯地平Amlodipine besylate Amlodipine besylateAmlodipine besylate
C23C23 阿折地平Azelnidipine AzelnidipineAzelnidipine
C25C25 双硫仑disulfiram DisulfiramDisulfiram
C75C75 法舒地尔Fasudil FasudilFasudil
C76C76 双膦酸盐诸如氯屈膦酸盐Bisphosphonates such as clodronate ClodronateClodronate
实施例1、细胞培养(Cell culture)Example 1. Cell culture
将肺癌细胞(A549)、乳腺癌细胞(MCF-7)、肝癌细胞(HepG2)、非小 细胞肺癌细胞(H460)、胰腺癌细胞(BxPC-3)、大肠癌细胞(HCT116)、卵巢癌细胞(TOV-21G)及三阴性乳腺癌细胞株(MDA-MB-231)，培养在含10％(v/v)胎牛血清(Fetal Bovine Serum、Penicillin-Streptomycin Solution)(100X)(ACE Biolabs,CC1009)及含有Glutamine(谷氨酰胺)的Dulbecco’s Modified Eagle’s Medium(DMEM)(Invitrogen Carlsbad,CA,USA)培养基中，之后将个别细胞株放入5％CO 2、37℃的培养箱(Astec-SCA-165DS)。 Lung cancer cells (A549), breast cancer cells (MCF-7), liver cancer cells (HepG2), non-small cell lung cancer cells (H460), pancreatic cancer cells (BxPC-3), colorectal cancer cells (HCT116), ovarian cancer cells (TOV-21G) and triple negative breast cancer cell line (MDA-MB-231), cultured in 10% (v/v) fetal bovine serum (Fetal Bovine Serum, Penicillin-Streptomycin Solution) (100X) (ACE Biolabs, CC1009) and Dulbecco's Modified Eagle's Medium (DMEM) (Invitrogen Carlsbad, CA, USA) containing Glutamine (Invitrogen Carlsbad, CA, USA) medium, then individual cell lines were placed in a 5% CO 2 , 37°C incubator (Astec- SCA-165DS).
实施例2、细胞活力测验(Cell Viability)Example 2. Cell Viability
将1×10 4个不同细胞株接种到96-well plate(96孔板)中24小时，使细胞贴附于底盘后，经由不同的药物联合处理48小时，无药物处理的细胞为对照组，加入10μL WST-1试剂(BioVision,USA),在37℃下放置三个小时,使用ELISA reader酶标仪(Thermo Scientific Multiskan FC)，在450nm的波长下测定吸光值，评估细胞活性及增殖能力。细胞活力计算公式如下: 1×10 4 different cell lines were inoculated into a 96-well plate (96-well plate) for 24 hours. After the cells were attached to the plate, they were treated with different drugs for 48 hours. The cells without drug treatment were used as the control group. 10 μL of WST-1 reagent (BioVision, USA) was added and placed at 37° C. for three hours. Using an ELISA reader microplate reader (Thermo Scientific Multiskan FC), absorbance was measured at a wavelength of 450 nm to evaluate cell viability and proliferation ability. The formula for calculating cell viability is as follows:
Figure PCTCN2021111714-appb-000001
Figure PCTCN2021111714-appb-000001
实施例3、本发明医药组合物对癌细胞具协同作用效果试验Example 3. Test of the synergistic effect of the pharmaceutical composition of the present invention on cancer cells
协同值α算式用于评估联合药物的相互作用，对于癌细胞的毒杀效果是加成、协同或拮抗：α＝SFA×SFB/SF(A+B)，其中SFA表示A药物的作用下细胞的存活率，SFB表示B药物作用下细胞的存活率，及SF(A+B)是联合A与B药物作用下细胞的存活率。The synergy value α formula is used to evaluate the interaction of combined drugs, and the poisoning effect on cancer cells is additive, synergistic or antagonistic: α=SFA×SFB/SF(A+B), where SFA represents the cells under the action of drug A The survival rate of , SFB indicates the survival rate of cells under the action of drug B, and SF(A+B) is the survival rate of cells under the action of combined A and B drugs.
实验一、对胰腺癌细胞株(BxPC-3)进行双药组合实验结果Experiment 1. Results of double drug combination experiment on pancreatic cancer cell line (BxPC-3)
表三、各双药组合对胰腺癌细胞株(BxPC-3)细胞存活率及协同效果汇整Table 3. Summary of cell survival rate and synergistic effect of each dual-drug combination on pancreatic cancer cell line (BxPC-3)
Figure PCTCN2021111714-appb-000002
Figure PCTCN2021111714-appb-000002
Figure PCTCN2021111714-appb-000003
Figure PCTCN2021111714-appb-000003
Figure PCTCN2021111714-appb-000004
Figure PCTCN2021111714-appb-000004
Figure PCTCN2021111714-appb-000005
Figure PCTCN2021111714-appb-000005
Figure PCTCN2021111714-appb-000006
Figure PCTCN2021111714-appb-000006
Figure PCTCN2021111714-appb-000007
Figure PCTCN2021111714-appb-000007
实验结果显示，表三中仅有特定组别可以具有良好的抑制胰腺癌细胞存活率的效果且具有显著的协同作用，其中特别是(C4)氯硝柳胺(50nM)与(C18)氟苯达唑(50nM)的组合以及(C11)金诺芬与(C25)双硫仑的组合具有最佳的协同效果，其协同作用协同值可达6以上。The experimental results show that only specific groups in Table 3 can have a good effect on inhibiting the survival rate of pancreatic cancer cells and have a significant synergistic effect, especially (C4) niclosamide (50nM) and (C18) fluorobenzene. The combination of dazole (50nM) and the combination of (C11) auranofin and (C25) disulfiram had the best synergistic effect, and the synergy value of the synergistic effect could reach more than 6.
实验二、对卵巢细胞癌细胞株(TOV-21G)进行双药组合实验结果Experiment 2. The results of the double-drug combination experiment on ovarian cancer cell line (TOV-21G)
表4各双药组合对卵巢癌细胞株(TOV-21G)细胞存活率及协同效果汇整Table 4. Summary of the cell survival rate and synergistic effect of each dual-drug combination on ovarian cancer cell line (TOV-21G)
Figure PCTCN2021111714-appb-000008
Figure PCTCN2021111714-appb-000008
Figure PCTCN2021111714-appb-000009
Figure PCTCN2021111714-appb-000009
Figure PCTCN2021111714-appb-000010
Figure PCTCN2021111714-appb-000010
Figure PCTCN2021111714-appb-000011
Figure PCTCN2021111714-appb-000011
Figure PCTCN2021111714-appb-000012
Figure PCTCN2021111714-appb-000012
Figure PCTCN2021111714-appb-000013
Figure PCTCN2021111714-appb-000013
实验结果显示，表四中仅有特定组别可以具有良好的抑制卵巢癌细胞存活率的效果且具有显著的协同作用，其中特别是(C4)氯硝柳胺(50nM)与(C18)氟苯达唑(50nM)的组合、(C19)洛伐他汀与(C25)双硫仑的组合以及(C4)氯硝柳胺(50nM)与(C25)双硫仑(50nM)的组合具有最佳的协同效果，其协同作用高达88～97的协同值。The experimental results show that only specific groups in Table 4 can have a good effect on inhibiting the survival rate of ovarian cancer cells and have a significant synergistic effect, especially (C4) niclosamide (50nM) and (C18) fluorobenzene The combination of dazole (50 nM), (C19) lovastatin with (C25) disulfiram, and (C4) niclosamide (50 nM) with (C25) disulfiram (50 nM) had the best results Synergistic effect, its synergistic effect is as high as 88-97 synergy value.
实验三、对三阴性乳腺癌细胞株(MDA-MB-231)进行双药组合实验结果Experiment 3. Results of double-drug combination experiment on triple-negative breast cancer cell line (MDA-MB-231)
表5、双药组合对三阴性乳腺癌细胞株(MDA-MB-231)细胞存活率及协同效果汇整Table 5. Summary of cell survival rate and synergistic effect of double drug combination on triple negative breast cancer cell line (MDA-MB-231)
Figure PCTCN2021111714-appb-000014
Figure PCTCN2021111714-appb-000014
Figure PCTCN2021111714-appb-000015
Figure PCTCN2021111714-appb-000015
Figure PCTCN2021111714-appb-000016
Figure PCTCN2021111714-appb-000016
Figure PCTCN2021111714-appb-000017
Figure PCTCN2021111714-appb-000017
Figure PCTCN2021111714-appb-000018
Figure PCTCN2021111714-appb-000018
实验结果显示，表五中仅有特定组别可以具有良好的抑制三阴性乳腺癌细胞存活率的效果且具有显著的协同作用，其中特别是(C3)吡维铵与(C75)法舒地尔的组合具有最佳的协同效果，其协同作用协同值可达 3.159。The experimental results show that only specific groups in Table 5 can have a good effect on inhibiting the survival rate of triple-negative breast cancer cells and have a significant synergistic effect, especially (C3) piraverium and (C75) fasudil. The combination has the best synergistic effect, and its synergy value can reach 3.159.
实验四、对乳腺癌细胞株(MCF-7)进行双药组合实验结果Experiment 4. Results of double-drug combination experiment on breast cancer cell line (MCF-7)
表六、各双药组合对乳腺癌细胞株(MCF-7)细胞存活率及协同效果汇整Table 6. Summary of the cell survival rate and synergistic effect of each two-drug combination on breast cancer cell line (MCF-7)
Figure PCTCN2021111714-appb-000019
Figure PCTCN2021111714-appb-000019
Figure PCTCN2021111714-appb-000020
Figure PCTCN2021111714-appb-000020
Figure PCTCN2021111714-appb-000021
Figure PCTCN2021111714-appb-000021
Figure PCTCN2021111714-appb-000022
Figure PCTCN2021111714-appb-000022
Figure PCTCN2021111714-appb-000023
Figure PCTCN2021111714-appb-000023
实验结果显示，表六中仅有特定组别可以具有良好的抑制乳腺癌细胞存活率的效果且具有显著的协同作用，其中特别是(C11)金诺芬与(C25)双硫仑(50nM)的组合具有最佳的协同效果，其协同作用协同值高达8.12。The experimental results show that only specific groups in Table 6 can have a good effect on inhibiting the survival rate of breast cancer cells and have a significant synergistic effect, especially (C11) Auranofin and (C25) Disulfiram (50nM) The combination has the best synergistic effect, and its synergy synergy value is as high as 8.12.
实验五、对肝癌细胞株(HepG2)进行双药组合实验结果Experiment 5. Results of double-drug combination experiment on liver cancer cell line (HepG2)
表七、各双药组合对肝癌细胞株(HepG2)细胞存活率及协同效果汇整Table 7. Summary of the cell survival rate and synergistic effect of each two-drug combination on liver cancer cell line (HepG2)
Figure PCTCN2021111714-appb-000024
Figure PCTCN2021111714-appb-000024
Figure PCTCN2021111714-appb-000025
Figure PCTCN2021111714-appb-000025
Figure PCTCN2021111714-appb-000026
Figure PCTCN2021111714-appb-000026
Figure PCTCN2021111714-appb-000027
Figure PCTCN2021111714-appb-000027
Figure PCTCN2021111714-appb-000028
Figure PCTCN2021111714-appb-000028
Figure PCTCN2021111714-appb-000029
Figure PCTCN2021111714-appb-000029
实验结果显示，表七中仅有特定组别可以具有良好的抑制肝癌细胞存活率的效果且具有显著的协同作用，其中特别是(C4)氯硝柳胺(50nM)与(C18)氟苯达唑(50nM)的组合以及(C4)氯硝柳胺(50nM)与(C25)双硫仑(50nM)的组合具有最佳的协同效果，其协同作用协同值高达7.49与7.39。The experimental results show that only specific groups in Table 7 can have a good effect on inhibiting the survival rate of liver cancer cells and have a significant synergistic effect, especially (C4) Niclosamide (50nM) and (C18) Flubenda The combination of azoles (50 nM) and the combination of (C4) niclosamide (50 nM) and (C25) disulfiram (50 nM) had the best synergistic effect, and the synergistic values were as high as 7.49 and 7.39.
实验六、对非小细胞肺癌细胞株(H460)进行双药组合实验结果表八、各双药组合对非小细胞肺癌细胞株(H460)细胞存活率及协同效果汇整Experiment 6. Experiment results of double-drug combination on non-small cell lung cancer cell line (H460) Table 8. Summary of cell survival rate and synergistic effect of each double-drug combination on non-small cell lung cancer cell line (H460)
Figure PCTCN2021111714-appb-000030
Figure PCTCN2021111714-appb-000030
Figure PCTCN2021111714-appb-000031
Figure PCTCN2021111714-appb-000031
Figure PCTCN2021111714-appb-000032
Figure PCTCN2021111714-appb-000032
Figure PCTCN2021111714-appb-000033
Figure PCTCN2021111714-appb-000033
Figure PCTCN2021111714-appb-000034
Figure PCTCN2021111714-appb-000034
Figure PCTCN2021111714-appb-000035
Figure PCTCN2021111714-appb-000035
实验结果显示，表八中仅有特定组别可以具有良好的抑制非小细胞肺癌细胞存活率的效果且具有显著的协同作用，其中特别是(C4)氯硝柳胺(50nM)与(C18)氟苯达唑(50nM)的组合以及(C4)氯硝柳胺(50nM)与(C25)双硫仑(50nM)的组合具有最佳的协同效果，其协同作用协同值高达9.14与8.12。The experimental results show that only specific groups in Table 8 can have a good effect on inhibiting the survival rate of non-small cell lung cancer cells and have a significant synergistic effect, especially (C4) niclosamide (50nM) and (C18) The combination of flubendazole (50 nM) and the combination of (C4) niclosamide (50 nM) and (C25) disulfiram (50 nM) had the best synergistic effect, and the synergistic values were as high as 9.14 and 8.12.
实验七、对大肠癌细胞株(HCT116)进行双药组合实验结果Experiment 7. Results of double drug combination experiment on colorectal cancer cell line (HCT116)
表九、各双药组合对大肠癌细胞株(HCT116)细胞存活率及协同效果汇整Table 9. Summary of the cell survival rate and synergistic effect of each two-drug combination on colorectal cancer cell line (HCT116)
Figure PCTCN2021111714-appb-000036
Figure PCTCN2021111714-appb-000036
Figure PCTCN2021111714-appb-000037
Figure PCTCN2021111714-appb-000037
Figure PCTCN2021111714-appb-000038
Figure PCTCN2021111714-appb-000038
Figure PCTCN2021111714-appb-000039
Figure PCTCN2021111714-appb-000039
Figure PCTCN2021111714-appb-000040
Figure PCTCN2021111714-appb-000040
实验结果显示，表九中仅有特定组别可以具有良好的抑制大肠癌细胞存活率的效果且具有显著的协同作用，其中特别是(C11)金诺芬与(C25)双硫仑的组合具有最佳的协同效果，其些同作用协同值高达5.486。The experimental results show that only specific groups in Table 9 can have a good effect on inhibiting the survival rate of colorectal cancer cells and have a significant synergistic effect, especially the combination of (C11) auranofin and (C25) disulfiram has The best synergistic effect, the synergy value of some synergies is as high as 5.486.
另外，在本次实验的过程中我们发现，(C11)金诺芬以及(C25)双硫 仑在100nM时单独使用在大肠癌细胞(HCT116)上不论是在抑制癌细胞存活率(分别为1.34以及1.16)或是协同值(分别为1.008以及0.94)上均无明显的效果，但是将两者进行双药组合搭配使用可以有效的抑制癌细胞的存活率(细胞存活率0.28)，并且具有显著的协同作用(α值>5)，此为完全意想不到的结果。In addition, in the course of this experiment, we found that (C11) auranofin and (C25) disulfiram alone at 100 nM on colorectal cancer cells (HCT116) could inhibit the cancer cell survival rate (respectively 1.34 and 1.16) or the synergy value (1.008 and 0.94, respectively), there is no obvious effect, but the combination of the two drugs can effectively inhibit the survival rate of cancer cells (cell survival rate 0.28), and has a significant synergy (α value>5), which is a completely unexpected result.
实验八、对肺癌细胞株(A549)进行双药组合实验结果Experiment 8. Results of double-drug combination experiment on lung cancer cell line (A549)
表十、各双药组合对肺癌细胞株(A549)细胞存活率及协同效果汇整Table 10. Summary of cell survival rate and synergistic effect of each dual-drug combination on lung cancer cell line (A549)
Figure PCTCN2021111714-appb-000041
Figure PCTCN2021111714-appb-000041
Figure PCTCN2021111714-appb-000042
Figure PCTCN2021111714-appb-000042
Figure PCTCN2021111714-appb-000043
Figure PCTCN2021111714-appb-000043
Figure PCTCN2021111714-appb-000044
Figure PCTCN2021111714-appb-000044
Figure PCTCN2021111714-appb-000045
Figure PCTCN2021111714-appb-000045
实验结果显示，表十中仅有特定组别可以具有良好的抑制肺癌细胞存活率的效果且具有显著的协同作用，其中特别是(C4)氯硝柳胺与(C76)双膦酸盐诸如氯屈膦酸盐的组合以及(C4)氯硝柳胺与(C21)乙胺嘧啶的组合具有最佳的协同效果，其协同作用协同值高达5.66以及5.25。The experimental results show that only specific groups in Table 10 can have a good effect on inhibiting the survival rate of lung cancer cells and have a significant synergistic effect, especially (C4) niclosamide and (C76) bisphosphonates such as chlorine. The combination of ledronate and the combination of (C4) niclosamide and (C21) pyrimethamine had the best synergistic effect, and the synergy value of synergy was as high as 5.66 and 5.25.
综上所述，结果显示本发明所提出的药物组合对于不同的癌种会有 不同的结果，每个癌种最有效的组别都不尽相同，因此本发明的双药医药组合物具有癌种专一性、特异性。To sum up, the results show that the drug combination proposed by the present invention will have different results for different cancer types, and the most effective groups for each cancer type are different. Therefore, the dual-drug pharmaceutical composition of the present invention has cancer specificity, specificity.
此外，实验结果显示相加性治疗癌症功效但没有副作用或副作用极小的药物组合就临床的角度来看，也是重要的，因为低剂量的组合可提供相同的抗癌作用又可降低其副作用。In addition, experimental results showing additive efficacy in treating cancer with no or minimal side effects are also important from a clinical point of view, as lower doses of the combination provide the same anti-cancer effect with reduced side effects.
上述实验数据为在特定条件之下所获得的初步实验结果，其仅用以易于了解或参考本发明的技术内容而已，其尚需进行其他相关实验。该实验数据及其结果并非用以限制本发明的权利范围。The above experimental data are preliminary experimental results obtained under specific conditions, which are only used to facilitate understanding or reference to the technical content of the present invention, and other related experiments are still required. The experimental data and its results are not intended to limit the scope of the present invention.
本发明所揭露的所有特征应可以任何结合方式实现。本发明所揭露的每一特征应可以相同、均等或相似目的的取代物所取代。因此，除非有明确的指定，否则所揭露的每一个特征仅仅只是均等物或相似特征的一个种类的一实施例。All features disclosed in the present invention should be implemented in any combination. Each feature disclosed herein may be replaced by a substitute of the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only one embodiment of a class of equivalent or similar features.

Claims (22)

  1. 一种双非癌药物用于制备治疗胰腺癌的医药组合物的用途，其特征是，所述双非癌药物选自吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，所述医药组合物可以抑制癌症细胞存活率至0.325以下且协同值达1.33以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for treating pancreatic cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Pyrvinium, Niclosamide, Zidovudine (Zidovudine), Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Flubendazole , Lovastatin, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate Any two drugs in the group consisting of Clodronate, the pharmaceutical composition can inhibit the cancer cell survival rate to below 0.325 and the synergy value to be above 1.33.
  2. 如权利要求1所述的双非癌药物用于制备治疗胰腺癌的医药组合物的用途，其特征是，所述双非癌药物为金诺芬(Auranofin)和双硫仑(Disulfiram)，所述医药组合物抑制癌症细胞存活率至0.134且协同值为6.672。The use of the dual non-cancer drug as claimed in claim 1 for preparing a pharmaceutical composition for treating pancreatic cancer, wherein the dual non-cancer drug is Auranofin and Disulfiram, and the The pharmaceutical composition inhibited the cancer cell survival rate to 0.134 and the synergy value was 6.672.
  3. 如权利要求1所述的双非癌药物用于制备治疗胰腺癌的医药组合物的用途，其特征是，所述双非癌药物选自氯硝柳胺(Niclosamide)、氟苯达唑(Flubendazole)或双硫仑(Disulfiram)所组成的群组中的任两种药物，且所述双非癌药物有效剂量为50nM，所述医药组合物协同值达1.392以上。The use of the dual non-cancer drug as claimed in claim 1 for preparing a pharmaceutical composition for treating pancreatic cancer, wherein the dual non-cancer drug is selected from the group consisting of Niclosamide, Flubendazole ) or any two drugs in the group consisting of Disulfiram, and the effective dose of the dual non-cancer drugs is 50 nM, and the synergy value of the pharmaceutical composition is above 1.392.
  4. 一种双非癌药物用于制备治疗卵巢癌的医药组合物的用途，其特征是，所述双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平 (Azelnidipine)、双硫仑(Disulfiram)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，所述医药组合物抑制癌症细胞存活率至0.17以下且协同值达1.6以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for treating ovarian cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Paroxetine, Pyrvinium, Niclosamide ), Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone, Fluorine Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, or Bisphosphonates Any two drugs in the group consisting of Clodronate, the pharmaceutical composition inhibited cancer cell survival to below 0.17 and synergy value above 1.6.
  5. 如权利要求4所述的双非癌药物用于制备治疗卵巢癌的医药组合物的用途，其特征是，所述双非癌药物为氟苯达唑(Flubendazole)和双硫仑(Disulfiram)，且有效剂量为50nM，所述医药组合物抑制癌症细胞存活率至0.008且协同值为97.265。The purposes of the dual non-cancer drug for the preparation of a pharmaceutical composition for treating ovarian cancer as claimed in claim 4, wherein the dual non-cancer drugs are Flubendazole and Disulfiram, And the effective dose was 50 nM, the pharmaceutical composition inhibited the cancer cell survival rate to 0.008 and the synergy value was 97.265.
  6. 如权利要求4所述的双非癌药物用于制备治疗卵巢癌的医药组合物的用途，其特征是，所述双非癌药物选自氯硝柳胺(Niclosamide)、氟苯达唑(Flubendazole)或双硫仑(Disulfiram)所组成的群组中的任两种药物，且所述双非癌药物有效剂量为50nM，医药组合物协同值达88.212以上。The use of the dual non-cancer drug for preparing a pharmaceutical composition for treating ovarian cancer according to claim 4, wherein the dual non-cancer drug is selected from the group consisting of Niclosamide, Flubendazole ) or any two drugs in the group consisting of Disulfiram, and the effective dose of the dual non-cancer drugs is 50 nM, and the synergy value of the pharmaceutical composition is above 88.212.
  7. 一种双非癌药物用于制备治疗三阴性乳腺癌的医药组合物的用途，其特征是，所述双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，所述医药组合物抑制癌症细胞存活率至0.485以下且协同值达1.305以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for treating triple-negative breast cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Paroxetine, Pyrvinium, Niclosamide (Niclosamide), Zidovudine, Albendazole, Carbimazole, Dexamethasone, Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasudil, or a bisphosphonate such as clodronate Any two drugs in the group consisting of (Clodronate), the pharmaceutical composition inhibits the cancer cell survival rate below 0.485 and the synergy value is above 1.305.
  8. 如权利要求7所述的双非癌药物用于制备治疗三阴性乳腺癌的医药组合物的用途，其特征是，所述双非癌药物为吡维铵(Pyrvinium)和法舒地尔(Fasudil)，所述医药组合物抑制癌症细胞存活率至0.171且协同值为3.159。The use of the dual non-cancer drug for preparing a pharmaceutical composition for treating triple-negative breast cancer as claimed in claim 7, wherein the dual non-cancer drug is Pyrvinium and Fasudil ), the pharmaceutical composition inhibited the cancer cell survival rate to 0.171 and the synergy value was 3.159.
  9. 如权利要求7所述的双非癌药物用于制备治疗三阴性乳腺癌的医药组合物的用途，其特征是，所述双非癌药物选自氯硝柳胺(Niclosamide)、氟苯达唑(Flubendazole)或双硫仑(Disulfiram)所组成的群组中的任两种药物，且所述双非癌药物有效剂量为50-100nM，医药组合物协同值达1.392以上。The use of the dual non-cancer drug for preparing a pharmaceutical composition for treating triple-negative breast cancer according to claim 7, wherein the dual non-cancer drug is selected from the group consisting of Niclosamide, Flubendazole Any two drugs in the group consisting of (Flubendazole) or Disulfiram (Disulfiram), and the effective dose of the dual non-cancer drugs is 50-100 nM, and the synergy value of the pharmaceutical composition is above 1.392.
  10. 一种双非癌药物用于制备治疗乳腺癌的医药组合物的用途，其特征是，所述双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、金诺芬(Auranofin)或双硫仑(Disulfiram)所组成的群组中的任两种药物，所述医药组合物抑制癌症细胞存活率至0.47以下且协同值达1.335以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for treating breast cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Paroxetine, Pyrvinium, Niclosamide ), Zidovudine (Zidovudine), any two drugs in the group consisting of Auranofin (Auranofin) or Disulfiram (Disulfiram), the pharmaceutical composition inhibits cancer cell survival rate below 0.47 and synergistically The value is above 1.335.
  11. 如权利要求10所述的双非癌药物用于制备治疗乳腺癌的医药组合物的用途，其特征是，所述双非癌药物为金诺芬(Auranofin)和50nM的双硫仑(Disulfiram)，所述医药组合物抑制癌症细胞细胞存活率至0.118且协同值为8.124。The use of the dual non-cancer drug as claimed in claim 10 for preparing a pharmaceutical composition for treating breast cancer, wherein the dual non-cancer drug is Auranofin and 50nM Disulfiram , the pharmaceutical composition inhibited the cancer cell survival rate to 0.118 and the synergy value was 8.124.
  12. 一种双非癌药物用于制备治疗肝癌的医药组合物的用途，其特征是，所述双非癌药物选自吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、金诺芬(Auranofin)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)或双硫仑(Disulfiram)所组成的群组中的任两种药物，所述医药组合物抑制癌症细胞存活率至0.451以下且协同值达1.334以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for treating liver cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Pyrvinium, Niclosamide, Zidovudine ( Zidovudine), Albendazole (Auranofin), Dexamethasone (Dexamethasone), Flubendazole (Flubendazole), Lovastatin (Lovastatin), Pyrimethamine (Pyrimethamine), benzenesulfonic acid Any two drugs in the group consisting of Amlodipine besylate or Disulfiram, the pharmaceutical composition inhibits the survival rate of cancer cells to below 0.451 and the synergy value is above 1.334.
  13. 如权利要求12所述的双非癌药物用于制备治疗肝癌的医药组合物的用途，其特征是，所述双非癌药物为氯硝柳胺(Niclosamide)和氟苯达唑 (Flubendazole)，且有效剂量为50nM，所述医药组合物抑制癌症细胞存活率至0.109且协同值为7.491。The use of the dual non-cancer drugs for preparing a pharmaceutical composition for treating liver cancer according to claim 12, wherein the dual non-cancer drugs are Niclosamide and Flubendazole, And the effective dose was 50 nM, the pharmaceutical composition inhibited the cancer cell survival rate to 0.109 and the synergy value was 7.491.
  14. 如权利要求12所述的双非癌药物用于制备治疗肝癌的医药组合物的用途，其特征是，所述双非癌药物选自氯硝柳胺(Niclosamide)、氟苯达唑(Flubendazole)或双硫仑(Disulfiram)所组成的群组中的任两种药物，且所述双非癌药物有效剂量为50nM，医药组合物协同值达7.391以上。The use of the dual non-cancer drug for preparing a pharmaceutical composition for treating liver cancer according to claim 12, wherein the dual non-cancer drug is selected from Niclosamide, Flubendazole Or any two drugs in the group consisting of Disulfiram, and the effective dose of the dual non-cancer drugs is 50nM, and the synergy value of the pharmaceutical composition is above 7.391.
  15. 一种双非癌药物用于制备治疗非小细胞肺癌的医药组合物的用途，其特征是，所述双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、齐多夫定(Zidovudine)、阿苯达唑(Albendazole)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、氟苯达唑(Flubendazole)、洛伐他汀(Lovastatin)、乙胺嘧啶(Pyrimethamine)、苯磺酸胺氯地平(Amlodipine besylate)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，所述医药组合物抑制癌症细胞存活率至0.5以下且协同值达1.456以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for treating non-small cell lung cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Paroxetine, Pyrvinium, Niclosamide (Niclosamide), Zidovudine, Albendazole, Alendronic Acid, Auranofin, Carbimazole, Dexamethasone , Flubendazole, Lovastatin, Pyrimethamine, Amlodipine besylate, Azelnidipine, Disulfiram, Fasu Any two drugs in the group consisting of Fasudil or a bisphosphonate such as Clodronate, the pharmaceutical composition inhibits cancer cell survival to below 0.5 and a synergy value above 1.456 .
  16. 如权利要求15所述的双非癌药物用于制备治疗非小细胞肺癌的医药组合物的用途，其特征是，所述双非癌药物为氯硝柳胺(Niclosamide)和氟苯达唑(Flubendazole)且有效剂量为50nM，所述医药组合物抑制癌症细胞细胞存活率至0.089且协同值为9.143。The use of the dual non-cancer drug as claimed in claim 15 for preparing a pharmaceutical composition for treating non-small cell lung cancer, wherein the dual non-cancer drug is niclosamide and flubendazole ( Flubendazole) and the effective dose was 50 nM, the pharmaceutical composition inhibited the cancer cell survival rate to 0.089 and the synergy value was 9.143.
  17. 如权利要求15所述的双非癌药物用于制备治疗非小细胞肺癌的医药组合物的用途，其特征是，所述双非癌药物选自氯硝柳胺(Niclosamide)、氟苯达唑(Flubendazole)或双硫仑(Disulfiram)所组成的群组中的任两种药物，且所述双非癌药物有效剂量为50-100nM，协同值达2.354以上。The use of the dual non-cancer drug for preparing a pharmaceutical composition for treating non-small cell lung cancer according to claim 15, wherein the dual non-cancer drug is selected from the group consisting of Niclosamide, Flubendazole Any two drugs in the group consisting of (Flubendazole) or Disulfiram (Disulfiram), and the effective dose of the dual non-cancer drugs is 50-100 nM, and the synergy value is above 2.354.
  18. 一种双非癌药物用于制备治疗大肠癌的医药组合物的用途，其特征是，所述双非癌药物选自氯硝柳胺(Niclosamide)、阿仑膦酸(Alendronic Acid)、金诺芬(Auranofin)或双硫仑(Disulfiram)所组成的群组中的任两种药物，所述医药组合物抑制癌症细胞存活率至0.493以下且协同值达1.321以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for the treatment of colorectal cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Niclosamide, Alendronic Acid, Jinnuo Any two drugs in the group consisting of Auranofin or Disulfiram, the pharmaceutical composition inhibits the cancer cell survival rate to below 0.493 and the synergy value to above 1.321.
  19. 如权利要求18所述的双非癌药物用于制备治疗大肠癌的医药组合物的用途，其特征是，所述双非癌药物为金诺芬(Auranofin)和双硫仑(Disulfiram)，所述医药组合物抑制癌症细胞细胞存活率至0.284且协同值为5.486。The use of the dual non-cancer drug as claimed in claim 18 for preparing a pharmaceutical composition for the treatment of colorectal cancer, wherein the dual non-cancer drug is Auranofin and Disulfiram, wherein The pharmaceutical composition inhibited the cell survival rate of cancer cells to 0.284 and the synergy value was 5.486.
  20. 一种双非癌药物用于制备治疗肺癌的医药组合物的用途，其特征是，所述双非癌药物选自帕罗西汀(Paroxetine)、吡维铵(Pyrvinium)、氯硝柳胺(Niclosamide)、卡比马唑(Carbimazole)、地塞米松(Dexamethasone)、乙胺嘧啶(Pyrimethamine)、阿折地平(Azelnidipine)、双硫仑(Disulfiram)、法舒地尔(Fasudil)或双膦酸盐诸如氯屈膦酸盐(Clodronate)所组成的群组中的任两种药物，所述医药组合物抑制癌症细胞存活率至0.493以下且协同值达1.343以上。Use of a dual non-cancer drug for preparing a pharmaceutical composition for treating lung cancer, characterized in that the dual non-cancer drug is selected from the group consisting of Paroxetine, Pyrvinium, and Niclosamide. , Carbimazole, Dexamethasone, Pyrimethamine, Azelnidipine, Disulfiram, Fasudil or bisphosphonates such as Any two drugs in the group consisting of Clodronate, the pharmaceutical composition inhibits the cancer cell survival rate below 0.493 and the synergy value is above 1.343.
  21. 如权利要求20所述的双非癌药物用于制备治疗肺癌的医药组合物的用途，其特征是，所述双非癌药物为氯硝柳胺(Niclosamide)和双膦酸盐诸如氯屈膦酸盐(Clodronate)，所述医药组合物抑制癌症细胞细胞存活率至0.111且协同值为5.655。The use of the dual non-cancer drug for preparing a pharmaceutical composition for treating lung cancer as claimed in claim 20, wherein the dual non-cancer drug is Niclosamide and a bisphosphonate such as clodronate Clodronate, the pharmaceutical composition inhibited cancer cell viability to 0.111 with a synergy value of 5.655.
  22. 如权利要求20所述的双非癌药物用于制备治疗肺癌的医药组合物的用途，其特征是，所述双非癌药物选自50nM帕罗西汀(Paroxetine)、氯硝 柳胺(Niclosamide)或阿折地平(Azelnidipine)所组成的群组中的任两种药物，所述医药组合物协同值达1.662以上。The use of the dual non-cancer drug as claimed in claim 20 for preparing a pharmaceutical composition for treating lung cancer, wherein the dual non-cancer drug is selected from 50nM Paroxetine, Niclosamide or For any two drugs in the group consisting of Azelnidipine, the pharmaceutical composition has a synergistic value of more than 1.662.
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