Application of lenvatinib combined with ursodeoxycholic acid in treatment of liver cancer

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to application of lenvatinib combined with ursodeoxycholic acid in liver cancer treatment. Specifically, the application constructs a cell strain Huh7R of human liver cancer cell Huh7 cells resistant to lenvatinib to carry out experiments. The results show that lenvatinib and UDCA can produce a synergistic inhibitory effect on HCC at multiple concentrations. Further, animal experiments also confirm the anti-HCC effect of the drug combination. The application provides a method capable of effectively inhibiting HCC progression, thereby overcoming the drug resistance problem of lenvatinib in clinical treatment, bringing new treatment options for liver cancer patients, and hopefully improving tumor treatment effect and improving the quality of life of patients, and therefore has important clinical significance and social value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to application of lenvatinib combined with ursodeoxycholic acid in liver cancer treatment. BACKGROUND

[0002] The information disclosed in this Background section is for the purpose of providing an understanding of the overall background of the application, and does not necessarily constitute an acknowledgement or any form of suggestion that this information forms part of the prior art.

[0003] Primary liver cancer is the most common type of liver cancer. According to the statistical data in 2022, primary liver cancer is the sixth most common tumor in terms of incidence, and is the third leading cause of death from cancer worldwide, with about 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 overall survival (OS) between patients treated with lenvatinib or sorafenib, lenvatinib treatment can improve the survival rate of liver cancer patients and prolong their progression-free survival, which is more clinically meaningful. However, most patients with advanced liver cancer develop innate or acquired resistance to lenvatinib, and only 10-30% of patients show therapeutic 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

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

[0006] To achieve the above technical purposes, the present application adopts the following technical solutions:

[0007] In a first aspect, the present application provides the application of lenvatinib combined with ursodeoxycholic acid in any one or more of the following:

[0008] a) preparing a product that synergistically inhibits tumor cell proliferation;

[0009] b) preparing a product that synergistically inhibits tumor cell invasion and migration;

[0010] c) preparing a product that promotes tumor cell apoptosis;

[0011] d) preparing a product that synergistically inhibits tumor growth;

[0012] e) preparing a product that inhibits the degree of tumor tissue malignancy;

[0013] f) preparing a product that inhibits tumor resistance to lenvatinib;

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

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

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

[0017] a) synergistically inhibiting tumor cell proliferation;

[0018] b) synergistically inhibiting tumor cell invasion and migration;

[0019] c) promoting tumor cell apoptosis;

[0020] d) synergistically inhibiting tumor growth;

[0021] e) inhibiting the degree of tumor tissue malignancy;

[0022] f) inhibiting tumor resistance to lenvatinib;

[0023] g) tumor treatment.

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

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

[0026] The above-mentioned technical solution constructs Huh7R cell, a cell strain of human hepatocellular carcinoma Huh7 cells resistant to lenvatinib, and conducts experiments. The results show that lenvatinib and UDCA can produce a synergistic inhibitory effect on HCC at multiple concentrations. Further, animal experiments also confirm the anti-HCC effect of the drug combination.

[0027] In summary, the above technical scheme provides a method capable of effectively inhibiting HCC progression, thereby overcoming the drug resistance problem of lenvatinib in clinical treatment, bringing new treatment options for liver cancer patients, and expected to improve tumor treatment effect and improve patient quality of life, and therefore has good potential practical application value. BRIEF DESCRIPTION OF DRAWINGS

[0028] The accompanying drawings, which form a part of the specification, are included to provide a further understanding of the application and are incorporated herein in conjunction with the description of the application. The drawings are not to be construed as a limitation of the application.

[0029] Figure 1 Inhibition of Huh7 and Huh7R cell proliferation by lenvatinib. 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 MTT method.

[0030] Figure 2 Lenvatinib and UDCA synergistically inhibit the proliferation of Huh7R cells. Huh7R cells were treated with different concentrations of lenvatinib and 0.3 mM UDCA (a) and 0.5 mM UDCA (b) respectively or simultaneously for 48 h, and then the cell viability was detected by MTT method, and the proliferation inhibition rate was calculated.

[0031] Figure 3 Lenvatinib and UDCA synergistically inhibit the clonogenic ability of Huh7R cells. (a) After Huh7R cells were treated with lenvatinib and UDCA respectively or simultaneously for 48 h, they were cultured in normal complete medium for about 1 week, then fixed, stained and photographed; (b) quantitative analysis of three independent repeated experiments.

[0032] Figure 4 Lenvatinib and UDCA synergistically inhibit the migration of Huh7R cells. (a) Huh7R cells were treated with 2.5 μM lenvatinib, 0.3 mM UDCA and their combination, respectively, and photographed under a fluorescence inverted microscope at 0 h, 24 h and 48 h after drug addition (100x, scale bar 200 μm); (b) quantitative analysis of three independent repeated experiments.

[0033] Figure 5Levatinib and UDCA synergistically inhibited Huh7R cell migration and invasion. Huh7R cells were treated with 2.5 μΜ levatinib, 0.3 mM UDCA, and the combination of both for 24 h, and the transwell assay (without Matrigel) was used to detect the migration ability of Huh7R cells (a), and the transwell assay (with Matrigel) was used to detect the invasion ability of Huh7R cells (b). (100x, scale bar 200 μιη), and three independent experiments were quantitatively analyzed.

[0034] Figure 6 Levatinib and UDCA synergistically induced Huh7R cell apoptosis. Huh7R cells were treated with 20 μΜ levatinib, 0.5 mM UDCA, and the combination of both for 48 h, and the cells were stained with Hoechst 33342, and the apoptosis was detected by fluorescence inverted microscope (100x, scale bar 200 μιη). Figure 7 Levatinib and UDCA synergistically induced Huh7R cell apoptosis. (a) Huh7R cells were treated with 20 μΜ levatinib, 0.5 mM UDCA, and the combination of both for 48 h, and the cells were labeled, and the proportion of apoptotic cells was detected by flow cytometry. (b) Three independent experiments were quantitatively analyzed.

[0035] Figure 8 Levatinib and UDCA synergistically inhibited the growth of orthotopic liver tumors in nude mice. (a) The photos of liver tumors in each group of nude mice. (b) The formation of liver tumors in each group of mice was observed by small animal ultrasound photoacoustic imaging system. (c) The tumor volume of each group of nude mice was statistically analyzed. (d) The body weight change curve of each group of nude mice.

[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 imaging and display, with a scale bar of 100 μιη (200x) or 50 μιη (400x). Figure 10 Ki67 protein expression and distribution in liver tumor tissues of nude mice. The Ki67 protein in the orthotopic tumor tissues of nude mice was labeled by IHC, and the images were taken under a microscope, with a scale bar of 100 μιη (200x) or 50 μιη (400x). DETAILED DESCRIPTION

[0037] It should be noted that the following detailed description is illustrative only, and is intended to provide further description in connection with the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0038] It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, steps, operations, elements, components, and / or groups thereof, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof.

[0039] In one exemplary embodiment of the present application, there is provided the use of lenvatinib in combination with ursodeoxycholic acid in any one or more of:

[0040] a) preparing a product that synergistically inhibits proliferation of tumor cells;

[0041] b) preparing a product that synergistically inhibits invasion and migration of tumor cells;

[0042] c) preparing a product that promotes apoptosis of tumor cells;

[0043] d) preparing a product that synergistically inhibits growth of tumor;

[0044] e) preparing a product that inhibits the degree of malignancy of tumor tissue;

[0045] f) preparing a product that inhibits tumor resistance to lenvatinib;

[0046] g) preparing a product for treatment of tumor.

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

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

[0049] It is to be understood that tumor is used in the present application as known by those skilled in the art, which includes benign tumor and / or malignant tumor. Benign tumor is defined as excessive proliferation of cells that cannot form aggressive, metastatic tumors in vivo. Conversely, malignant tumor is defined as cells with various cellular abnormalities and biochemical abnormalities that can form systemic disease (e.g., tumor metastasis in distant organs).

[0050] In yet another embodiment of the present application, the drug of the present application can be used for the treatment of malignant tumor. Examples of malignant tumor that can be treated with the drug of the present application are liver cancer, further primary liver cancer, and further hepatocellular carcinoma.

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

[0052] The pharmaceutically inactive ingredient can be a pharmaceutically acceptable carrier, which can be determined by those skilled in the art to meet clinical standards. It can be any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Generally, the nature of the carrier depends on the particular mode of administration employed. For example, parenteral formulations usually contain injectable fluids that include pharmaceutically acceptable and physiologically acceptable fluids, such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol, and the like. For solid compositions (e.g., in the form of powders, pills, tablets, or capsules), conventional non-toxic solid carriers can include, for example, pharmaceutical grade mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, the pharmaceutical composition to be administered can contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents, and the like, such as sodium acetate or sorbitan monolaurate, and the like. No specific limitation is made herein.

[0053] In yet another embodiment of the present application, the drug of the present application can be administered into the body by known means. For example, by intravenous systemic delivery. Alternatively, administration can be via intravenous, transdermal, intranasal, mucosal, or other delivery methods. Such administration can be via single or multiple doses. Those skilled in the art understand that the actual dose to be administered in the present application can vary greatly depending on a variety of factors, such as target cells, biological type or its tissue, general condition of the subject to be treated, route of administration, mode of administration, and the like.

[0054] In yet another embodiment of the present application, the drug administration subject can be a human and a non-human mammal, including mice, rats, guinea pigs, cows, sheep, cats, dogs, horses, monkeys, orangutans, and the like, among which humans are preferred.

[0055] In yet another embodiment of the present application, a composition is provided, which has at least the active ingredients of the above-mentioned lenvatinib and ursodeoxycholic acid.

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

[0057] a) synergistically inhibiting tumor cell proliferation;

[0058] b) synergistically inhibiting tumor cell invasion and migration;

[0059] c) promoting tumor cell apoptosis;

[0060] d) synergistically inhibiting tumor growth;

[0061] e) inhibiting the degree of tumor tissue malignancy;

[0062] f) inhibiting tumor resistance to lenvatinib;

[0063] g) tumor treatment.

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

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

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

[0067] In the present application, the term "therapeutically effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic result at the necessary dosage and time period. A therapeutically effective amount of an agent, for example, eliminates, reduces, delays, minimizes or prevents adverse effects of a disease.

[0068] The subject can be a human and a non-human mammal, including mouse, rat, guinea pig, cow, sheep, cat, dog, horse, monkey, chimpanzee, etc., wherein the human is preferred.

[0069] The present application is further illustrated in conjunction with specific examples, which are only intended to explain the present application and do not limit the content thereof. Any simple modification, equivalent change and modification made according to the technical essence of the present application to the embodiments are within the scope of the technical solutions of the present application.

[0070] Example

[0071] I. Cell experiment

[0072] 1. Construction of human hepatocellular carcinoma lenvatinib-resistant cell Huh7R cells and detection of the drug resistance and drug resistance fold of the cells

[0073] MTT experiment: Lenvatinib-sensitive Huh7 cells and lenvatinib-resistant Huh7R cells were inoculated in 96-well plates, and lenvatinib was added to the 96-well plates according to the experimental concentration setting. The 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, and incubated at 37°C for 4 h. Then, all the liquid in the well was carefully aspirated and 150 μL of DMSO solution was added to dissolve the formazan crystals in the well. The absorbance value (OD value) of each group was measured at 570 nm wavelength on a microplate reader for 5 min. The drug inhibition rate of the cells was calculated as follows: inhibition rate (%) = (blank control group absorbance value - drug group absorbance value) / blank control group absorbance value x 100%. It was detected that with the increase of the concentration of lenvatinib, the inhibition of the proliferation of Huh7 and Huh7R cells was gradually enhanced, and the IC 50 values were 2.775 μM and 25.93 μM, respectively. Compared with the sensitive cell strain, the drug resistance multiple of the drug-resistant cells was 9.34 times. Figure 1 , Table 1

[0074] Table 1 IC 50 values and drug resistance multiples (RIs) of lenvatinib on hepatocellular carcinoma cells for 48 h

[0075]

[0076] 2. Detection of the synergistic inhibition of lenvatinib and UDCA on HCC proliferation

[0077] MTT experiment: Huh7R cells were inoculated in 96-well plates, and the cells were treated with specific concentration gradients of lenvatinib and UDCA alone or in combination for 48 h. Then, 20 μl of MTT detection reagent was added to each well, and incubated at 37°C for 4 h. The inhibition of cell growth by the two drugs alone or in combination was evaluated. The synergistic index q value of the two drugs was calculated by the Jin Zhengjun formula to indicate whether lenvatinib and UDCA had a combined effect. The q value = the inhibition rate of the two drugs combined / (the sum of the inhibition rates of the two drugs alone - the product of the inhibition rates of the two drugs alone). When the q value < 0.85, it indicates that the two drugs have an antagonistic effect, 0.85 ≤ q value ≤ 1.15 indicates that the two drugs have an additive effect, and q value > 1.15 indicates that the two drugs have a synergistic effect. The results showed that lenvatinib and UDCA combined 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 Synergistic index of lenvatinib and UDCA in Huh7R cells

[0079]

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

[0081] Colony formation experiment: logarithmic growth phase Huh7R cells were digested and centrifuged, 3x10 3 / well in a six-well plate, and after the cells adhered overnight, drug treatment (20 μM lenvatinib and 0.5 mM UDCA alone or in combination) was added for 48 h, and fresh medium without drugs was replaced every 3 days. When the blank control group formed large colonies, they were fixed, stained, washed, photographed, and counted using Image J software, and the cell colony formation rate of each group was calculated. The results showed that the average inhibition rates of the lenvatinib group, UDCA group, and combination group on colony formation were 21.28%, 56.17%, and 90.67%, Figure 3 respectively. This showed that lenvatinib or UDCA alone could inhibit colony formation, and the combination of the two could significantly inhibit the proliferation ability of Huh7R cells.

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

[0083] Scratch test: logarithmic growth phase Huh7R cells were plated in a six-well plate, and when the cell density reached 80-90%, three parallel and perpendicular lines were drawn on the bottom of the cell plate with a sterile gun head. 1% FBS medium without drugs, containing 2.5 μM lenvatinib, 0.3 mM UDCA, and 2.5 μM lenvatinib + 0.3 mM UDCA was added, respectively. The cells were placed under an inverted fluorescence microscope (100x) for fixed-point photography at 0h, 24h, and 48h, respectively. The cell migration rate was calculated by Image J software. Migration rate (%) = (0h scratch area - scratch area at each time point) / 0h scratch area x 100%. The results showed that lenvatinib alone could significantly inhibit the migration ability of Huh7R cells, while UDCA had a weaker inhibitory effect, but the inhibitory effect of the combination of the two drugs was significantly higher than that of lenvatinib alone. Figure 4

[0084] Transwell experiment: tumor cells were plated in the upper chamber of a transwell at 2x10 4 ​Huh7R cells were seeded in transwell chambers with 8 μm pore size. Matrigel was not added in transwell experiments to detect the migration ability of cells under different treatment conditions, while Matrigel was added to detect the invasion ability of cells under different treatment conditions. Serum-free medium containing drugs was added to the upper layer of the transwell chamber, and 600 μL medium containing 15% serum was added to the lower layer. After incubation at 37°C for 24 h, the migrated cells were fixed, stained, washed and counted. The results showed that the combination of lenvatinib and UDCA synergistically inhibited the migration and invasion of Huh7R cells. Figure 5 )

[0085] 5. Detection of the effect of the combination of lenvatinib and UDCA on Huh7R cell apoptosis

[0086] Hoechst 33342 experiment: logarithmically growing Huh7R cells were plated in a six-well plate, and when the cells were attached and the density was about 60%, drug treatment was added for 48 h, and then fixed and stained. Prepare a Hoechst 33342 staining solution with a concentration of 20 μg / mL, and stain in the dark for 20 min. After staining, observe the nuclear morphology of each group under the UV (340 / 460 nm) channel of the fluorescence inverted microscope and take pictures. The results showed that the use of lenvatinib or UDCA alone caused a small number of cells to undergo apoptosis, and the number of cells with nuclear shrinkage increased significantly after combined use, indicating that the two drugs can promote Huh7R cell apoptosis. Figure 6 )

[0087] Annexin V-FITC / PI double staining to detect apoptosis: logarithmically growing Huh7R cells were plated in a six-well plate, and when the cells were attached, drugs were added, and Annexin V-FITC and PI single staining wells were set up, respectively. After drug treatment for 48 h, the supernatant of each group was collected. The cells were digested with trypsin without EDTA, and the corresponding wells were terminated with pre-collected culture supernatant. The cell precipitate of each group was resuspended with 1x binding buffer. 5 μL Annexin V-FITC and 5 μL PI were added to the single staining Annexin V-FITC and PI groups, respectively, and 5 μL Annexin V-FITC and 5 μL PI were added to the other groups. After 20 min of incubation at room temperature in the dark, the cells were passed through a 200-mesh screen and detected by flow cytometry. The results showed that the use of lenvatinib or UDCA alone could induce a small number of cells to undergo apoptosis, and the use of both drugs could significantly increase the number of early apoptotic cells. Figure 7 ).

[0088] II. Animal experiments

[0089] 1. In vivo tumor inhibition effect of the drug combination of lenvatinib and UDCA on Huh7R

[0090] Intraperitoneal injection of 50 μL of 3 million Huh7R cells into the liver, silk suture of the abdominal incision, and drug-resistant hepatocellular carcinoma cell transplantation in nude mice. The nude mice were randomly divided into groups, 5 in each group, and drug administration started on day 10. Lenvatinib and UDCA were prepared into 10 mg / kg and 100 mg / kg concentrations with DMSO:20% SBE-β-CD in Saline = 1:9 (V / V), ultrasonic dissolution, and freshly prepared. Both drugs were administered by gavage, and continuous administration for 21 days. The formation of tumors and the observation of tumor size were monitored by a small animal ultrasonic photoacoustic imaging system. The results showed that, compared with the control group, lenvatinib and UDCA alone can inhibit the growth of orthotopic liver tumors in nude mice, and the combination of the two drugs can more significantly inhibit tumor growth than single drug, but has no significant effect on mouse body weight. During the experiment, the size of the tumor was monitored by a small animal ultrasonic photoacoustic imaging system, and the results confirmed the synergistic inhibition of the combination of the two drugs on tumor growth. Figure 8 ).

[0091] 2. H&E staining and immunohistochemical staining method for detecting the in vivo tumor inhibition effect of the drug combination of lenvatinib and UDCA on Huh7R

[0092] After the end of in vivo drug administration, the liver was removed, the tumor volume was measured, and photographs were taken for record. The liver tissue was fixed with 4% paraformaldehyde solution and stored at 4°C for H&E staining and immunohistochemical staining. Ki67 is an antigen that characterizes cell proliferation, its function is closely related to mitosis, and it is an important cell proliferation marker. To further verify the inhibitory effect of the combination of the two drugs on HCC tumors, we detected the protein expression of Ki67 (brown) in different treatment groups by immunohistochemical experiments. The results of H&E staining showed that the interstitial and necrotic areas of tumor cells increased after treatment with lenvatinib and combination, and 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 combination of lenvatinib and UDCA can inhibit the degree of tumor tissue deterioration. Figure 9 ,10)

[0093] In summary, the present application provides a novel and effective method for treating lenvatinib-resistant HCC. The combination of lenvatinib and UDCA will bring new treatment options for patients with hepatocellular carcinoma, and is expected to improve tumor treatment effect and improve the quality of life of patients.

[0094] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Those skilled in the art can make various modifications and changes to the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. Use of lenvatinib in combination with ursodeoxycholic acid in the manufacture of a product for inhibiting the development of resistance to lenvatinib in a tumor, characterized in that, The tumor is liver cancer. The molar ratio of lenvatinib to ursodeoxycholic acid is 5:300 or 20:300 or 10:500 or 20:

500. The product is a drug or a general test reagent for non-medical use.

2. The use according to claim 1, characterized in that, The liver cancer is primary liver cancer.

3. The use according to claim 2, wherein the compound is ###0002### The primary liver cancer is hepatocellular carcinoma.

4. The use according to claim 1, characterized in that, The drug includes at least one pharmaceutical inactive ingredient.

5. The use according to claim 4, wherein the compound is ###0002### The pharmaceutical inactive ingredient is a pharmaceutically acceptable carrier. The drug administration subject is a human and a non-human mammal.

6. The use according to claim 1, characterized in that, Lenvatinib combined with ursodeoxycholic acid synergistically inhibits tumor cell proliferation.

7. The use according to claim 1, characterized in that, Lenvatinib combined with ursodeoxycholic acid synergistically inhibits tumor cell invasion and migration.

8. The use according to claim 1, characterized in that, Lenvatinib combined with ursodeoxycholic acid promotes tumor cell apoptosis.

9. The use according to claim 1, characterized in that, Lenvatinib combined with ursodeoxycholic acid synergistically inhibits tumor growth.

10. The use according to claim 1, characterized in that, Lenvatinib combined with ursodeoxycholic acid inhibits the degree of tumor tissue malignancy.

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