CN113633632A - Application of siponimod in preparation of anti-tumor metastasis drugs - Google Patents
Application of siponimod in preparation of anti-tumor metastasis drugs Download PDFInfo
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- CN113633632A CN113633632A CN202111054912.3A CN202111054912A CN113633632A CN 113633632 A CN113633632 A CN 113633632A CN 202111054912 A CN202111054912 A CN 202111054912A CN 113633632 A CN113633632 A CN 113633632A
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- A61P35/04—Antineoplastic agents specific for metastasis
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Abstract
The invention discloses application of siponimod in preparation of an anti-tumor metastasis medicament, and belongs to the technical field of medicines. The invention discovers for the first time that siponimod can be used for inhibiting invasion and metastasis of cancer cells, and has the advantages of high safety, good development and utilization prospects and low price. Meanwhile, the invention also discovers that siponimod can increase the sensitivity of intestinal cancer cells to oxaliplatin, and the combination of the siponimod and oxaliplatin can achieve a better effect of inhibiting intestinal cancer metastasis. The invention provides a new application of siponimod and a new idea and method for the adjuvant therapy of cancer.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of siponimod in preparation of an anti-tumor metastasis medicine.
Background
Cancer is the most common type of malignant tumor, has the biological characteristics of abnormal cell differentiation and proliferation, uncontrolled growth, infiltrative property, metastatic property and the like, is a multi-factor and multi-step complex process, is divided into three processes of carcinogenesis, cancer promotion and evolution, and is closely related to smoking, infection, occupational exposure, environmental pollution, unreasonable diet, genetic factors and the like. Colorectal cancer (cancer of colon and recatum) is a common malignant tumor in gastrointestinal tract, has unobvious early symptoms, shows symptoms such as defecation habit change, hematochezia, diarrhea and constipation alternation, local abdominal pain and the like along with the increase of cancer, and shows general symptoms such as anemia, weight loss and the like at late stage. The incidence and fatality rate of the cancer are only second to those of gastric cancer, esophageal cancer and primary liver cancer in digestive system malignant tumors. At present, the treatment of intestinal cancer is limited to radiotherapy, 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, the chemotherapy is carried out for a long time, and the drug resistance is easily generated in malignant tumor cells. 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.
Siponimod (sibonimod, code BAF312), with the chemical name 1- [ [4- [ (1E) -1- [ [ [ 4-cyclohexyl-3- (trifluoromethyl) phenyl ] methoxy ] imino ] ethyl ] -2-ethylphenyl ] methyl ] -3-azetidinyl carboxylic acid, is a new generation of selective sphingosine-1-phosphate (S1-phosphate, S1P) receptor-1 modulators. The S1P-1 receptor is present on the surface of specific cells of the CNS (autoimmune central nervous system) and drives impairment of CNS function in MS (multiple sclerosis) patients. Simonimod crosses the blood brain barrier, enters the brain and CNS of MS patients, binds to the S1P receptor (S1P1 and S1P5 receptors), promotes remyelination, prevents activation of harmful cells, delays progression of disability and preserves cognitive function in patients. Previously, Novartis, switzerland, announced that BAF312 (once daily oral) has been successful in a phase III clinical study conducted in patients with Secondary Progressive Multiple Sclerosis (SPMS), data showing that BAF312 significantly reduces the risk of disability progression (3 months corroborating the risk of disability progression) compared to placebo, showing superior efficacy. And BAF312 has little toxic and side effects and is relatively cheap.
Patents US7939519 and CN1791395B are patents filed by novain for siponimod compounds and compositions thereof, respectively. Patents WO 2012/093161a1 and WO 2015/155711 a1 disclose tablets containing siponimod, WO 2007/021666 a2 relates to oral solutions of S1P receptor agonists, and CN111107837A discloses a parenteral formulation comprising siponimod, all of which are useful for treating autoimmune diseases such as Multiple Sclerosis (MS) and neurodegenerative diseases.
However, no studies have shown that siponimod is associated with metastasis of cancer cells.
Disclosure of Invention
In order to overcome the defects, the invention provides application of siponimod in preparing an anti-tumor metastasis medicament. According to the invention, through experimental research, the fact that the siponimod can inhibit the metastasis of cancer cells is firstly discovered, a new application of the siponimod is provided, and a new thought and method are provided for the adjuvant therapy of cancer.
In order to achieve the above object, the technical solution of the present invention is as follows:
in one aspect, the invention provides the use of siponimod in the preparation of a medicament for the treatment of tumour metastases.
Specifically, the concentration of siponimod is 2.5 to 5. mu.M.
Specifically, the tumor includes but is not limited to lung cancer, breast cancer, colorectal cancer, gastric cancer, esophageal cancer or primary liver cancer, and colorectal cancer is preferred.
In another aspect, the invention provides an anti-tumor metastasis agent comprising siponimod.
Specifically, the concentration of siponimod is 2.5 to 5. mu.M.
Specifically, the anti-tumor metastasis medicament further comprises a pharmaceutically acceptable carrier, wherein the carrier is any one or more of a slow release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption enhancer, an adsorption carrier, a surfactant or a lubricant.
Specifically, the anti-tumor metastasis medicament is any one of an external preparation, an oral preparation or an injection preparation.
Further specifically, the external preparation is a spray or an aerosol.
More specifically, the oral preparation is any one of granules, capsules, tablets or vesicular agents.
More specifically, the injection preparation adopts intradermal, subcutaneous, intramuscular, topical or intravenous injection as the administration mode.
Specifically, the tumor includes but is not limited to lung cancer, breast cancer, colorectal cancer, gastric cancer, esophageal cancer or primary liver cancer, and colorectal cancer is preferred.
In a further aspect, the invention provides the use of siponimod in combination with oxaliplatin in the manufacture of a medicament for the treatment of tumour metastasis.
Specifically, the concentration of siponimod is 2.5 μ M, and the concentration of oxaliplatin is 5 μ M.
Specifically, the tumor includes but is not limited to lung cancer, breast cancer, colorectal cancer, gastric cancer, esophageal cancer or primary liver cancer, and colorectal cancer is preferred.
In yet another aspect, the invention provides an anti-tumor metastasis medicament comprising siponimod and oxaliplatin.
Specifically, the concentration of siponimod is 2.5 μ M, and the concentration of oxaliplatin is 5 μ M.
Specifically, the anti-tumor metastasis medicament further comprises a pharmaceutically acceptable carrier, wherein the carrier is any one or more of a slow release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption enhancer, an adsorption carrier, a surfactant or a lubricant.
Specifically, the tumor includes but is not limited to lung cancer, breast cancer, colorectal cancer, gastric cancer, esophageal cancer or primary liver cancer, and colorectal cancer is preferred.
Compared with the prior art, the invention has the advantages that:
the invention discovers for the first time that siponimod can be used for inhibiting invasion and transfer of intestinal cancer cells, and has high safety, good development and utilization prospects and low price. Meanwhile, the invention also discovers that siponimod can increase the sensitivity of intestinal cancer cells to oxaliplatin, and the combination of the siponimod and oxaliplatin can achieve a better effect of inhibiting intestinal cancer metastasis. The invention provides a new application of siponimod and a new idea and method for the adjuvant therapy of cancer.
Drawings
FIG. 1 is a graph of the results of an in vitro assay for siponimod inhibition of tumor cell invasion.
FIG. 2 is a graph of the results of in vivo tumor cell metastasis inhibition assays using siponimod.
FIG. 3 is a graph showing the results of the tumor cell invasion inhibition assay using a combination of Siponimod and oxaliplatin.
Detailed Description
The present invention will be further illustrated in detail with reference to the following specific examples, which are not intended to limit the present invention but are merely illustrative thereof. The experimental methods used in the following examples are not specifically described, and the materials, reagents and the like used in the following examples are generally commercially available under the usual conditions without specific descriptions.
The examples, where no specific techniques or conditions are indicated, are carried out according to the techniques or conditions described in the literature of the art (for example, see J. SammBruk et al, molecular cloning, A laboratory Manual, third edition, scientific Press, ed. by Huang Pe, et al) or according to the instructions of the product.
The invention adopts SPSS 19.0 statistical software to measure the data use
Statistical analysis was performed using one-way anova and t-test.
1. Reagents or materials for the experiments
(1) Human colon cancer cells HCT 116/RKO: purchased from ATCC (Rockville, Md.).
(2) BAF312 (siponimod)/oxaliplatin: selleck Chemicals (Huston, TX).
(3) NCG mice: purchased from Jiangsu Jiejiaokang and bred in the animal management center of river-south university.
Example 1 in vitro inhibition of tumor cell invasion by siponimod
HCT116 and RKO cells were seeded at a density of 60% in well plates and placed at 37 ℃ with 5% CO2The culture was carried out overnight in an incubator. After treatment with different concentrations of BAF312(siponimod) (dosing concentrations of 2.5. mu.M and 5. mu.M) for 24h, transwell experiments were performed to examine the ability of cells to invade.
And further detecting the proliferation capacity of the cells. Cells were plated into 96-well plates at a density of 3000 cells per well; after cell adherence, the cells were treated with different concentrations of BAF312(siponimod) (dosing concentration 2.5 μ M, 5 μ M) for 24 h; the medium in the 96-well plate was removed, washed twice with PBS, and medium containing 10% WST-1 (purchased from Biyunyan/BeyotimeBiotechnology, Shanghai, China) was added and left at 37 ℃ for 2 h; the absorbance at the wavelength of 450nm was measured by a microplate reader, and the cell proliferation inhibition rate was calculated.
The results of the detection are shown in FIG. 1.
From the results in fig. 1, it is clear that siponimod did not have a significant effect on the inhibition of intestinal cancer cell proliferation within 24 hours, but significantly inhibited the invasion of tumor cells.
Example 2 inhibition of tumor cell metastasis in vivo by siponimod
12 female mice (NCG) with age of 6 weeks, 6 control groups and 6 experimental groups are selected to construct a tumor metastasis model, and the tumor metastasis model is used for detecting the influence of the drug on cancer cell metastasis in vivo by intragastric administration after tail vein injection of HCT116-luc cells.
The specific experimental steps are as follows:
a. expanding and culturing the HCT116-luc cells;
b. cells were digested with pancreatin and counted, and the amount of intravenous injection per mouse was 105Taking the corresponding number of cells, and washing the cells for 2 times by using PBS;
c. injecting 100 mu L of cell suspension into each mouse, resuspending the cell sediment by using PBS with the corresponding volume, and injecting the tail vein of the mouse;
after 2 weeks, mice were randomly divided into a control group (drug solvent) and an experimental group (siponimod), and were administered by gavage, with siponimod (10mg/kg) administered 2 times a week, and the control group was administered 2 times a week with the same dose of drug solvent. The administration was carried out for 4 weeks.
And e.1, performing in vivo animal imaging on the mice to observe the transfer condition of the mice.
The detection result is shown in fig. 2, and in vivo experiments show that siponimod can obviously inhibit the metastasis of tumor cells.
Example 3 combination assay of siponimod and oxaliplatin
HCT116 and RKO cells were seeded at a density of 60% in well plates and placed at 37 ℃ with 5% CO2The culture was carried out overnight in an incubator. The cell invasion capacity is detected by transwell experiments after the drug treatment is carried out for 24 hours by dividing the drug treatment into a control group (DMSO) and a BAF312(siponimod) drug adding group (the drug concentration is 2.5 mu M), an oxaliplatin drug adding group (the drug concentration is 5 mu M), and a BAF312(siponimod) and oxaliplatin combined drug group (the siponimod drug concentration is 2.5 mu M and the oxaliplatin drug concentration is 5 mu M). The results of the detection are shown in FIG. 3.
From the results in fig. 3, it is clear that siponimod can increase the sensitivity of intestinal cancer cells to oxaliplatin, and the combination of the two can achieve a better effect of inhibiting intestinal cancer metastasis.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. An application of siponimod in preparing an anti-tumor metastasis medicament.
2. Use according to claim 1, characterized in that: the concentration of siponimod is 2.5-5. mu.M.
3. Use according to claim 2, characterized in that: the tumor includes but is not limited to lung cancer, breast cancer, colorectal cancer, gastric cancer, esophageal cancer or primary liver cancer.
4. Use according to claim 3, characterized in that: the tumor is colorectal cancer.
5. An anti-tumor metastasis medicament, which is characterized in that: the anti-tumor metastasis drug comprises siponimod.
6. The anti-tumor metastasis agent according to claim 5, wherein: the concentration of siponimod is 2.5-5. mu.M.
7. The anti-tumor metastasis drug according to claim 6, characterized in that: the anti-tumor metastasis medicine also comprises a pharmaceutically acceptable carrier, wherein the carrier is any one or more of a slow release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption enhancer, an adsorption carrier, a surfactant or a lubricant.
Use of siponimod in combination with oxaliplatin for the preparation of a medicament for the treatment of tumor metastases.
9. An anti-tumor metastasis medicament, which is characterized in that: the anti-tumor metastasis drugs comprise siponimod and oxaliplatin.
10. The anti-tumor metastasis agent according to claim 9, wherein: the concentration of siponimod is 2.5 mu M, and the concentration of oxaliplatin is 5 mu M.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111054912.3A CN113633632A (en) | 2021-09-09 | 2021-09-09 | Application of siponimod in preparation of anti-tumor metastasis drugs |
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| CN202111054912.3A CN113633632A (en) | 2021-09-09 | 2021-09-09 | Application of siponimod in preparation of anti-tumor metastasis drugs |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106163502A (en) * | 2014-04-10 | 2016-11-23 | 诺华股份有限公司 | Immunosuppressant agent prescription |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106163502A (en) * | 2014-04-10 | 2016-11-23 | 诺华股份有限公司 | Immunosuppressant agent prescription |
Non-Patent Citations (4)
| Title |
|---|
| GONG, KE 等: "Nanoparticle BAF312@CaP-NP Overcomes Sphingosine-1-Phosphate Receptor-1-Mediated Chemoresistance Through Inhibiting S1PR1/P-STAT3 Axis in Ovarian Carcinoma", 《INTERNATIONAL JOURNAL OF NANOMEDICINE》 * |
| SATHYA NARAYANAN PATMANATHAN 等: "Mechanisms of sphingosine 1-phosphate receptor signalling in cancer", 《CELLULAR SIGNALLING》 * |
| 徐燮渊 等主编: "《肿瘤综合治疗学 新理论 新观点 新技术》", 31 October 2001, 人民军医出版社 * |
| 第1期: "The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer", 《JOURNAL OF NANOBIOTECHNOLOGY》 * |
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