CN113425721A - Application of lomitapide in preparation of antitumor drugs - Google Patents
Application of lomitapide in preparation of antitumor drugs Download PDFInfo
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- CN113425721A CN113425721A CN202110798169.6A CN202110798169A CN113425721A CN 113425721 A CN113425721 A CN 113425721A CN 202110798169 A CN202110798169 A CN 202110798169A CN 113425721 A CN113425721 A CN 113425721A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses an application of lometasapine in preparing an anti-tumor medicament. Belongs to the technical field of biological medicine. The lometasapine can be applied to antitumor drugs. The lomitapide is an FDA approved clinical medicine, has high safety, good development and utilization prospect, small toxic and side effects and low price. The invention provides application of lometasai in preparing an anti-tumor medicament, which can be dissolved in water and orally taken to assist in treating colon cancer. In vitro and in vivo experiments show that: lomantapide can inhibit intestinal cancer growth. The invention provides a new application of lomitapide, and provides a new medicine source for the adjuvant therapy of cancer.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of lometasan in preparation of an anti-tumor medicine.
Background
Lomitapide was approved in 12/21/2012 for the treatment of homozygous familial hypercholesterolemia with a low-fat diet and other lipid-lowering drugs by a mechanism in which the drug product can directly bind to and inhibit MTP, thereby preventing the assembly of apoB-containing lipoproteins in intestinal epithelial cells and hepatocytes, and inhibiting the synthesis of chylomicrons and very low-density lipoproteins. Inhibiting synthesis of very low density lipoprotein, and reducing low density lipoprotein in blood plasma. At present, the application of lomitapide in inhibiting tumor proliferation is not found.
Cancer is one of the most refractory diseases in the world. The mortality rate of colorectal cancer (CRC) is the second of the global mortality rates of malignant tumors. In our country, colorectal cancer occupies the fifth place of the mortality rate of malignant tumors. Current treatment of colorectal cancer is limited to radiation therapy, chemotherapy, and the like. Although the radiotherapy and chemotherapy can inhibit most of cancer cells, normal cells can be killed while the cancer cells are killed, gastrointestinal dysfunction, bone marrow inhibition and other toxic and side effects can be caused, the life quality of a patient is greatly reduced, and drug resistance is easily generated in malignant tumor cells after long-term chemotherapy. Most of the drugs for treating cancer are expensive, and the application of the drugs is limited. Therefore, the search for a safe anticancer drug with little toxic and side effect, good drug effect and low price is urgent.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide the application of lometaside in preparing anti-tumor drugs.
It is another object of the present invention to provide a pharmaceutical composition comprising lometaside.
The above object of the present invention is achieved by the following technical solutions:
application of lomitapide in preparing antitumor drugs.
The effective concentration of the lometaside is preferably 1.25-10 mu M.
The molecular formula of the lomitapide is C39H37F6N3O2The relative molecular mass is 693.7, and the chemical name is N- (2,2, 2-trifluoroethyl) -9- [4- [4'- (trifluoromethyl) - [1,1' -biphenyl]-2-ylcarboxamide]Piperidin-1-yl radical]Butyl radical]-9H-fluorene-9-carboxamide having the following structural formula:
the anti-tumor drug is a drug capable of treating and/or preventing colon cancer.
Use of lometasapine for the preparation of a pharmaceutical composition having the effect of inhibiting the growth and proliferation of colon cancer.
A pharmaceutical composition for inhibiting the growth and proliferation of colon cancer comprises lometasib.
The pharmaceutical composition with the effect of inhibiting the growth and proliferation of the colon cancer also comprises pharmaceutically acceptable auxiliary materials.
The pharmaceutically acceptable auxiliary material is preferably at least one of a sustained-release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption enhancer, an adsorption carrier, a surfactant and a lubricant.
The administration form of the pharmaceutical composition with the effect of inhibiting the growth and proliferation of the colon cancer is preferably oral administration.
The pharmaceutical composition with the effect of inhibiting the growth and proliferation of the colon cancer can be prepared by a conventional method.
Compared with the prior art, the invention has the following advantages and effects:
the lomitapide is an FDA approved clinical medicine, has high safety, good development and utilization prospect, small toxic and side effects and low price. The invention provides application of lometasai in preparing an anti-tumor medicament, which can be dissolved in water and orally taken to assist in treating colon cancer. In vitro and in vivo experiments show that: lomantapide can inhibit intestinal cancer growth. The invention provides a new application of lomitapide, and provides a new medicine source for the adjuvant therapy of cancer.
Drawings
FIG. 1 is a graph showing the effect of lomethazine on the proliferation of human colon cancer cells HCT116 and HT 29.
FIG. 2 is a graph showing the effect of lomethazine on apoptosis of human colon cancer cells HCT116 and HT 29.
FIG. 3 is a graph showing the results of an in vivo subcutaneous tumor formation experiment in nude mice; wherein, the picture A is a real picture of the influence of the lometasai pie on the tumorigenic capacity of intestinal cancer cells in a nude mouse; FIG. B is a graph showing the effect of lometasai on tumor weight in nude mice; panel C is a plot of tumor growth.
FIG. 4 is a graph showing the results of body weight changes of nude mice treated with lometasai.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1: in vitro assay
Colorectal cancer cells are treated by using different concentrations of lometasib, and then the WST-1 experiment is used for detecting the cell activity, so that the influence of the different concentrations of lometasib on the intestinal cancer cell proliferation is researched. Meanwhile, the apoptosis is detected by using the flow cytometry, and the influence of the lometasipine with different concentrations on the apoptosis of the intestinal cancer cells is researched.
1. WST-1 experiment
(1) Plate paving: human colon cancer cell HCT116 (purchased from ATCC) and human colon cancer cell HT29 (purchased from ATCC) were digested into single cells in suspension with 0.25% trypsin, counted and seeded into 96-well plates at 3000 cells at 100. mu.L per well, at 37 ℃ with 5% CO2Culturing under the condition.
(2) And (3) drug treatment: after the cells were attached, 1640 medium (purchased from Sigma-Aldrich) containing Lomitatapi at various concentrations (0, 1.25. mu.M, 2.5. mu.M, 5. mu.M, 10. mu.M) was added and the cells were treated with chemicals for 24h, 48h, 72 h.
(3) And (3) CCK-8 detection: the medium was aspirated, and CCK-8 diluted 10-fold with DMEM medium was added to a 96-well plate at 100. mu.L/well, incubated at 37 ℃ in the dark for 1 hour, and then the absorbance was measured at 450 nm.
2. Flow cytometry experiments
(1) HCT116 and HT29 cells were digested, centrifuged, resuspended, diluted 10-fold and counted, cells were plated in 6-well plates 20 ten thousand per well, and Lomitapide (0, 1.25. mu.M, 2.5. mu.M, 5. mu.M) was added at different concentrations after the cells were attached to the wall.
(2) After the cells were treated for a certain period of time, cell supernatants were collected, the cells were digested after washing with PBS buffer (pH 7.4, 0.1M, the same applies hereinafter), and the cells were washed once with PBS buffer after the medium was terminated and centrifuged together with the cell supernatants.
(3) The cells were resuspended in 500. mu.L of loading buffer, 5. mu.L of Annexin V-FITC was added, incubated for 15min at room temperature in the dark, and 5. mu.L of Propidium Iodide (PI) was added before testing on the machine.
(4) The sample was filtered through a 400 mesh sieve with excitation wavelength Ex 488nm and emission wavelength Em 530 nm. Green fluorescence of Annexin V-FITC can be detected through a FL1 channel, and PI can be detected through a FL2 or FL3 channel.
The results are shown in fig. 1 and fig. 2, respectively, and show that lomitapide can inhibit proliferation of human colon cancer cells HCT116 and HT29 and promote cell cycle arrest. As can be seen from fig. 1: the proliferative activity of human colon cancer cells HCT116 and HT29 decreased with increasing concentration of lometasib, and this effect was more pronounced over time. As can be seen from fig. 2: the number of apoptosis of human colon cancer cells HCT116 and HT29 increased with increasing concentrations of lometasib.
Example 2: in vivo assay
Selecting 12 female nude mice (BALB/c nu/nu immunodeficient mice, purchased from Nanjing university model animal research institute, 6 control groups and 6 experimental groups) with 6 weeks of age to construct subcutaneous tumor models, (1) suspending human colon cancer cells HT29 in PBS buffer (pH 7.4, 0.1M) to obtain resuspended cells, (2) anesthetizing the nude mice before the experiment, evaluating the anesthetic degree through painless and painful stimulation, and determining that the nude mice are in the anesthetic state, (3) mixing the resuspended cells with matrigel according to the volume ratio of 1:1 to obtain a mixed solution, and taking 100 mu L of a microinjector with a 25G needle to obtain a mixed solution containing 2 × 106Injecting the mixed solution of the individual colon cancer cells HT29 into nude mice subcutaneously; (4) lomitapide treatment: ten days after subcutaneous injection, administration by intragastric administration was started. In the experiment, the concentration of 1 Lomitapide is set to be 20mg/kg, 6 Lomitapide per group are taken once a day. Lomitapide was dissolved in purified water and 100. mu.L of each mouse was administered. The control group was gavaged with equal amount of distilled water. Tumor size and body weight of nude mice were measured for each dose. After 2 to 3 weeks, nude mice were euthanized and tumors were removed.
The results are shown in FIGS. 3 and 4. The results show that lomitapide can inhibit tumor growth of intestinal cancer. The growth curve of the tumor in fig. 3C shows that subcutaneous neoplasia in nude mice is significantly inhibited by lometasa, which inhibits tumor growth of intestinal cancer. As can be seen from fig. 4, there was no significant difference in body weight between the two groups of mice, indicating that lomitapide is safe and reliable for use as an antitumor drug.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. Application of lomitapide in preparing antitumor drugs.
2. The use according to claim 1, wherein the effective concentration of lometasdep is 1.25 to 10 μ M.
3. Use according to claim 1, characterized in that the lomitapide has the formula C39H37F6N3O2The relative molecular mass is 693.7, and the chemical name is N- (2,2, 2-trifluoroethyl) -9- [4- [4'- (trifluoromethyl) - [1,1' -biphenyl]-2-ylcarboxamide]Piperidin-1-yl radical]Butyl radical]-9H-fluorene-9-carboxamide having the following structural formula:
4. the use according to claim 1, wherein the anti-tumor drug is a drug capable of treating and/or preventing colon cancer.
5. Use of lometasapine for the preparation of a pharmaceutical composition having the effect of inhibiting the growth and proliferation of colon cancer.
6. A pharmaceutical composition having the effect of inhibiting the growth and proliferation of colon cancer, comprising lometasapine.
7. The pharmaceutical composition with the effect of inhibiting the growth and proliferation of colon cancer according to claim 6, further comprising pharmaceutically acceptable excipients.
8. The pharmaceutical composition for inhibiting the growth and proliferation of colon cancer according to claim 7, wherein said pharmaceutically acceptable excipient is at least one of sustained release agent, excipient, filler, binder, wetting agent, disintegrant, absorption enhancer, adsorption carrier, surfactant and lubricant.
9. The pharmaceutical composition for inhibiting the growth and proliferation of colon cancer according to claim 6, wherein said pharmaceutical composition for inhibiting the growth and proliferation of colon cancer is administered orally.
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| CN202110798169.6A CN113425721A (en) | 2021-07-15 | 2021-07-15 | Application of lomitapide in preparation of antitumor drugs |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114209698A (en) * | 2021-12-31 | 2022-03-22 | 中国药科大学 | Application of lomitapide in preparation of medicine for treating ulcerative colitis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112138008A (en) * | 2020-09-30 | 2020-12-29 | 郑州大学 | Application of lomitapide in preparation of antitumor drugs |
| WO2021102279A1 (en) * | 2019-11-20 | 2021-05-27 | University Of Kentucky Research Foundation | Anti-cancer compositions and methods |
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- 2021-07-15 CN CN202110798169.6A patent/CN113425721A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021102279A1 (en) * | 2019-11-20 | 2021-05-27 | University Of Kentucky Research Foundation | Anti-cancer compositions and methods |
| CN112138008A (en) * | 2020-09-30 | 2020-12-29 | 郑州大学 | Application of lomitapide in preparation of antitumor drugs |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114209698A (en) * | 2021-12-31 | 2022-03-22 | 中国药科大学 | Application of lomitapide in preparation of medicine for treating ulcerative colitis |
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