Application of ammonium thiomolybdate combined copper preparation in tumor treatment
By combining ammonium thiomolybdate with copper preparations, the problems of poor efficacy and severe toxic side effects of existing anticancer drugs have been solved, achieving effective inhibition of various cancers.
Patent Information
- Application Number
- CN202411176614.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-26
- Publication Date
- 2026-03-03
AI Technical Summary
Existing single-metal ion anticancer drugs are not effective enough in tumor treatment, and traditional anticancer drugs have problems with drug tolerance and toxic side effects.
Ammonium thiomolybdate combined with copper preparations was used as an anticancer drug. Through the synergistic effect of molybdenum and copper, the inhibitory effect on tumor cells was enhanced.
It significantly improved the inhibitory effect on cancer cells of different types of cancer, reduced drug toxicity, and improved drug stability.
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Abstract
Description
Technical Field
[0001] This application relates to the field of biomedical technology, specifically to the application of ammonium thiomolybdate combined with copper preparations in tumor treatment. Background Technology
[0002] Traditional anticancer drugs often suffer from problems such as drug tolerance and significant toxic side effects, prompting researchers to seek new anticancer drug design strategies. With a deeper understanding of the causes and mechanisms of cancer treatment, researchers have gradually realized the limitations of single-metal ions in anticancer drugs. Therefore, they have begun to explore the role and potential of bimetallic complexes in anticancer therapy, and the development of bimetallic anticancer drugs has gradually become an emerging research direction in the field of cancer treatment. Many bimetallic combination anticancer drugs have emerged, such as ruthenium-platinum complexes, copper-platinum complexes, and gold-copper complexes, which have significantly improved the survival of cancer patients, exhibiting lower toxicity and better drug stability. Nevertheless, the effects of these treatment methods are still not ideal, and there are currently no bimetallic anticancer drugs put into clinical use. Summary of the Invention
[0003] In view of the shortcomings of the prior art described above, the inventors of this application have discovered that molybdenum exists mainly in the form of Mo(VI) in organisms, playing an important role in oxidative stress and cellular oxidative damage, and also interfering with the cell cycle and regulating gene expression. Copper, on the other hand, is a component of many enzymes, participating in redox reactions and cellular metabolic processes, and is crucial for cell proliferation and growth. The combined use of these two metals holds promise for improving the efficacy of malignant tumor treatment. Therefore, this application provides the application of ammonium thiomolybdate combined with copper preparations in tumor treatment.
[0004] To achieve the above and other related objectives, the first aspect of this application provides the use of ammonium thiomolybdate combined with copper preparations in the preparation of antitumor drugs.
[0005] A second aspect of this application provides an antitumor pharmaceutical composition comprising an effective dose of ammonium thiomolybdate and a copper preparation.
[0006] A third aspect of this application provides a method for treating tumors, comprising administering the aforementioned antitumor drug composition to a subject.
[0007] Compared with the prior art, the beneficial effects of this application are as follows:
[0008] This invention is the first to combine a molybdenum-copper complex as an anticancer drug, providing a broad-spectrum anticancer effect. Ammonium thiomolybdate, when used alone, has limited inhibitory ability on tumor cells; however, when combined with copper preparations, it exhibits a synergistic and enhanced inhibitory effect on cancer cells, and shows different effects on different types of cancer. Detailed Implementation
[0009] To make the inventive objectives, technical solutions, and beneficial effects of this application clearer, the following description, in conjunction with embodiments, further illustrates this application. It should be understood that the embodiments described are for illustrative purposes only and are not intended to limit the scope of the application. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and those skilled in the art can easily understand other advantages and effects of this application from the content disclosed in this description.
[0010] The inventors of this application, through extensive research and exploration, discovered the application of ammonium thiomolybdate combined with copper preparations in tumor treatment, and completed this application based on this discovery.
[0011] The first aspect of this application provides the use of ammonium thiomolybdate combined with copper preparations in the preparation of antitumor drugs. This invention is the first to use a molybdenum-copper complex in combination as an anticancer drug. Research in this application has found that ammonium thiomolybdate, when used alone, has limited inhibitory ability on tumor cells, but when combined with copper preparations, it has a synergistic and enhanced inhibitory effect on cancer cells, and exhibits different effects on different types of cancer.
[0012] In some embodiments, the copper preparation is selected from CuET or Cu(DTC-OH)2; preferably, the copper preparation is Cu(DTC-OH)2. When the copper preparation is Cu(DTC-OH)2, ammonium thiomolybdate combined with Cu(DTC-OH)2 can exhibit a synergistic and enhanced inhibitory effect on lung cancer cells.
[0013] In some embodiments, the copper preparation is formed by mixing disulfiram and copper(II) D-gluconate. In a specific embodiment of this application, the molar ratio of disulfiram to copper(II) D-gluconate is 1:(0.1 to 10); specifically, it can be 1:(0.1 to 1), 1:(1 to 5), or 1:(5 to 10), etc.
[0014] In some embodiments, the molar ratio of ammonium thiomolybdate to copper preparation is 1:(0.1 to 10); specifically, it can be 1:(0.1 to 1), 1:(1 to 5), or 1:(5 to 10), etc.
[0015] In one specific embodiment, when the copper preparation is disulfiram and copper(II) D-gluconate, the molar ratio between ammonium thiomolybdate and disulfiram and copper(II) D-gluconate is 1:1:(0.1-10); in a preferred embodiment, the molar ratio between ammonium thiomolybdate and disulfiram and copper(II) D-gluconate is 1:1:1.
[0016] In some embodiments, the tumor for which the antitumor drug is derived is selected from one or more of the following: lung cancer, liver cancer, gastric cancer, adrenocortical carcinoma, bladder urothelial carcinoma, breast cancer, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, bile duct carcinoma, colonic adenocarcinoma, lymphoid tumor, diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, low-grade glioma of the brain, lung adenocarcinoma, lung squamous cell carcinoma, mesothelial cell carcinoma, ovarian cancer, pancreatic cancer, pheochromocytoma and paraganglioma, prostate cancer, rectal cancer, malignant sarcoma, melanoma, testicular germ cell tumor, thyroid cancer, thymic carcinoma, endometrial cancer, uterine sarcoma, uveal melanoma, multiple myeloma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, lymphoma, sarcoma, anal cancer, melanoma, and retinoblastoma. In one specific embodiment of this application, the tumor targeted by the antitumor drug is lung cancer, liver cancer, or stomach cancer.
[0017] A second aspect of this application provides an antitumor drug composition comprising an effective dose of ammonium thiomolybdate and a copper preparation. An effective dose refers to the dose at which a drug can exert its therapeutic effect. This is because a drug needs to be absorbed by the body in a certain dose to reach a certain drug concentration, and only when a certain drug concentration is reached can the drug exert its effect. If the dose is too small, an effective concentration cannot be achieved in the body, and the drug cannot exert its effective effect. However, if the dose is too large, exceeding a certain limit, the drug's effect may undergo a qualitative change, potentially causing varying degrees of toxicity to the body. Therefore, to achieve the effective effect of a drug while avoiding adverse reactions, it is essential to strictly control the dosage range.
[0018] In some embodiments, the tumor for which the antitumor drug is derived is selected from one or more of the following: lung cancer, liver cancer, gastric cancer, adrenocortical carcinoma, bladder urothelial carcinoma, breast cancer, cervical squamous cell carcinoma, cervical endometrial adenocarcinoma, bile duct carcinoma, colonic adenocarcinoma, lymphoid tumor, diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, head and neck squamous cell carcinoma, renal chromophobe carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, acute myeloid leukemia, low-grade glioma of the brain, lung adenocarcinoma, lung squamous cell carcinoma, mesothelial cell carcinoma, ovarian cancer, pancreatic cancer, pheochromocytoma and paraganglioma, prostate cancer, rectal cancer, malignant sarcoma, melanoma, testicular germ cell tumor, thyroid cancer, thymic carcinoma, endometrial cancer, uterine sarcoma, uveal melanoma, multiple myeloma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, lymphoma, sarcoma, anal cancer, melanoma, and retinoblastoma.
[0019] In some embodiments, the antitumor drug composition includes a pharmaceutically acceptable carrier or excipient.
[0020] "Pharmaceutical acceptable" means that when the molecular bulk and composition are properly administered to animals or humans, they will not produce adverse, allergic, or other adverse reactions. "Pharmaceutical acceptable carriers or excipients" should be compatible with ammonium thiomolybdate and copper preparations, meaning they can be mixed with them without significantly reducing the efficacy of the pharmaceutical composition under normal circumstances. Specific examples of substances that can serve as pharmaceutically acceptable carriers or excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium methylcellulose, ethylcellulose, and methylcellulose; tragacanth gum powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as Tween; wetting agents such as sodium lauryl sulfate; colorants; flavoring agents; tableting agents, stabilizers, antioxidants; preservatives; pyrogen-free water; isotonic salt solutions; and phosphate buffers, etc. These substances are used as needed to aid in the stability of the formulation or to contribute to its activity or bioavailability, or to produce an acceptable taste or aroma when taken orally. In this invention, unless otherwise specified, the drug dosage form is not particularly limited and can be formulated as any one of the following: suspension, granules, capsules, powders, tablets, emulsions, solutions, pellets, injections, suppositories, enemas, aerosols, patches, or drops. The choice of drug dosage form should match the route of administration. The route of administration can be a conventional method, such as intravenous injection, intravenous infusion, arterial perfusion, gastrointestinal administration, or parenteral administration.
[0021] In some embodiments, the copper preparation is selected from CuET or Cu(DTC-OH)2; preferably, the copper preparation is Cu(DTC-OH)2.
[0022] In some embodiments, the copper preparation is formed by mixing disulfiram and copper(II) D-gluconate. In a specific embodiment of this application, the molar ratio of disulfiram to copper(II) D-gluconate is 1:(0.1 to 10); specifically, it can be 1:(0.1 to 1), 1:(1 to 5), or 1:(5 to 10), etc.
[0023] In some embodiments, the molar ratio of ammonium thiomolybdate to copper preparation is 1:(0.1 to 10); specifically, it can be 1:(0.1 to 1), 1:(1 to 5), or 1:(5 to 10), etc.
[0024] A third aspect of this application provides a method for treating tumors, comprising administering the aforementioned antitumor drug composition to a subject.
[0025] In some implementations, the object is a mammal or mammalian cells. Mammals include, for example, rodents, even-toed ungulates, perissodactyls, lagomorphs, primates, etc. Primates include, for example, monkeys, apes, or Homo sapiens. Mammalian cells include, for example, tumor cells, more specifically, lung cancer cells, liver cancer cells, and gastric cancer cells.
[0026] The present application will be further illustrated by the following examples, but these examples do not limit the scope of the present application.
[0027] Example 1
[0028] The combination of ammonium thiomolybdate and CuET, a copper preparation with proven anticancer effects, was used as a novel broad-spectrum anticancer drug to inhibit the proliferation of different types of tumor cells. CCK-8 analysis revealed that the two components, at different premixing times, exhibited good inhibitory effects on three common tumor cell types (lung cancer A459, liver cancer HEPG2, and gastric cancer SGC790 cells).
[0029] 1. Human tumor cells A459, HEPG2, and SGC790 were cultured in DMEM high-glucose medium containing 10% fetal bovine serum and 1% penicillin and streptomycin, respectively, and incubated at 37°C in a 5% CO2 incubator. Once the cells reached over 80% confluence, the medium was discarded, and the cells were digested with 0.8% trypsin containing 0.02% EDTA at 37°C. After centrifugation and discarding the supernatant, fresh culture medium was added, and the cells were passaged at a ratio of 1:3. Cells in the logarithmic growth phase with good growth were used for experiments.
[0030] 2. Cells in the logarithmic growth phase were digested with trypsin, counted under a microscope, and then prepared into 6×10⁶ cells. 4 Cell suspension at 100 μl / ml. Transfer 100 μl to each well of a 96-well culture plate, seeding each cell type in duplicate (two replicates per plate), 6 × 10⁶ cells / ml. 3 Cells per well, with 100 μl of culture medium as a blank control, incubated overnight at 37°C.
[0031] 3. Prepare two stock solutions with an initial concentration of 20 mM. After waiting for 0, 30, and 60 min, mix them at a molar ratio of 1:1. Dilute the mixture according to the concentration gradient and add it to three replicates of each concentration into a 96-well plate. After treating the cells for 72 h, mix Cell Counting Kit-8 (CCK-8) and serum-free essential basal medium at a volume ratio of 1:10. Add 100 μL to each well and incubate at 37 °C in a 5% CO2 incubator for 1 h.
[0032] 4. The absorbance at 450 nm was measured using an ELISA reader, and the value for each plate was recorded. Cell viability in each group was measured using the CCK-8 assay, and the inhibition rate was calculated as follows: Inhibition rate = (OD value of control group - OD value of drug-treated group) / (OD value of control group) × 100%. The half-maximal inhibitory concentration (IC50) was calculated using GraphPad Prism 9 software based on the effects of different drug concentrations on cells, as shown in Table 1.
[0033] Table 1. IC50 of ammonium thiomolybdate with different copper formulations (unit: μmol / L)
[0034]
[0035] It is known that when ammonium thiomolybdate exists alone, its inhibitory effect on the three cell types is very limited. However, when used in combination with CuET, it significantly enhances the inhibitory ability on tumor cells and exhibits the best inhibitory ability on gastric cancer SGC790 cells.
[0036] Example 2
[0037] The combined use of ammonium thiomolybdate and Cu(DTC-OH)2, a derivative of the copper preparation CuET, at a molar ratio of 1:1, can inhibit the proliferation of different types of tumor cells. CCK-8 analysis revealed that the two components, at different premixing times, exhibited specific inhibitory effects against three common tumor cell types (lung cancer A459, liver cancer HEPG2, and gastric cancer SGC790 cells).
[0038] The experimental procedure was the same as in Example 1, and the half-maximal inhibitory concentration (IC50) values are shown in Table 1.
[0039] It can be seen that the combined use of ammonium thiomolybdate and copper preparation Cu(DTC-OH)2 significantly enhanced the inhibitory effect on two types of liver cancer HEPG2 and gastric cancer SGC790 cells, and showed the best inhibitory ability on lung cancer A459 cells, and demonstrated a significant synergistic enhancement of cancer cell inhibition effect on lung cancer A459 cells.
[0040] Example 3
[0041] The combined use of ammonium thiomolybdate, disulfiram, and copper(II) D-gluconate in a molar ratio of 1:1:1 inhibited the proliferation of different types of tumor cells. CCK-8 analysis revealed that the two components, at different premixing times, exhibited good inhibitory effects against three common tumor cell types (lung cancer A459, liver cancer HEPG2, and gastric cancer SGC790 cells).
[0042] The experimental procedure was the same as in Example 1, and the half-maximal inhibitory concentration (IC50) values are shown in Table 1.
[0043] It is known that when ammonium thiomolybdate exists alone, its inhibitory effect on the three types of cells is very limited. However, when the three components are used in combination, the inhibitory ability on tumor cells is significantly enhanced, and the inhibitory ability on gastric cancer SGC790 cells is the best.
[0044] In summary, this application is the first to combine molybdenum-copper complexes as an anticancer drug, providing a broad-spectrum anticancer effect. When used alone, ammonium thiomolybdate has limited inhibitory ability on tumor cells; however, when combined with copper preparations, it exhibits a synergistic and enhanced inhibitory effect on cancer cells, with different effects on different types of cancer.
[0045] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit this application. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of this application. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in this invention should still be covered by the claims of this application.
Claims
1. Application of ammonium thiomolybdate combined with copper preparations in the preparation of antitumor drugs.
2. The application as described in claim 1, characterized in that, The copper preparation is selected from CuET or Cu(DTC-OH)2; preferably, the copper preparation is Cu(DTC-OH)2. And / or, the copper preparation is formed by mixing disulfiram and copper(II) D-gluconate; preferably, the molar ratio of disulfiram to copper(II) D-gluconate is 1:(0.1 to 10).
3. The application as described in claim 1, characterized in that, The molar ratio of ammonium thiomolybdate to copper preparation is 1:(0.1-10).
4. The application as described in claim 1, characterized in that, The tumors for which the antitumor drugs are selected are lung cancer, liver cancer, gastric cancer, adrenocortical carcinoma, urothelial carcinoma of the bladder, breast cancer, cervical squamous cell carcinoma, cervical endogenous adenocarcinoma, bile duct carcinoma, colonic adenocarcinoma, lymphoid tumors, diffuse large B-cell lymphoma, esophageal cancer, glioblastoma multiforme, squamous cell carcinoma of the head and neck, chromophobe renal carcinoma, clear cell renal carcinoma, papillary renal carcinoma, acute myeloid leukemia, low-grade glioma of the brain, lung adenocarcinoma, lung squamous cell carcinoma, mesothelial cell carcinoma, and ovarian cancer. The antitumor drug is formulated for one or more of the following cancers: cancer, pancreatic cancer, pheochromocytoma and paraganglioma, prostate cancer, rectal cancer, malignant sarcoma, melanoma, testicular germ cell tumor, thyroid cancer, thymic cancer, endometrial cancer, uterine sarcoma, uveal melanoma, multiple myeloma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia, lymphoma, sarcoma, anal cancer, melanoma, and retinoblastoma; preferably, the tumor targeted by the antitumor drug is lung cancer, liver cancer, or gastric cancer.
5. An antitumor drug composition comprising an effective dose of ammonium thiomolybdate and a copper preparation.
6. The antitumor pharmaceutical composition according to claim 5, characterized in that, It also includes pharmaceutically acceptable carriers or excipients.
7. The antitumor pharmaceutical composition according to claim 5, characterized in that, The copper preparation is selected from CuET or Cu(DTC-OH)2; preferably, the copper preparation is Cu(DTC-OH)2. And / or, the copper preparation is formed by mixing disulfiram and copper(II) D-gluconate; preferably, the molar ratio of disulfiram to copper(II) D-gluconate is 1:(0.1 to 10).
8. The antitumor pharmaceutical composition according to claim 5, characterized in that, The molar ratio of ammonium thiomolybdate to copper preparation is 1: (0.1～10)。 9. A method of antitumor treatment, comprising administering to a subject the antitumor pharmaceutical composition as described in any one of claims 5 to 8.
10. The method as described in claim 9, characterized in that, The object is a mammal or a mammalian cell.