Application of teriflunomide in preparation of medicine for treating ovarian cancer and medicine

Abstract

The invention provides application of teriflunomide in preparation of a medicine for treating ovarian cancer and the medicine. The application provided by the invention can provide an effective, safe and drug-resistant ovarian cancer treatment drug for further treatment of ovarian cancer.

Description

Technical Field

[0001] This invention relates to a medicament for treating ovarian cancer, and more particularly to the use of teriflunomide in the preparation of a medicament for treating ovarian cancer and the medicament thereof. Background Technology

[0002] Ovarian cancer ranks among the leading causes of death and morbidity among female reproductive system malignancies. The median age at diagnosis is 63 years, and the vast majority of ovarian cancers (>90%) are epithelial ovarian cancer (EOC). Due to the lack of obvious early symptoms and effective screening methods, more than 80% of patients are diagnosed at an advanced stage (FIGO stage III / IV), with pelvic and distant metastases. Currently, clinical treatment options for ovarian cancer are very limited. The standard treatment for intermediate to advanced (FIGO stage IC-IV) epithelial ovarian cancer is a combination of surgical cytoreductive surgery and chemotherapy drugs such as paclitaxel, platinum-based drugs, and fluorouracil (FU). However, due to the difficulty in achieving R0-level surgical resection and the drug resistance of ovarian cancer cells, the five-year survival rate after treatment is only 5%, and the recurrence rate within 18 months is as high as 70%. Currently, the main molecularly targeted drugs for ovarian cancer used in clinical practice internationally are bevacizumab and the PPAR inhibitor olaparib. However, the treatment effect on recurrent and metastatic tumors remains limited, and there has been little progress in the clinical development of other targeted inhibitors and immunotherapies. The lack of a cure for recurrent ovarian cancer has prevented improvements in survival rates. Therefore, exploring new and effective therapeutic targets and methods has become a core issue in ovarian cancer treatment research.

[0003] Cancer stem cells (CSCs) are a small group of cells within tumor cell populations that possess multipotent differentiation potential, self-renewal capabilities, high tumorigenicity, and drug resistance. They can migrate to distant organs to form new tumors. Conventional treatments such as chemotherapy and radiotherapy can effectively kill dividing tumor cells, but they cannot effectively kill cancer stem cells. These cells survive treatment and thus mediate tumor drug resistance, tumor metastasis, and tumor recurrence. Studies have shown that cancer stem cells play a crucial role in the development, recurrence, drug resistance, and metastasis of ovarian cancer, and are one of the fundamental factors affecting the prognosis of ovarian cancer. Therefore, targeted therapy against ovarian cancer cancer stem cells is one of the most promising research hotspots in ovarian cancer treatment.

[0004] It should be noted that the information disclosed in the background section above is only for understanding the background of this application, and therefore may include information that does not constitute prior art known to those skilled in the art. Summary of the Invention

[0005] To overcome the shortcomings of the prior art, the present invention provides the application of teriflunomide in the preparation of a drug for treating ovarian cancer and the drug itself.

[0006] To achieve the above objectives, the present invention adopts the following technical solution.

[0007] The use of teriflunomide in the preparation of a drug for treating ovarian cancer.

[0008] Preferably, in the application, the teriflunomide is used to kill ovarian cancer tumor stem cells.

[0009] Preferably, teriflunomide effectively kills ovarian cancer stem cells by inhibiting the calcium channel Orai1, which is highly expressed in ovarian cancer, and the signaling pathway mediated by diorotic acid dehydrogenase (DHODH).

[0010] Preferably, in the application, the teriflunomide is used to inhibit the growth of solid tumors formed from ovarian cancer tumor stem cells.

[0011] Preferably, in the application, the teriflumine is used alone.

[0012] Preferably, in the application, teriflunomide is used in combination with chemotherapeutic drugs as a chemotherapeutic sensitizer to eliminate tumor drug resistance.

[0013] Preferably, the ovarian cancer stem cells are COV362 and / or SKOV3 tumor stem cells.

[0014] Preferably, the chemotherapy drug is fluorouracil.

[0015] Preferably, in the application, the dose of teriflunomide is 1.5 mg / kg body weight / day to 30 mg / kg body weight / day, administered every other day.

[0016] Preferably, the drug comprises a dosage form formulated for administration via intraperitoneal injection.

[0017] The present invention also provides a drug for treating ovarian cancer, comprising teriflunomide and chemotherapy drugs.

[0018] Preferably, the chemotherapy drug is fluorouracil.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] This invention provides the application of teriflunomide in the preparation of drugs for treating ovarian cancer. Experiments demonstrate that teriflunomide, at its clinical dosage in mice, can effectively inhibit ovarian cancer tumor growth and overcome chemotherapy resistance in a mouse subcutaneous tumor model; and effectively inhibit peritoneal metastasis of ovarian cancer in a mouse intraperitoneal metastatic tumor model. Attached Figure Description

[0021] Figure 1A and Figure 1B The study showed that Orai1 messenger RNA expression was upregulated in ovarian cancer, and further upregulated in metastatic ovarian cancer (M1).

[0022] Figures 2A-2D In in vitro experiments, 25 μM teriflunomide effectively inhibited Orai1-mediated calcium store manipulation of calcium in the advanced serous ovarian cancer cell line COV362 and the endometrioid ovarian cancer cell line SKOV3. 2+ Internal flow (SOCE).

[0023] Figures 3A-3D This study demonstrates the effects of teriflunomide and fluorouracil on the growth curves of tumor stem cells in the advanced serous ovarian cancer cell line COV362 and the endometrioid ovarian cancer cell line SKOV3 in in vitro experiments.

[0024] Figures 4A-4D This study demonstrates the effects of teriflunomide, fluorouracil, and their combination on the growth curve, final tumor volume, and final tumor weight of subcutaneous tumors in mice established from COV362 tumor stem cells, in vivo.

[0025] Figures 5A-5D This study demonstrates the effects of teriflunomide, fluorouracil, and their combination on the growth curve, final tumor volume, and final tumor weight of subcutaneous tumors in mice established from SKOV3 tumor stem cells of endometrioid ovarian cancer cells in vivo.

[0026] Figures 6A-6B This study demonstrates the effects of teriflunomide, fluorouracil, and their combination on intraperitoneal metastasis of mouse tumors established from SKOV3 and COV362 tumor stem cells in in vivo experiments.

[0027] Figures 7A-7C This study demonstrates the effects of teriflunomide, fluorouracil, and their combination on the expression levels of Ki67, a cell growth marker, and CD133 and CD44, tumor stem cell markers, in mouse subcutaneous tumors established from COV362 tumor stem cells in an in vivo experiment.

[0028] Figures 8A-8C This study demonstrates the effects of teriflunomide, fluorouracil, and their combination on the expression levels of Ki67, a cell growth marker, and CD133 and CD44, tumor stem cell markers, in mouse subcutaneous tumors established from SKOV3 tumor stem cells in an in vivo experiment.

[0029] Figures 9A-9C In in vivo experiments, teriflunomide, fluorouracil, and their combination did not cause damage to the heart, liver, or kidney tissues of mice.

[0030] Figures 10A-10BThe results showed that teriflunomide, fluorouracil, and their combination had no effect on mouse body weight in in vivo experiments. Detailed Implementation

[0031] The embodiments of the present invention will be described in detail below. It should be emphasized that the following description is merely exemplary and not intended to limit the scope and application of the present invention. Unless otherwise specified, the embodiments and features in the embodiments of this application can be combined with each other.

[0032] Tumor stem cells are a major cause of high mortality rates due to recurrence and drug resistance in ovarian cancer. This invention utilizes teriflunomide (e.g., brand name: Aubagio), an FDA-approved drug, to effectively kill ovarian cancer tumor stem cells by inhibiting the Orai1 calcium channel and the DHODH-mediated signaling pathway, which are highly expressed in ovarian cancer. In animal studies, it significantly inhibits the growth of solid tumors formed by ovarian cancer tumor stem cells. Furthermore, it can function as a chemosensitizer for the clinical chemotherapy drug fluorouracil, significantly eliminating tumor drug resistance, and can be used to treat ovarian cancer. This invention reveals the relevant mechanisms of this repurposing of an existing drug for the treatment of ovarian cancer and completes the optimal inhibitory dosage and safety evaluation for inhibiting ovarian cancer growth.

[0033] The overall approach to the research process of this invention is as follows:

[0034] (1) Using the TCGA database, the expression level of Orai1 in ovarian cancer was analyzed by bioinformatics analysis method, and the differential expression in ovarian cancer samples of patients at different metastatic stages was analyzed to preliminarily determine the role of Orai1 in ovarian cancer.

[0035] (2) Using laser scanning confocal microscopy and Flou-4 / AM staining, it was verified that teriflunomide can inhibit calcium ions manipulated by Orai1-mediated calcium stores in ovarian cancer cells. 2+ Internal flow (SOCE).

[0036] (3) Tumor stem cells were enriched in high-grade serous ovarian cancer cell line COV362 and endometrioid ovarian cancer cell line SKOV3 using 3D fibrin gel. SKOV3 and COV362 tumor stem cells were treated with teriflunomide at concentrations of 12.5 μM and 50 μM (control group and fluorouracil group). Teriflunomide at concentrations of 12.5 μM and 50 μM was used in combination with fluorouracil. The growth curve of tumor stem cell spheroids and tumor stem cell markers were detected to determine the effectiveness of teriflunomide in inhibiting tumor stem cell growth and overcoming chemotherapy resistance in vitro.

[0037] (4) High-grade serous ovarian cancer cell line COV362 and endometrioid ovarian cancer cell line SKOV3 tumor stem cells were enriched using 3D fibrin gel. Subcutaneous tumor models of tumor stem cells were established in NOD / SCID mice (n=80). PBS was injected intraperitoneally; teriflunomide (1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, 30 mg / kg body weight / day, every other day); the first-line chemotherapy drug fluorouracil (25 mg / kg / day, twice a week); and teriflunomide was combined with chemotherapy (teriflunomide 1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, 30 mg / kg body weight / day, every other day; fluorouracil 25 mg / kg body weight / day, twice a week). Tumor growth rate, final volume, metastasis, and other malignant biological behaviors were observed to determine the effectiveness of teriflunomide in inhibiting tumor growth and overcoming chemotherapy resistance in vivo.

[0038] (5) SKOV3 and COV362 cell lines were cultured, and an intraperitoneal metastatic tumor model was established in 80 NOD / SCID mice. The mice were injected intraperitoneally with PBS, teriflunomide (1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, 30 mg / kg body weight / day, every other day), the first-line chemotherapy drug fluorouracil (25 mg / kg body weight / day, twice a week), and a combination of teriflunomide and fluorouracil (teriflunomide 1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, 30 mg / kg body weight / day, every other day; fluorouracil 25 mg / kg body weight / day, twice a week). The accumulation of ascites in the mice was observed, and the number of intraperitoneal metastases was counted after the mice were sacrificed. The effectiveness of teriflunomide in inhibiting tumor growth and eliminating intraperitoneal metastases in vivo was determined.

[0039] (6) After the above experiments, mouse tumor tissue was collected to detect the expression of ovarian cancer tumor stem cell markers CD44 and CD133, and to determine the effect of teriflunomide in reducing the stemness of ovarian cancer tumors. Furthermore, for the mice that established the tumor model, heart, liver, and kidney tissues were collected after the experiments for safety evaluation.

[0040] It should be noted that the dosages selected in this study (1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, and 30 mg / kg body weight / day) are the corresponding mouse animal experimental doses for the current clinical doses of teriflunomide. When used in other species, including humans, the dosage may need to be adjusted based on age, weight, and overall health. The invention is described in detail below.

[0041] Experimental methods

[0042] 1. Bioinformatics Analysis

[0043] For 374 patients in the Cancer Genome Atlas (TCGA) database, tumor RNA-seq data were downloaded from the Genomic Data Commons (GDC) data portal (TCGA). Data from all 187 normal tissue samples were obtained from the GTEx V8 release (https: / / gtexportal.org / home / datasets). The GTEx official documentation provides a complete description of donor sex, multiple ethnic groups, a wide age range, biosample procurement methods, and sample fixation. Statistical analysis was performed using R software v4.0.3. A p-value <0.05 was considered statistically significant.

[0044] 2. Detection of cytoplasmic calcium ions (Ca) 2+ concentration

[0045] First, put the cells in Ca 2+ Incubate the cells in the sensitive fluorescent staining agent Fluo-4 / AM for 30 minutes. Then place the cells in a Ca-free environment. 2+ In the solution, 10 μM cyclopiazonic acid (CPA) was added to deplete calcium ions in the intracellular calcium pool, followed by the addition of 2 mM Ca. 2+ To trigger calcium reservoir manipulation mediated by Orai1 2+ SOCE (Solar Flow-Effect) was used. Fluorescence signals of Fluo-4 cells were recorded at room temperature using an FV1000 laser scanning confocal imaging system with excitation / emission wavelengths of 488 / 515 nm. Data were analyzed using META-FLOUR software. Each experiment contained at least 20 cells. Results are expressed as fluorescence intensity relative to pre-stimulation levels (Ft / F0).

[0046] 3. Ovarian cancer tumor stem cells were enriched and finally isolated using 3D fibrin gel.

[0047] Ovarian cancer cells were suspended in DMEM (10% FBS). The cell density was adjusted to 100 cells / ml. Fibrinogen solution and cell solution were mixed 1:1 (volume ratio) to obtain a cell / fibrinogen mixture. 1 mg / ml fibrinogen contained 5000 cells / ml. 250 μL of the cell / fibrinogen mixture was seeded into each well of a cell culture plate (24-well plate in this example) and thoroughly mixed with 5 μL thrombin (0.1 U / μl). The cell culture plate was then incubated at 37°C for 10 minutes. Finally, 1 ml of DMEM medium containing 10% FBS and penicillin-streptomycin was added. After gel polymerization, only tumor stem cells could survive and grow into tumor spheroids under this environment. The spheroid growth curve is an important indicator for assessing the stemness of tumor stem cells. Non-tumor stem cells died and could not form tumor spheroids. The tumor stem cell spheroids were photographed under a microscope, and their volume was calculated. On the eighth day of growth, the fibrin gel was dissolved with collagenase and dispersant to obtain ovarian cancer stem cells.

[0048] 4. Establishment of a mouse tumor-bearing model

[0049] To conduct tumor growth analysis experiments, tumor stem cells were first enriched from the high-grade serous ovarian cancer cell line COV362 and the endometrioid ovarian cancer cell line SKOV3. Then, the tumor stem cells were injected subcutaneously / intestinal wall of NOD / SCID mice to establish a xenograft CDX tumor model, in order to test the effect of teriflunomide on inhibiting tumor growth in mice.

[0050] 4.1 Subcutaneous Tumor Formation: Ovarian cancer tumor stem cells were mixed with 50 μL of PBS and injected subcutaneously into the hind legs of nude mice. Tumor size was measured every two days using calipers, and the volume was calculated using the formula: Volume (cm²) 3 ) = (width) 2 × length / 2. Collect the tumor and measure its weight on day 30.

[0051] 4.2 Intraperitoneal tumor formation: Ovarian cancer tumor stem cells were mixed in 150 μL PBS and injected into the peritoneal cavity of mice. The mice were sacrificed 30 days later, and the number of metastatic tumors was counted by dissection.

[0052] 5. Histochemical detection and immunostaining of tumor tissue sections

[0053] After euthanizing the mice, the xenografted tumor tissue was fixed, sectioned, and subjected to H&E and immunohistochemical staining. The malignancy of the tumor was assessed using ovarian cancer markers CD133 and CD44, and the cell growth marker Ki67.

[0054] Teriflunomide is FDA-approved for the treatment of rheumatoid arthritis and multiple sclerosis. The inventors' research found that this drug can inhibit the activity of the Orai1 ion channel and the activity of the orotic acid dehydrogenase (DHODH). First, this invention tested the effect of teriflunomide on the growth of tumor spheroids formed by human ovarian cancer cell lines in 3D fibrin gel in vitro. Using previously reported pharmacokinetic data on the safe plasma concentration of the drug (teriflunomide), it was used to inhibit the growth of COV362 and SKOV3 ovarian cancer stem cells. Experimental results showed that teriflunomide successfully inhibited the growth of COV362 and SKOV3 tumor stem cells in 3D fibrin gel and eliminated the resistance of ovarian cancer stem cells to fluorouracil. Furthermore, mouse models of subcutaneous ovarian cancer tumors and peritoneal metastases were established using COV362 and SKOV3 ovarian cancer stem cells. Teriflunomide significantly inhibited the growth of subcutaneous ovarian cancer tumors and overcame chemotherapy resistance, and also significantly reduced intraperitoneal tumor formation and metastasis of ovarian cancer. Furthermore, teriflunomide, used alone or in combination with the chemotherapeutic drug fluorouracil, did not affect the body weight or the structure of the heart, liver, and kidneys in mice, preliminarily demonstrating its safety at tumor-inhibiting concentrations. These experiments reveal that teriflunomide possesses remarkable antitumor effects and chemosensitizing properties, showing great potential for clinical translation and application.

[0055] result

[0056] 1. Orai1 is significantly upregulated in ovarian cancer and further upregulated in metastatic ovarian cancer (M1).

[0057] See Figure 1A-1B Analysis using the TCGA database and bioinformatics tools showed that the expression level of Orai1 messenger RNA in normal ovarian tissue was approximately 4 TPM. Figure 1A (Green), however, its expression level reached 6 TPM in ovarian cancer tissue. Figure 1A (Red) Orai1 expression was upregulated by 50% relative to normal tissue. Meanwhile, in ovarian cancer tissue, Orai1 expression in non-metastatic ovarian cancer tissue (M0 stage) was approximately 5.6 TPM (…). Figure 1B Indigo), and reached 6.2 TPM in metastatic ovarian cancer tissue (M1 stage). Figure 1B (Purple). Considering the sampling method and microarray data processing method, the actual difference between the two will be even greater.

[0058] 2. Teriflunomide can effectively block calcium storage manipulation mediated by Orai1 in ovarian cancer cells. 2+ internal flow

[0059] In ovarian cancer cells, calcium stores manipulate Ca2+. 2+ The internal flow (SOCE) is mediated by Orai1. Figures 2A-2D This demonstrates the Ca manipulation of the calcium pool by teriflunomide. 2+ The impact of internal flow (SOCE). Figure 2A and 2C SOCE curves of COV362 and SKOV3 cell lines after treatment with 25 μM teriflunomide are shown. The blue line represents the control group (CTL), and the red line represents the teriflunomide-treated group. After the addition of cyclodiazepine (CPA), the calcium pool was depleted, and subsequently, 2 mM Ca was added. 2+ It was observed that the calcium influx in the control group increased significantly, while the increase in calcium influx in the teriflumine treatment group was significantly reduced. Figure 2B and 2D The bar chart compared the changes in the first and second calcium peaks in the two groups. The results showed that teriflunomide significantly inhibited the second calcium peak (SOCE), while the first peak showed no significant change. These results indicate that 25 μM teriflunomide has a significant inhibitory effect on SOCE in ovarian cancer cells.

[0060] 3. Teriflunomide can effectively inhibit the growth of tumor stem cell spheroids and overcome resistance to fluorouracil.

[0061] See Figures 3A-3D In vitro experiments showed that tumor stem cells enriched using 3D fibrin gel exhibited strong resistance to the clinical chemotherapy drug fluorouracil. 5 μM fluorouracil (red curve and bar chart) failed to effectively inhibit the spheroidization of COV362 and SKOV3 tumor stem cells. However, treatment with teriflunomide at concentrations of 12.5 μM and 50 μM significantly inhibited the spheroidization of both ovarian cancer cell lines, with the inhibitory effect increasing with increasing teriflunomide concentration, reaching an optimal concentration of 50 μM. When teriflunomide was used in combination with fluorouracil, a low dose (12.5 μM) of teriflunomide was sufficient to overcome resistance to fluorouracil and completely inhibit tumor stem cell growth.

[0062] Figures 4A-4D This study demonstrates the effects of teriflunomide, fluorouracil, and their combination on the growth curve, final tumor volume, and final tumor weight of subcutaneous tumors in mice established from COV362 tumor stem cells, in vivo. Figures 5A-5D This study demonstrates the effects of teriflunomide, fluorouracil, and their combination on the growth curve, final tumor volume, and final tumor weight of subcutaneous tumors in mice established from SKOV3 tumor stem cells of endometrioid ovarian cancer cells in vivo.

[0063] 4. Teriflunomide effectively inhibited the growth of subcutaneous tumors established by tumor stem cells in a mouse subcutaneous CDX tumor model and overcame their drug resistance.

[0064] See Figures 4A-4D , Figures 5A-5DIt is known that subcutaneous tumors in mice established from tumor stem cells are resistant to the clinical chemotherapy drug fluorouracil. Fluorouracil at a concentration of 25 mg / kg body weight / day showed some inhibitory effect on tumor growth in mouse subcutaneous CDX models established from COV362 and SKOV3 tumor stem cells, but the effect was weak. Figures 4A-4D , Figures 5A-5D However, teriflunomide treatment at concentrations of 1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, and 30 mg / kg body weight / day inhibited tumor growth in mouse subcutaneous CDX models established from COV362 and SKOV3 tumor stem cells, and reduced final tumor volume and weight. The inhibitory effect increased with increasing teriflunomide concentration, and was superior to or not significantly inferior to the traditional first-line chemotherapy drug fluorouracil. Furthermore, in combination with fluorouracil, different concentrations of teriflunomide (1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, and 30 mg / kg body weight / day) significantly reduced ovarian cancer tumor resistance to fluorouracil, inhibited tumor growth, and significantly reduced final tumor volume and weight, showing better effects than teriflunomide alone.

[0065] 5. Teriflunomide effectively inhibited the formation of metastatic tumors from SKOV3 and COV362 tumor stem cells and overcame their drug resistance in a mouse intraperitoneal metastatic tumor model.

[0066] See Figures 6A-6B It was found that in the intraperitoneal metastatic ovarian cancer model established using COV362 and SKOV3 tumor stem cell lines enriched by 3D fibrin gel, fluorouracil at 25 mg / kg body weight / day showed a certain inhibitory effect on metastatic tumors. Teriflunomide treatment at 1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, and 30 mg / kg body weight / day also inhibited metastatic tumor formation, with the inhibitory effect increasing with increasing teriflunomide concentration, showing a superior or no significantly inferior effect to fluorouracil. Furthermore, when teriflunomide was used in combination with fluorouracil, different concentrations of teriflunomide (1.5 mg / kg body weight / day, 3.0 mg / kg body weight / day, and 30 mg / kg body weight / day) significantly inhibited the metastasis of intraperitoneal tumors in mice established using tumor stem cells, with a superior effect compared to fluorouracil, and the inhibitory effect increasing with increasing teriflunomide concentration. The combination of teriflunomide at 30 mg / kg body weight / day and fluorouracil at 25 mg / kg body weight / day can almost completely eliminate the formation of metastatic lesions.

[0067] 6. Teriflunomide can significantly reduce the stemness of ovarian cancer tumor stem cells.

[0068] See Figures 7A-7C , Figures 8A-8CIt was found that mouse subcutaneous xenograft tumors established using COV362 and SKOV3 tumor stem cells enriched by 3D fibrin gel exhibited strong stem cell characteristics. Immunohistochemical experiments showed high expression of tumor stem cell markers CD133 (PROM1) and CD44 in ovarian cancer. The cell proliferation marker Ki67 was also highly expressed in ovarian cancer. Meanwhile, the clinical chemotherapy drug fluorouracil did not significantly reduce the expression levels of either tumor stem cell markers or the cell proliferation marker Ki67. Teriflunomide at 1.5-30 mg / kg body weight / day could slightly reduce the expression levels of both tumor stem cell markers. However, in the combined use of teriflunomide and fluorouracil, different concentrations of teriflunomide significantly inhibited the expression of tumor stem cell markers.

[0069] 7. Teriflunomide showed no significant toxicity at the experimental dosage.

[0070] See Figures 9A-9C It was found that after the experiment, tissue sections of the mouse heart, liver, and kidneys were taken and stained with hematoxylin and eosin. Compared with the control group, no significant tissue structural lesions were found in the teriflunomide treatment group or the teriflunomide plus fluorouracil group. This demonstrates that at this dose, teriflunomide alone or in combination with fluorouracil does not have significant tissue toxicity in animals.

[0071] See Figures 10A-10B It was found that teriflunomide, used alone or in combination with fluorouracil, did not cause significant weight loss in mice, further demonstrating that there was no acute toxicity at the dosage used in this experiment.

[0072] The above description provides a further detailed explanation of the present invention in conjunction with specific / preferred embodiments, and it should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various substitutions or modifications can be made to these described embodiments without departing from the concept of the present invention, and all such substitutions or modifications should be considered within the scope of protection of the present invention. In the description of this specification, the reference to terms such as "an embodiment," "some embodiments," "preferred embodiment," "example," "specific example," or "some examples," etc., indicates that the specific features, structures, materials, or characteristics described in connection with that embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in any suitable manner in one or more embodiments or examples. Without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification and the features of different embodiments or examples. Although the embodiments of the present invention and their advantages have been described in detail, it should be understood that various changes, substitutions, and modifications can be made herein without departing from the scope of protection of the patent application.

Claims

1. The use of teriflunomide in the preparation of a drug for treating ovarian cancer.

2. The application as described in claim 1, characterized in that, In the aforementioned application, teriflunomide is used to kill ovarian cancer tumor stem cells.

3. The application as described in claim 2, characterized in that, Teriflunomide effectively kills ovarian cancer stem cells by inhibiting the calcium channel Orai1, which is highly expressed in ovarian cancer, and the signaling pathway mediated by double orotic acid dehydrogenase (DHODH).

4. The application as described in claim 1, characterized in that, In the aforementioned application, teriflunomide is used to inhibit the growth of solid tumors formed from ovarian cancer stem cells.

5. The application as described in claim 1, characterized in that, In the aforementioned application, teriflunomide is used alone.

6. The application as described in claim 1, characterized in that, In the aforementioned application, teriflunomide is used as a chemotherapy sensitizer in combination with chemotherapeutic drugs to eliminate tumor drug resistance.

7. The application as described in any one of claims 2-4, characterized in that, The ovarian cancer stem cells are COV362 and / or SKOV3 tumor stem cells.

8. The application as described in claim 6, characterized in that, The chemotherapy drug is fluorouracil.

9. The application as described in any one of claims 1-6, characterized in that, In the application described, the dose of teriflunomide is 1.5 mg / kg body weight / day to 30 mg / kg body weight / day, administered every other day.

10. The application as described in claim 1, characterized in that, The drug comprises a dosage form formulated for administration via intraperitoneal injection.

11. A drug for treating ovarian cancer, characterized in that, It includes teriflunomide and a chemotherapy drug; preferably, the chemotherapy drug is fluorouracil.

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