Application of lenvatinib combined with ursodesoxycholic acid in liver cancer treatment

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to application of lenvatinib combined with ursodesoxycholic acid in liver cancer treatment. Specifically, a human hepatoma carcinoma cell Huh7 cell is constructed to carry out an experiment on a lenvatinib drug-resistant cell strain Huh7R cell. The result shows that the lenvatinib and the UDCA can generate a synergistic inhibition effect on the HCC under multiple concentrations. Further, animal experiments also prove the anti-HCC effect of the pharmaceutical composition. The invention provides a method capable of effectively inhibiting the progress of HCC, so that the problem of drug resistance of lenvatinib in clinical treatment is solved, a new treatment choice is brought to a liver cancer patient, the tumor treatment effect is expected to be improved, the life quality of the patient is improved, and therefore, the lenvatinib has important clinical significance and social value.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and specifically relates to the application of lenvatinib combined with ursodeoxycholic acid in the treatment of liver cancer. Background Art

[0002] Disclosing the information of this background art section is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Primary liver cancer is the most common type of liver cancer. Statistical data in 2022 shows that primary liver cancer is the sixth most common cancer in terms of incidence, and is the third leading cause of cancer death globally, with approximately 750,000 people dying from liver cancer each year. Among them, hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for more than 80% of primary liver cancer.

[0004] Lenvatinib is a multi-target tyrosine kinase inhibitor that can inhibit the kinase activity of vascular endothelial growth factor receptors and block other tyrosine kinase-related pro-angiogenic and oncogenic signaling pathways. Currently, lenvatinib is approved for first-line treatment of patients with advanced HCC. A phase III clinical study showed that although there was no significant difference in the overall survival (OS) of patients treated with lenvatinib or sorafenib, lenvatinib treatment could improve the survival rate of liver cancer patients and extend their progression-free survival, which was more clinically significant. However, most patients with advanced liver cancer develop congenital or acquired resistance to lenvatinib, and only 10%-30% of patients show treatment sensitivity to lenvatinib. Therefore, there is an urgent need to find other drugs to be combined with lenvatinib to improve its efficacy and enhance the clinical benefit of HCC patients. Summary of the Invention

[0005] In view of the deficiencies in the above-mentioned prior art, through long-term technical and practical exploration, the inventors provide the application of lenvatinib combined with ursodeoxycholic acid in the treatment of liver cancer. Specifically, the present invention first proves that lenvatinib and ursodeoxycholic acid (UDCA) have a synergistic effect against HCC, thereby effectively overcoming the drug resistance problem existing in the clinical treatment of lenvatinib. Based on the above research results, the present invention is completed.

[0006] To achieve the above technical objectives, the present invention adopts the following technical solutions:

[0007] In the first aspect of the present invention, there is provided the application of lenvatinib combined with ursodeoxycholic acid in any one or more of the following:

[0008] a) Preparing a product for synergistically inhibiting the proliferation of tumor cells;

[0009] b) Preparing a product for synergistically inhibiting the invasion and migration of tumor cells;

[0010] c) Preparing a product for promoting the apoptosis of tumor cells;

[0011] d) Preparing a product for synergistically inhibiting tumor growth;

[0012] e) Preparing a product for inhibiting the degree of tumor tissue deterioration;

[0013] f) Preparing a product for inhibiting the tumor drug resistance of lenvatinib;

[0014] g) Preparing a product for tumor treatment.

[0015] In a second aspect of the present invention, there is provided a composition, the active ingredients of which at least include the above-mentioned lenvatinib and ursodeoxycholic acid.

[0016] The composition has any one or more of the following uses:

[0017] a) Synergistically inhibiting the proliferation of tumor cells;

[0018] b) Synergistically inhibiting the invasion and migration of tumor cells;

[0019] c) Promoting the apoptosis of tumor cells;

[0020] d) Synergistically inhibiting tumor growth;

[0021] e) Inhibiting the degree of tumor tissue deterioration;

[0022] f) Inhibiting the tumor drug resistance of lenvatinib;

[0023] g) Tumor treatment.

[0024] In a third aspect of the present invention, there is provided a method for tumor treatment, the method comprising administering the above-mentioned composition to a subject.

[0025] Compared with the prior art solutions, the above one or more technical solutions have the following beneficial effects:

[0026] The above technical solutions conducted experiments on the cell line Huh7R cells resistant to lenvatinib in human hepatocellular carcinoma cells Huh7 cells. The results showed that lenvatinib and UDCA could have a synergistic inhibitory effect on HCC at multiple concentrations. Further, animal experiments also confirmed the anti-HCC effect of this drug combination.

[0027] In summary, the above technical solution provides a method that can effectively inhibit the progression of HCC, thereby overcoming the drug resistance problem of lenvatinib in clinical treatment, bringing new treatment options for liver cancer patients, and promising to improve the tumor treatment effect and the quality of life of patients. Therefore, it has good potential practical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The accompanying drawings forming a part of this invention are used to provide a further understanding of the invention. The schematic embodiments and descriptions of the invention are used to explain the invention and do not constitute an improper limitation of the invention.

[0029] Figure 1 Inhibitory effect of lenvatinib on the proliferation of Huh7 cells and Huh7R cells. Huh7 cells (a) and Huh7R cells (b) were treated with different concentrations of lenvatinib for 48 h, and the cell proliferation inhibition rate was detected by the MTT method.

[0030] Figure 2 Combined use of lenvatinib and UDCA synergistically inhibits the proliferation ability of Huh7R cells. Huh7R cells were treated with different concentrations of lenvatinib alone or in combination with 0.3 mM UDCA (a) and 0.5 mM UDCA (b) for 48 h, and then the cell viability was detected by the MTT method to calculate the proliferation inhibition rate.

[0031] Figure 3 Combined use of lenvatinib and UDCA synergistically inhibits the colony formation ability of Huh7R cells. (a) Huh7R cells were treated with lenvatinib and UDCA alone or in combination for 48 h, then replaced with normal complete medium and cultured for about 1 week, fixed, stained and photographed; (b) Quantitative analysis of three independent repeated experiments.

[0032] Figure 4 Combined use of lenvatinib and UDCA synergistically inhibits the migration of Huh7R cells. (a) Huh7R cells were treated with 2.5 μM lenvatinib, 0.3 mM UDCA, and their combination. At 0 h, 24 h, and 48 h after drug addition, fixed-point photographs were taken under a fluorescence inverted microscope (100×, scale bar is 200 μm). (b) Quantitative analysis of three independent repeated experiments.

[0033] Figure 5Lenvatinib and UDCA synergistically inhibit the migration and invasion of Huh7R cells. Huh7R cells were treated with 2.5 μM lenvatinib, 0.3 mM UDCA, or their combination for 24 h. The migration ability of Huh7R cells was detected by transwell (without Matrigel) assay (a), and the invasion ability of Huh7R cells was detected by transwell (with Matrigel) assay (b). (100×, scale bar = 200 μm), and quantitative analysis was performed on three independent repeated experiments.

[0034] Figure 6 Lenvatinib and UDCA synergistically induce apoptosis in Huh7R cells. Huh7R cells were treated with 20 μM lenvatinib, 0.5 mM UDCA, or their combination for 48 h. The cells were stained with Hoechst 33342, and the apoptosis of the cells was detected by fluorescence inverted microscope (100×, scale bar = 200 μm). Figure 7 Lenvatinib and UDCA synergistically induce apoptosis in Huh7R cells. (a) Huh7R cells were treated with 20 μM lenvatinib, 0.5 mM UDCA, or their combination for 48 h, and the cells were labeled. The apoptosis ratio of the cells was detected by flow cytometry. (b) Quantitative analysis of the total apoptotic cell ratio was performed on three independent repeated experiments.

[0035] Figure 8 Lenvatinib and UDCA synergistically inhibit the growth of orthotopic liver tumors in nude mice. (a) Photographs of liver tumors in nude mice of each group. (b) The formation of liver tumors in each group of mice was observed and photographed by a small animal ultrasound photoacoustic imaging system. (c) Statistical chart of tumor volume in nude mice of each group. (d) Curve of body weight change in nude mice of each group.

[0036] Figure 9 H&E staining results of tumor tissues. Bright-field images were taken using an inverted microscope. Representative tissue sections were selected for photography and display, scale bar = 100 μm (200×) or 50 μm (400×). Figure 10 Protein expression and distribution of Ki67 in liver tumor tissues of nude mice. Ki67 protein in liver orthotopic tumor tissues of nude mice was labeled by IHC and photographed under a microscope, scale bar = 100 μm (200×) or 50 μm (400×). Detailed implementation manners

[0037] It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present application belongs.

[0038] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, they specify the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0039] In a typical specific embodiment of the present invention, the application of lenvatinib combined with ursodeoxycholic acid in any one or more of the following is provided:

[0040] a) Preparing a product for synergistically inhibiting the proliferation of tumor cells;

[0041] b) Preparing a product for synergistically inhibiting the invasion and migration of tumor cells;

[0042] c) Preparing a product for promoting the apoptosis of tumor cells;

[0043] d) Preparing a product for synergistically inhibiting tumor growth;

[0044] e) Preparing a product for inhibiting the degree of tumor tissue deterioration;

[0045] f) Preparing a product for inhibiting the tumor drug resistance of lenvatinib;

[0046] g) Preparing a product for tumor treatment.

[0047] Among them, the molar ratio of lenvatinib to ursodeoxycholic acid is 2.5 - 40:300 - 500; further including 5 - 20:300; and 10 - 20:500.

[0048] Among them, the product can be a drug or a general test reagent for non-medical use, and the general test reagent can be used for basic research to explore the occurrence and development mechanism of tumors.

[0049] It should be noted that tumors are used as known to those skilled in the art in the present invention, and include benign tumors and / or malignant tumors. Benign tumors are defined as the excessive proliferation of cells that cannot form aggressive and metastatic tumors in the body. Conversely, malignant tumors are defined as cells with various cell abnormalities and biochemical abnormalities that can form a systemic disease (such as forming tumor metastases in distant organs).

[0050] In another specific embodiment of the present invention, the drug of the present invention can be used to treat malignant tumors. Examples of malignant tumors that can be treated with the drug of the present invention are liver cancer, further primary liver cancer, and even more hepatocellular carcinoma.

[0051] According to the present invention, when the product is a drug, the drug may further comprise at least one pharmaceutically inactive ingredient.

[0052] The pharmaceutically inactive ingredient may be a pharmaceutically acceptable carrier, which can be determined by those of ordinary skill in the art to meet clinical standards. It can be any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like that are physiologically compatible. Generally, the nature of the carrier depends on the specific mode of administration employed. For example, parenteral preparations usually contain an injectable fluid as a vehicle, and the injectable fluid contains a pharmaceutically acceptable and physiologically acceptable fluid, such as water, physiological saline, balanced salt solution, aqueous glucose solution, glycerol, etc. For solid compositions (e.g., in the form of powders, pills, tablets, or capsules), conventional non-toxic solid carriers may include, for example, pharmaceutical grade mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, the pharmaceutical composition to be administered may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifying agents, preservatives, and pH buffering agents, etc., such as sodium acetate or sorbitan monolaurate, etc. Specific limitations are not made herein.

[0053] In another specific embodiment of the present invention, the drug of the present invention can be administered into the body by known methods. For example, by intravenous systemic delivery. Optionally, it can be administered via intravenous, transdermal, intranasal, mucosal, or other delivery methods. Such administration can be carried out via a single dose or multiple doses. Those skilled in the art understand that the actual dose to be administered in the present invention can vary to a large extent depending on various factors, such as target cells, biological type or its tissue, the general condition of the subject to be treated, the route of administration, the mode of administration, and so on.

[0054] In another specific embodiment of the present invention, the subject to which the drug is administered can be humans and non-human mammals, and the non-human mammals include mice, rats, guinea pigs, cows, sheep, cats, dogs, horses, monkeys, orangutans, etc., among which humans are preferred.

[0055] In another specific embodiment of the present invention, a composition is provided, and the active ingredient of the composition at least includes the above-mentioned lenvatinib and ursodeoxycholic acid.

[0056] The composition has any one or more of the following uses:

[0057] a) Coordinately inhibiting the proliferation of tumor cells;

[0058] b) Coordinately inhibiting the invasion and migration of tumor cells;

[0059] c) Promoting the apoptosis of tumor cells;

[0060] d) Coordinately inhibiting tumor growth;

[0061] e) Inhibiting the degree of tumor tissue deterioration;

[0062] f) Inhibiting the tumor drug resistance of lenvatinib;

[0063] g) Tumor treatment.

[0064] Specifically, the definition and scope of the tumor are as described above and will not be elaborated here.

[0065] Among them, the molar ratio of lenvatinib to ursodeoxycholic acid is 2.5 - 40:300 - 500; further including 5 - 20:300; and 10 - 20:500.

[0066] In another specific embodiment of the present invention, a method for tumor treatment is provided, and the method includes administering a therapeutically effective amount of the above - mentioned composition to a subject.

[0067] In the present invention, the term "therapeutically effective amount" refers to the amount that effectively achieves the desired therapeutic or prophylactic result at the required dose and time period. A therapeutically effective amount of an agent, for example, eliminates, reduces, delays, minimizes or prevents the adverse effects of a disease.

[0068] The subject can be a human and non - human mammals, and the non - human mammals include mice, rats, guinea pigs, cows, sheep, cats, dogs, horses, monkeys, chimpanzees, etc., among which humans are preferred.

[0069] The following further illustrates the present invention with specific examples. The following examples are only for explaining the present invention and do not limit its content. Any simple modification, equivalent change and modification made to the embodiments according to the technical essence of the present invention all fall within the scope of the technical solution of the present invention.

[0070] Examples

[0071] I. Cell experiments

[0072] 1. Construct human hepatocellular carcinoma lenvatinib - resistant cells Huh7R cells and detect the drug resistance and drug - resistance multiple of the cells

[0073] MTT assay: The Lenvatinib-sensitive Huh7 cells and Lenvatinib-resistant Huh7R cells were seeded in 96-well plates. Lenvatinib at corresponding concentrations was prepared according to the experimental concentrations and added to the 96-well plates, and a control group was set. After 48 h of drug treatment, 20 μL of 5 mg / mL MTT solution was added to each well in the dark. After incubation at 37 °C for 4 h, all the liquid in the wells was carefully aspirated, and 150 μL of DMSO solution was added to dissolve the formazan crystals in the wells. The absorbance values (OD values) of each group were measured at a wavelength of 570 nm on an enzyme-linked immunosorbent assay (ELISA) reader after shaking for 5 min. The formula for calculating the cell inhibition rate of the drug was: Inhibition rate (%) = (Absorbance value of the blank control group - Absorbance value of the drug-treated group) / Absorbance value of the blank control group × 100%. After detection, as the concentration of Lenvatinib increased, its inhibitory effect on the proliferation of Huh7 and Huh7R cells gradually increased, and the IC 50 values were 2.775 μM and 25.93 μM, respectively. Compared with the sensitive cell line, the drug resistance multiple of the resistant cells was 9.34-fold. ( Figure 1 , Table 1)

[0074] Table 1 IC 50 values and drug resistance multiple RI of Lenvatinib on hepatocellular carcinoma cells for 48 h

[0075]

[0076] 2. Detection of the synergistic inhibitory effect of the combination of Lenvatinib and UDCA on HCC proliferation

[0077] MTT assay: Huh7R cells were seeded in 96-well plates. After treating the cells with Lenvatinib and UDCA at specific concentration gradients alone or in combination for 48 h, 20 μl of MTT detection reagent was added to each well. After incubation at 37 °C for 4 h, the inhibitory effects of the two drugs alone and in combination on cell growth were evaluated. The combination index q value of the two drugs was calculated using the Chou-Talalay method to indicate whether Lenvatinib and UDCA had a combined effect. q value = Inhibition rate of the combination of the two drugs / (Sum of the inhibition rates of the two drugs alone - Product of the inhibition rates of the two drugs alone). When the q value < 0.85, it indicated that the two drugs had an antagonistic effect; when 0.85 ≤ q value ≤ 1.15, it indicated that the two drugs had an additive effect; when the q value > 1.15, it indicated that the two drugs had a synergistic effect. The results showed that the combination of Lenvatinib and UDCA at multiple different concentrations had a synergistic inhibitory effect on the proliferation of Huh7R cells (q > 1.15). ( Figure 2 , Table 2)

[0078] Table 2 Combination index of Lenvatinib and UDCA in Huh7R cells

[0079]

[0080] 3. Detection of the effect of combined use of lenvatinib and UDCA on the colony-forming ability of Huh7R cells

[0081] Colony formation assay: Huh7R cells in logarithmic growth phase were digested and centrifuged, and 3×10 3 / well in a six-well plate, add drug treatment (20μM lenvatinib and 0.5mM UDCA alone or in combination) for 48h after the cells adhered overnight, replace with fresh medium without drugs, and replace fresh medium every 3 days. When large colonies are formed in the blank control group, fix, stain, wash, and take pictures, count with Image J software, and calculate the cell clone formation rate of each group. The results showed that the average inhibition rate of clone formation in the lenvatinib group, UDCA group, and combination group was 21.28%, 56.17%, 90.67%, respectively ( Figure 3 ). This indicates that the use of lenvatinib or UDCA alone can inhibit colony formation, while there is almost no colony formation after combined use, indicating that the combination of the two can significantly inhibit the proliferation ability of Huh7R cells.

[0082] 4. Detect the effect of combined use of lenvatinib and UDCA on the invasion and migration ability of Huh7R cells

[0083] Scratch test: Huh7R cells in the logarithmic growth phase were plated in a six-well plate. When the cell density reached 80%-90%, three scratches were made on the bottom of the cell plate parallel to and perpendicular to the bottom line of the plate with a sterile pipette tip. 1% FBS culture medium containing no drug, 2.5μM lenvatinib, 0.3mM UDCA, and 2.5μM lenvatinib + 0.3mM UDCA were added respectively. The cells were placed under an inverted fluorescence microscope (100×) for fixed-point photography at 0h, 24h, and 48h. Cell migration rate was calculated using Image J software. Migration rate (%) = (0h scratch area - scratch area at each time point) / 0h scratch area × 100%. The results showed that lenvatinib alone could significantly inhibit the migration ability of Huh7R cells, while UDCA had a weaker inhibitory effect. However, the inhibitory effect of the two drugs combined was significantly higher than that of the lenvatinib group alone. ( Figure 4 )

[0084] Transwell assay: Tumor cells were plated at 2 × 10 4were seeded in transwell chambers with a pore size of 8 μm. In the transwell experiment, without adding Matrigel, it was used to detect the cell migration ability under different treatment conditions, while adding Matrigel was used to detect the cell invasion ability under different treatment conditions. Add serum-free medium containing drugs to the upper layer of the transwell chamber, and add 600 μL of medium containing 15% serum to the lower layer. After incubating at 37 °C for 24 h, the migrated cells were fixed, stained, washed and counted. The results proved that lenvatinib and UDCA synergistically inhibited the migration and invasion of Huh7R cells.( Figure 5 )

[0085] 5. Detect the effect of the combined application of lenvatinib and UDCA on the apoptosis of Huh7R cells

[0086] Hoechst 33342 experiment: Take logarithmically growing Huh7R cells and seed them in a six-well plate. When the cells adhere to the wall and the density is about 60%, add drugs and treat for 48 h, then fix and stain. Prepare a Hoechst 33342 staining working solution with a concentration of 20 μg / mL, and stain for 20 min in the dark. After staining, observe the nuclear morphology of each group under the UV (340 / 460 nm) channel of a fluorescence inverted microscope and take pictures for record. The results showed that a small number of cells underwent apoptosis when treated with lenvatinib or UDCA alone, and the number of cells with nuclear shrinkage increased significantly after the combination, indicating that the two could promote the apoptosis of Huh7R cells.( Figure 6 )

[0087] Annexin V-FITC / PI double staining to detect cell apoptosis: Take logarithmically growing Huh7R cells and seed them in a six-well plate. After the cells adhere to the wall, add drugs, and set up single-staining wells for Annexin V-FITC and PI respectively. After 48 h of drug treatment, collect the supernatants of each group. Add trypsin without EDTA to digest the cells, and use the pre-collected medium supernatant to terminate the digestion of the corresponding wells. Collect the cell precipitates of each group, and resuspend the cell precipitates with 1×binding buffer. Add 5 μL of Annexin V-FITC and 5 μL of PI to the single-staining Annexin V-FITC and PI groups respectively, and add 5 μL of Annexin V-FITC and 5 μL of PI to the remaining groups. Incubate at room temperature in the dark for 20 min, and then pass through a 200-mesh sieve and detect the apoptosis rate of each group with a flow cytometer. The experimental results showed that when lenvatinib or UDCA was applied alone, it could induce apoptosis in a small number of cells, and when the cells were treated with both drugs simultaneously, the number of early apoptotic cells could be significantly increased( Figure 7 )

[0088] II. Animal experiments

[0089] 1. Detect the in vivo tumor inhibitory effect of the drug combination of lenvatinib and UDCA on Huh7R

[0090] Inject 50 μL of 3 million Huh7R cells per mouse into the liver in situ, suture the abdominal incision with silk thread to obtain nude mice transplanted with drug-resistant liver cancer cells. Randomly divide the nude mice into groups of 5 each, and start drug administration on the 10th day. Lenvatinib and UDCA are respectively formulated into concentrations of 10 mg / kg and 100 mg / kg with DMSO:20% SBE-β-CD in Saline = 1:9 (V / V), assisted by ultrasonic dissolution, and prepared for immediate use. Both drugs are administered by gavage for 21 consecutive days. Monitor whether tumors are formed and observe tumor size through a small animal ultrasonic photoacoustic imaging system. The results show that compared with the control group, lenvatinib and UDCA alone can inhibit the growth of orthotopic liver tumors in nude mice. The combination of the two drugs can inhibit tumor growth more significantly than the single drug, but has no obvious effect on the body weight of mice. During the experiment, the tumor size was monitored through a small animal ultrasonic photoacoustic imaging system, and the results confirmed the synergistic inhibitory effect of the combination of the two drugs on tumor growth ( Figure 8 ).

[0091] 2. Detect the in vivo tumor inhibitory effect of the drug combination of lenvatinib and UDCA on Huh7R by H&E staining and immunohistochemical staining methods

[0092] After the in vivo drug administration is completed, take out the liver, measure the tumor volume and take pictures for record. Fix the liver tissue with 4% paraformaldehyde fixative and store it at 4 °C for H&E staining and immunohistochemical staining. Ki67 is an antigen that characterizes cell proliferation, and its function is closely related to mitosis. It is an important cell proliferation marker. To further verify the inhibitory effect of the combination of the two on HCC tumors, we detected the protein expression of Ki67 (brown) in different treatment groups through immunohistochemical experiments. The results of H&E staining showed that the interstitium and necrosis area of tumor cells increased after treatment with lenvatinib and the combination. The results of immunohistochemical experiments showed that the expression of Ki67 in the tumor site of the combination group was significantly reduced, suggesting that the combined administration of lenvatinib and UDCA can inhibit the deterioration of tumor tissue.( Figure 9 ,10)

[0093] In summary, the present invention provides a novel and effective method for treating lenvatinib-resistant HCC. The combined use of lenvatinib and UDCA will bring new treatment options for liver cancer patients, and is expected to improve the tumor treatment effect and the quality of life of patients.

[0094] The above are only the preferred embodiments of the present application, and are not used to limit the present application. For those skilled in the art, the present application can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. Use of lenvatinib combined with ursodeoxycholic acid in any one or more of the following: a) preparing products that synergistically inhibit tumor cell proliferation; b) preparing products that synergistically inhibit tumor cell invasion and migration; c) preparing products that promote apoptosis of tumor cells; d) preparing products that synergistically inhibit tumor growth; e) preparing products that inhibit the progression of tumor tissue; f) preparing a product that inhibits tumor resistance to lenvatinib; g) Preparation of products for tumor treatment.

2. The use according to claim 1, characterized in that: The tumor is a benign tumor and / or a malignant tumor.

3. The use according to claim 2, characterized in that: The malignant tumor is liver cancer, further is primary liver cancer, and further is hepatocellular carcinoma.

4. The use according to claim 1, characterized in that: The molar ratio of lenvatinib to ursodeoxycholic acid is 2.5-40:300-500; further including 5-20:300; and 10-20:

500.

5. The use according to claim 1, characterized in that: The product is a common test reagent for pharmaceutical or non-medical use.

6. The use according to claim 5, characterized in that The medicament includes at least one pharmaceutically inactive ingredient.

7. The use according to claim 6, characterized in that The inactive ingredient of the drug is a pharmaceutically acceptable carrier; The drug administration subjects are humans and non-human mammals.

8. A composition, characterized in that The active ingredients of the composition at least include lenvatinib and ursodeoxycholic acid.

9. The composition according to claim 8, characterized in that The composition has any one or more of the following uses: a) Synergistically inhibit tumor cell proliferation; b) Synergistically inhibit tumor cell invasion and migration; c) Promote apoptosis of tumor cells; d) synergistic inhibition of tumor growth; e) inhibiting the deterioration of tumor tissue; f) inhibiting tumor resistance to lenvatinib; g)Tumor treatment.

10. The composition according to claim 8, characterized in that The molar ratio of lenvatinib to ursodeoxycholic acid is 2.5-40:300-500; further including 5-20:300; and 10-20:500.

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