WO2021023290A1 - Application de pyrithione de zinc dans le traitement du cancer du poumon - Google Patents

Application de pyrithione de zinc dans le traitement du cancer du poumon Download PDF

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WO2021023290A1
WO2021023290A1 PCT/CN2020/107668 CN2020107668W WO2021023290A1 WO 2021023290 A1 WO2021023290 A1 WO 2021023290A1 CN 2020107668 W CN2020107668 W CN 2020107668W WO 2021023290 A1 WO2021023290 A1 WO 2021023290A1
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zinc pyrithione
lung cancer
pharmaceutically acceptable
pharmaceutical composition
stereoisomers
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PCT/CN2020/107668
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English (en)
Chinese (zh)
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陈毅歆
王国松
洪俊平
吴倩
陈瑞琪
黄鹏飞
夏宁邵
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厦门大学
养生堂有限公司
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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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application relates to the field of medicinal chemistry, specifically, to the application of zinc pyrithione in the treatment of lung cancer.
  • Non-small cell lung cancer can be divided into lung squamous cell carcinoma, lung adenocarcinoma, and large cell lung cancer.
  • Therapeutic drugs for lung cancer have very important prospects, but they will also face huge challenges.
  • Pyrithione zinc (Pyrithione zinc, zinc pyrithione, zinc pyrithion, PYZ, zinc pyridinethione, ZPT) CAS number is 13463-41-7, molecular formula is C 10 H 8 N 2 O 2 S 2 Zn, and its molecular structure is shown below,
  • Zinc pyrithione has a strong killing effect on fungi and bacteria, can effectively kill the fungi that produce dandruff, and play an anti-dandruff effect.
  • zinc pyrithione is also commonly used to treat psoriasis.
  • zinc pyrithione has a broad-spectrum therapeutic activity for lung cancer. It can inhibit the proliferation of lung cancer cells by inducing tumor cell apoptosis, inhibiting tumor cell cycle, inhibiting tumor migration and other mechanisms, thereby achieving the effect of inhibiting tumor growth or eliminating tumors.
  • This application relates to the use of zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications in the preparation of drugs for treating lung cancer.
  • This application also relates to the use of a pharmaceutical composition in the preparation of a medicament for the treatment of lung cancer, wherein the pharmaceutical composition contains zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications thereof, and pharmaceuticals Acceptable carrier or excipient.
  • This application also relates to the use of zinc pyrithione, its stereoisomers, or various pharmaceutically acceptable modifications, in combination with a second anti-tumor drug to prepare a drug for treating lung cancer.
  • the application also relates to zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications thereof, which are used for the treatment of lung cancer.
  • This application also relates to a pharmaceutical composition for the treatment of lung cancer, wherein the pharmaceutical composition contains zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications thereof, and a pharmaceutically acceptable carrier Or excipients.
  • the application also relates to a combination product comprising zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications and a second anti-tumor drug, which is used for the treatment of lung cancer.
  • This application also relates to a method for treating lung cancer, which comprises: administering a therapeutically effective amount of zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications thereof to a subject in need thereof.
  • This application also relates to another method for treating lung cancer, which comprises: administering a therapeutically effective amount of the pharmaceutical composition described in this application to a subject in need thereof.
  • This application also relates to another method of treating lung cancer, which comprises: administering a therapeutically effective amount of zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications thereof to a subject in need thereof, And a therapeutically effective amount of the second anti-tumor drug.
  • the lung cancer described in the present application is selected from: lung squamous cell carcinoma, lung adenocarcinoma, large cell lung cancer, small cell lung cancer, or any combination thereof.
  • the pharmaceutical composition described in the present application further contains a second anti-tumor drug.
  • the second anti-tumor drug described in the present application is an immune checkpoint inhibitor, a traditional chemotherapy drug, or a small molecule inhibitor.
  • the immune checkpoint inhibitors described in the present application include but are not limited to: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and the like.
  • the traditional chemotherapeutic drugs described in the present application include but are not limited to: paclitaxel, cisplatin, 5-fluorouracil and the like.
  • the small molecule inhibitors described in the present application include but are not limited to EGFR inhibitors, HER2 inhibitors, ALK inhibitors and the like.
  • the PD-1 inhibitors described in the application include, but are not limited to: Nivolumab, Pembrolizumab, IBI-308, Camrelizumab (SHR-1210), Tislelizumab, Cemiplimab, BCD-100, TSR-042 , PDR-001, JNJ-63723283) etc.
  • the PD-L1 inhibitors described in the present application include but are not limited to: Atezolizumab, Avelumab, Durvalumab, BMS-936559, M-7824, CX-072) and the like.
  • the CTLA4 inhibitors described in the present application include but are not limited to: Ipilimumab, Tremelimumab, AGEN-1884, AK-104) and the like.
  • the EGFR inhibitors described in the present application include but are not limited to: Cetuximab, Erlotinib, Gefitinib, Lapatinib Ditosylate, Neratinib, Theliatinib, Cyasterone, Osimertinib, Avitinib, Afatinib, Gefitinib, Canertinib, Lapatinib, AG -490, Pelitinib, Dacomitinib, etc.
  • the HER2 inhibitors described in this application include but are not limited to: Poziotinib, Trastuzumab, Pertuzumab, Irbinitinib and the like.
  • the ALK inhibitors described in this application include but are not limited to: Crizotinib, TAE684 (NVP-TAE684), Alectinib, AZD3463, ASP3026, Brigatinib (AP26113), Ensartinib (X-396), Alectinib Wait.
  • the pharmaceutical composition described in the present application may be a tablet, capsule, pill, oral liquid preparation, granule, powder or injection.
  • the pharmaceutical composition described in the present application can be administered to a subject by oral, injection, implantation, topical application, spraying or inhalation.
  • zinc pyrithione, its stereoisomers, or various pharmaceutically acceptable modifications of the present application are used as cytotoxic drugs, tumor growth inhibitors, and anti- Tumor metastasis drugs and/or anti-tumor invasion drugs.
  • zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications when zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications are combined with a second anti-tumor drug, zinc pyrithione, its stereoisomers or Various pharmaceutically acceptable modifications and the second anti-tumor drug are in the same preparation unit, or zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications and the second anti-tumor drug
  • the tumor drug combination is in different preparation units.
  • zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications when zinc pyrithione, its stereoisomers or various pharmaceutically acceptable modifications are combined with a second anti-tumor drug, zinc pyrithione, its stereoisomers or
  • the various pharmaceutically acceptable modifications and the second anti-tumor drug can be administered to the individual in need of treatment at the same time or separately; or zinc pyrithione, its stereoisomer or its pharmaceutically acceptable each Modifications, the second anti-tumor drug is administered after a certain interval of time; or the second anti-tumor drug is administered first, and zinc pyrithione, its stereoisomers or various pharmaceutically acceptable Modifications.
  • the carrier described in this application includes, but is not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated Partial glyceride mixture of plant fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, Cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human albumin
  • buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated Partial glyceride mixture of plant fatty acids, water,
  • excipients mentioned in this application refer to additions other than the main drug in the pharmaceutical preparation. It is stable in nature, has no compatibility with the main drug, does not produce side effects, does not affect the curative effect, is not easy to deform, dry, crack, mold, moth, is harmless to the human body, has no physiological effect, and does not produce chemical or physical effects with the main drug It does not affect the content determination of the main drug.
  • binders, fillers, disintegrants, lubricants in tablets; preservatives, antioxidants, flavors, fragrances, cosolvents, emulsifiers, solubilizers, and osmotic pressure regulators in oral liquid preparations , Coloring agents, etc. can all be called excipients, and so on.
  • subject as used in this application includes mammals and humans, preferably humans.
  • an effective amount refers to an amount sufficient to obtain or at least partially obtain the desired effect.
  • a therapeutically effective amount refers to an amount sufficient to cure or at least partially prevent the disease and its complications in patients who have already suffered from the disease. It is completely within the abilities of those skilled in the art to determine such an effective amount.
  • the effective amount for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient’s own immune system, the patient’s general conditions such as age, weight and sex, the way the drug is administered, and other treatments that are administered simultaneously and many more.
  • the amount of zinc pyrithione, its stereoisomers, or various pharmaceutically acceptable modifications or second anti-tumor drugs administered to the subject depends on the type and severity of the disease or condition and the test subject The characteristics of the patient, such as general health, age, sex, weight, and tolerance to the drug, also depend on the type of preparation and the way the drug is administered, as well as factors such as the period of administration or time interval. Those skilled in the art can determine the appropriate dosage based on these and other factors. Generally speaking, the daily dose of zinc pyrithione, its stereoisomers, or various pharmaceutically acceptable modifications or second anti-tumor drugs used for treatment may be about 0.0001 to 1000 mg/kg body weight/day. The dose can be given once or in multiples depending on the situation.
  • the anti-tumor drug zinc pyrithione provided in this application has broad-spectrum therapeutic activity on lung cancer. It can inhibit the proliferation of lung cancer cells by inducing tumor cell apoptosis, inhibiting tumor cell cycle, and inhibiting tumor migration, etc. The effect of tumor growth or tumor removal.
  • the advantage of zinc pyrithione is that it is easily accepted by patients, and it is inexpensive and easy to obtain. It is foreseeable that zinc pyrithione will change the market structure of existing tumor chemotherapy drugs and become a clinical drug that can be taken for a long time and effectively inhibits lung cancer metastasis, invasion and recurrence.
  • Figure 1 shows the inhibitory effect of zinc pyrithione on the proliferation of human lung adenocarcinoma cell lines
  • Figure 2 shows the inhibitory effect of zinc pyrithione on the proliferation of human lung squamous cell carcinoma cell lines
  • Figure 3 shows the inhibitory effect of zinc pyrithione on the proliferation of human large cell lung cancer cell lines
  • Figure 4 shows the inhibitory effect of zinc pyrithione on the proliferation of human small cell lung cancer cell lines
  • Figure 5 shows that zinc pyrithione can induce apoptosis in lung adenocarcinoma cell line A549;
  • Figure 6 shows that zinc pyrithione can induce apoptosis of lung squamous cell line H2170;
  • Figure 7 shows that zinc pyrithione can induce apoptosis in the large cell lung cancer cell line H661;
  • Figure 8 shows that zinc pyrithione can induce apoptosis in the small cell lung cancer cell line H1417;
  • Figure 9 shows that zinc pyrithione can inhibit lung cancer cell migration
  • Figure 10 shows that zinc pyrithione can inhibit the cell cycle of lung cancer cell division
  • Figure 11 shows that zinc pyrithione can inhibit the growth of lung cancer cell lines in the SCID mouse model.
  • test materials used and their sources include:
  • Zinc pyrithione purchased from MCE; high glucose DMEM medium, RIPM1640 medium, fetal bovine serum FBS (Gibco), CCK-8 kit purchased from Biyuntian Biotechnology Co., Ltd.; Annexin V-FITC cell apoptosis detection kit Purchased from Biyuntian Biotechnology Co., Ltd.; cell cycle detection kits were purchased from Biyuntian Biotechnology Co., Ltd.; 96-well plates (Nunc brand) were purchased from Thermo Company; SCID mice were purchased from Shanghai Slack Laboratory Animal Co., Ltd.
  • zinc pyrithione was diluted with a culture medium to a mother liquor with a concentration of 10 mmol/L, and then diluted with a culture medium to use concentrations of different gradients during use.
  • the zinc pyrithione injection used in Example 5 was prepared with phosphate buffered saline (PBS) with a concentration of 200 ⁇ g/mL.
  • PBS phosphate buffered saline
  • the cell line selected in the following examples is: human lung adenocarcinoma cell line A549 (medium: DMEM high glucose medium plus 10% FBS, purchased from CCL-185); human lung adenocarcinoma cell H1299 (medium: DMEM high glucose medium plus 10% FBS, purchased from CRL-5803); human lung adenocarcinoma cell H358 (medium: DMEM high glucose medium plus 10% FBS, purchased from CRL-5807); human lung squamous cell carcinoma SK-MES-1 (medium: DMEM high glucose medium plus 10% FBS, purchased from HTB-58); human lung squamous cell carcinoma cell Ebc-1 (medium: RIPM1640 plus 10% FBS, purchased from Thermo fisher scientific: 11875101); human lung squamous cell carcinoma cell H520 (medium: DMEM high glucose medium plus 10% FBS, purchased from HTB-182); human lung squamous cell carcinoma cell H2170 (medium: DMEM
  • Example 1 Experiment of the killing effect of zinc pyrithione on different tumor cells of lung cancer
  • the experimental method is to determine the viability of CCK-8 cells.
  • the CCK-8 reagent contains WST-8 [chemical name: 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonic acid) Acid benzene)-2H-tetrazole monosodium salt], it is activated by the dehydrogenase in the cell under the action of the electron carrier 1-methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS) It is reduced to a highly water-soluble yellow formazan product (Formazan dye). The amount of formazan produced is proportional to the number of living cells. Therefore, this feature can be used to directly analyze cell proliferation and toxicity.
  • the specific experimental procedure is: after the cells are digested with trypsin, they are dispersed into individual cells and suspended in the corresponding DMEM or RIPM1640 medium. Inoculate the cells in a 96-well culture plate, 5000cells/well, incubate for 8 hours in a 37°C/CO2 (5%) incubator to allow the cells to adhere to the wall. The next day, discard the culture solution and add zinc pyrithione Cell culture medium (the specific concentration is mentioned in the results of each cell), and set up control wells without adding drugs.
  • the inhibitory effects of zinc pyrithione on the proliferation of lung adenocarcinoma cell lines A549, H1299, and H358 are shown in Figure 1.
  • the concentration of zinc pyrithione used was 5 ⁇ mol/L. It can be seen from Figure 1 that the inhibitory effect of zinc pyrithione on the proliferation of the three lung adenocarcinoma cells can reach more than 90%, confirming that zinc pyrithione has a good proliferation inhibitory effect on lung adenocarcinoma cells.
  • the proliferation inhibitory effects of zinc pyrithione on lung squamous cell lines SK-MES-1, Ebc-1, H520, H2170, and H1703 are shown in Figure 2.
  • the concentration of zinc pyrithione used was 5 ⁇ mol/L. It can be seen from Figure 2 that the inhibitory effect of zinc pyrithione on the proliferation of five lung squamous cell carcinoma cells can reach more than 90%, confirming that zinc pyrithione has a good proliferation inhibitory effect on lung squamous cell carcinoma cells.
  • the inhibitory effect of zinc pyrithione on the proliferation of large cell lung cancer cell line H661 is shown in Figure 3.
  • the concentration of zinc pyrithione used was 5 ⁇ mol/L. It can be seen from Fig. 3 that the effect of zinc pyrithione on the proliferation of large cell lung cancer cells can reach more than 90%, confirming that zinc pyrithione has a good proliferation inhibitory effect on large cell lung cancer cells.
  • the inhibitory effect of zinc pyrithione on the proliferation of small cell lung cancer cell lines H510A, H1417, and DMS 114 is shown in Figure 4.
  • the concentration of zinc pyrithione used was 5 ⁇ mol/L. It can be seen from Fig. 4 that the effect of zinc pyrithione on the proliferation of small cell lung cancer cells can reach more than 90%, confirming that zinc pyrithione has a good proliferation inhibitory effect on small cell lung cancer cells.
  • the experimental method is to use Annexin V-FITC/PI double staining method and flow cytometer to detect cell apoptosis.
  • Annexin V-FITC/PI double staining method to detect cell apoptosis is as follows: the distribution of phospholipids in normal cell membranes is asymmetrical, the inner surface of the membrane contains negatively charged phospholipids (such as phosphatidylserine, PS), and the outer surface of the membrane contains Most neutral phospholipids. In the early stage of apoptosis, the PS in the cell membrane will flip from the inside to the surface of the cell membrane.
  • Annexin V is a calcium-dependent phospholipid binding protein that can specifically bind to PS with high affinity.
  • Propidium iodide is a nucleic acid dye that cannot penetrate the complete cell membrane, while the cell membrane of early apoptotic cells is intact, which is repellent to PI.
  • PI Propidium iodide
  • the simultaneous use of Annexin V and PI can distinguish cells in the early stage of apoptosis from other cells.
  • the specific experimental procedure is: after the cells are digested with trypsin, they are dispersed into individual cells and suspended in the corresponding DMEM or RIPM1640 medium. Inoculate the cells in a 6-well culture plate. After they grow up, add cell culture medium of different concentrations of zinc pyrithione (the specific concentration is mentioned in the results of each cell). After treatment for 24 hours, add trypsin (without EDTA, because EDTA can be combined with Annexin-V, affect the experiment) digest, centrifuge to collect the cells, if it is a suspension cell, collect the cell suspension and then centrifuge.
  • the lung adenocarcinoma cell line A549 was treated with different concentrations of zinc pyrithione, the tumor cells could undergo obvious apoptosis.
  • the results are shown in Figure 5.
  • the drug concentrations of zinc pyrithione were 10 ⁇ mol/L, 5 ⁇ mol/L, 2.5 ⁇ mol/L, 1.25 ⁇ mol/L, and the treatment time was 24 hours. It can be seen from Figure 5 that zinc pyrithione can induce apoptosis of lung adenocarcinoma cells.
  • the lung squamous cell line H2170 is treated with different concentrations of zinc pyrithione, the tumor cells can undergo obvious apoptosis.
  • the results are shown in Figure 6.
  • the drug concentrations of zinc pyrithione were 10 ⁇ mol/L, 5 ⁇ mol/L, 2.5 ⁇ mol/L, 1.25 ⁇ mol/L, and the treatment time was 24 hours. It can be seen from Figure 6 that zinc pyrithione can induce apoptosis of lung squamous cell carcinoma cells.
  • the large cell lung cancer cell line H661 was treated with different concentrations of zinc pyrithione, the tumor cells could undergo obvious apoptosis.
  • the results are shown in Figure 7.
  • the drug concentrations of zinc pyrithione were 10 ⁇ mol/L, 5 ⁇ mol/L, 2.5 ⁇ mol/L, 1.25 ⁇ mol/L, and the treatment time was 24 hours. It can be seen from Figure 7 that zinc pyrithione can induce apoptosis of large cell lung cancer cells.
  • the experimental method is a cell scratch test.
  • the cell scratch test is the simplest and most economical in vitro test method for studying cell migration.
  • the principle of this method is that when the cells grow to a monolayer state, a blank area is artificially created on the fused monolayer cells, called “scratches.” The cells on the edge of the scratch will gradually enter the blank area to make the "scratch" heal. The stronger the cell migration ability, the shorter the time to heal the scratch.
  • the specific experimental procedure is as follows: digest the cells with trypsin for 3 minutes, and add culture medium to terminate the digestion reaction. Then mix the cells by pipetting gently, and evenly seed the cells in a six-well plate. The cells were incubated in a 37°C incubator containing 5% CO 2 for 8-24 hours. The number of cells varies from cell to cell, and it should be fully covered overnight. On the next day, use the sterile tip of a 1mL pipette to compare with the straightedge, try to be perpendicular to the straightedge to make the scratch, and the tip should be vertical and not tilted.
  • the most important thing for cell scratches is to draw the line as straight as possible, and the width of the cells in the experimental group and the control group are similar to ensure that the zinc pyrithione treatment group and the control group are comparable. Wash the cells gently with PBS 3 times to remove the marked cells.
  • the experimental group was added with different concentrations of serum-free culture medium of zinc pyrithione, and the control group was added with the same volume of serum-free culture medium and placed in 37°C/5% CO 2 Incubator, cultivate. Sampling and taking pictures at 0, 12, and 24 hours. The direction of the "scratch" when taking pictures is best horizontal or vertical in the field of view.
  • the lung cancer cell line A549 was treated with cell culture medium of different concentrations of zinc pyrithione, all of which could significantly inhibit the migration ability of tumor cells.
  • the results are shown in Figure 9.
  • the drug concentrations of zinc pyrithione are 1 ⁇ mol/L, 2.5 ⁇ mol/L, and 5 ⁇ mol/L. It can be seen from Figure 9 that when the concentration of zinc pyrithione is as low as 2.5 ⁇ mol/L, compared with the control group, zinc pyrithione can still significantly inhibit the migration of tumor cells.
  • the experimental method is to analyze the cell cycle using propidium iodide (PI) DNA staining method. Because the DNA content of each phase of the cell cycle is different, normally the G1/G0 phase of normal cells has the DNA content of diploid cells (2N), while the G2/M phase has the DNA content of tetraploid cells (4N), while S The DNA content of the stage is between diploid and tetraploid.
  • PI is an intercalating nucleic acid fluorescent dye that can selectively intercalate between the bases of the nucleic acid DNA double helix and bind to it. The binding amount is proportional to the DNA content, and its fluorescence intensity directly reflects the DNA content in the cell.
  • the cell cycle phases can be divided into G1/G0 phase, S phase and G2/M phase, and the obtained flow histogram corresponds to each phase.
  • the cell cycle can be calculated by software to calculate the percentage of cells in each phase.
  • the specific experimental steps are as follows: digest the cells with trypsin for 3 minutes, and add culture medium to terminate the digestion reaction. Then mix the cells by pipetting gently, and evenly seed the cells in a six-well plate. The cells were placed in a 37°C incubator containing 5% CO 2 and incubated for 8-24 hours. The number of cells varies from cell to cell, and it should be fully covered overnight.
  • lung cancer cells (lung cancer cell line H1417) were treated with cell culture solutions of different concentrations of zinc pyrithione. After 48 hours, the supernatant was discarded and washed once with 1 mL of PBS. The supernatant was discarded, and 1 mL was added. The cells were digested with 0.25% trypsin.
  • PBS was added to terminate the digestion. Use a pipette to gently pipette the cells to suspend the cells.
  • the cell suspension was transferred to a centrifuge tube and centrifuged at 1500 rpm for 5 min to collect the cells. Add 3 ml of 4°C pre-cooled PBS to completely resuspend the cells, centrifuge at 1500 rpm for 5 min, and discard the supernatant. Precipitate and mix well. Slowly add 75% ethanol pre-cooled at -20°C to the pellet, and resuspend the cells at 4°C overnight.
  • mice 6-8 week old female C.B17SCID mice, which are from Shanghai Slack Experimental Animal Co., Ltd.; according to the protocol approved by the Experimental Animal Center of Xiamen University and the Ethics Committee, the mice were under SPF conditions Rearing.
  • tumor cells used for subcutaneous tumor formation in SCID mice were digested with 0.01% trypsin, and then resuspended into single cells in a cell culture medium containing 10% fetal bovine serum Suspension; count the cell density of the suspension, centrifuge at 1000g for 3min to pellet the cells, and then resuspend the cells with an appropriate volume of PBS to reach about 10 6 -10 7 cells/100 ⁇ L PBS; follow 10 6 -10 7 cells/ 100 ⁇ L PBS / site subcutaneously in SCID mice using a syringe back inoculation of tumor cells, to be about 14-21 days, tumor cells form tumor mass of approximately 100mm 3 in the subcutaneous SCID mice when the tumor-bearing SCID mice were randomly divided pyrazol Zinc thiozinc treatment group and negative control group, 4 mice in each group, mice in the zinc pyrithione treatment group were injected intraperitoneally with zinc pyrithi
  • Tumor size (mm 3 ) tumor length value x (tumor width value) 2 /2.
  • zinc pyrithione as a therapeutic drug for lung cancer.
  • the zinc pyrithione of the present application has incomparable advantages over other drugs, and it has good safety, low price, and easy access.
  • zinc pyrithione will become a clinical drug that can be taken for a long time and can effectively inhibit tumor metastasis, invasion and recurrence due to its good safety and effectiveness.

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Abstract

L'invention concerne une application de pyrithione de zinc, d'un stéréoisomère de celui-ci, ou de diverses variantes pharmaceutiquement acceptables de celui-ci dans la préparation d'un médicament utilisé pour le traitement du cancer du poumon. Le pyrithione de zinc peut inhiber la prolifération de cellules cancéreuses du poumon par de multiples mécanismes tels que l'induction de l'apoptose des cellules tumorales, l'inhibition du cycle des cellules tumorales et l'inhibition de la migration tumorale, ce qui permet d'obtenir l'effet d'inhibition de la croissance tumorale ou l'élimination de la tumeur.
PCT/CN2020/107668 2019-08-08 2020-08-07 Application de pyrithione de zinc dans le traitement du cancer du poumon WO2021023290A1 (fr)

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