Use of stiripentol in preparing Anti-tumor drug

Abstract

The present invention relates to the field of biopharmaceutical technology, and specifically, to use of stiripentol in preparing an anti-tumor drug. According to studies of the present invention, stiripentol, which is generally used for treating epilepsy, can reduce the activity of tumor cells in non-small cell lung cancer, colorectal cancer gastric cancer and the like, reduce the tumor volume, and prolong the survival of mice bearing a tumor, suggesting a significant anti-tumor effect. Stiripentol, when used in combination with a chemotherapeutic or a radiotherapeutic modality, can significantly enhance the anti-tumor effect, indicating a good synergistic effect.

Description

Application of stiripentol in the preparation of anti-tumor drugs Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to the application of stiripentol in the preparation of anti-tumor drugs. Background Art

[0002] Stiripentol, a new drug for the treatment of epilepsy launched in 2007, has the chemical name 4,4-dimethyl-1-(3,4-methylenedioxyphenyl)-1-penten-3-ol. French researchers have reported that adding stiripentol (Siripanto) to sodium valproate and clobazam can effectively treat severe myoclonic epilepsy of infancy. Stiripentol is a cytochrome P450 inhibitor. When used in combination with clobazam and sodium valproate, stiripentol (Siripanto) has shown efficacy in treating severe myoclonic epilepsy of infancy (SMEI). Washington University School of Medicine in Missouri, USA, believes that it is difficult to definitively determine whether stiripentol (Slipanto) reduces seizure frequency in patients undergoing combination therapy, as stiripentol's mechanism of action is to increase the blood levels of other medications, such as clobazam and sodium valproate. Stiripentol (Slipanto) has a unique mechanism of action, both increasing GABA release and inhibiting the activity of certain enzymes, thereby increasing the blood levels of other antiepileptic drugs. Stiripentol (Slipanto) was approved in the European Union in 2001 for adjunctive treatment of severe myoclonic seizures in infantile epilepsy. Stiripentol analogs targeting lactate dehydrogenase can treat epilepsy. Energy metabolism regulates neuronal excitability, so special dietary treatments may suppress drug-resistant epilepsy. A study published in the journal Science (DOI: 10.1126 / science.aaa129) found that stiripentol, an antiepileptic drug, is an inhibitor of lactate dehydrogenase A (LDHA). By modifying the chemical structure of stiripentol, the research team discovered a previously unknown LDH inhibitor that effectively suppresses epilepsy in vivo. In summary, stiripentol analogs—LDH inhibitors—are expected to become an emerging class of anti-epileptic drugs.

[0003] Lactate dehydrogenase (LDH) is a NAD-dependent kinase, a zinc-containing metalloprotein with a molecular weight of 135-140 kDa. It is a key enzyme in anaerobic glycolysis and gluconeogenesis, catalyzing the reduction and oxidation reactions between pyruvate and L-lactic acid, as well as related α-keto acids. LDH is widely present in human tissues, with the highest concentration in the kidney, followed by cardiac and skeletal muscle.

[0004] LDHA is widely overexpressed in tumor tissues, including hematologic malignancies and solid cancers. High LDH-A expression provides numerous benefits to cancer cells, such as increased invasiveness and metastasis, as well as resistance to radiation and chemotherapy. Over the past decade, numerous studies have observed the role of LDHA in promoting tumor cell metabolism, but the clinical application of LDH-A inhibitors as anticancer drugs remains unknown.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to overcome the shortcomings of the prior art and provide the use of stiripentol in the preparation of anti-tumor drugs.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] In a first aspect, the present invention provides use of stiripentol in the preparation of anti-tumor drugs.

[0009] Through research, the present invention found that stiripentol, which is used to treat epilepsy, can also reduce the survival percentage of tumor cells such as non-small cell lung cancer, colorectal cancer, and gastric cancer, can reduce the survival percentage of cells in gastric cancer organoids, can reduce the tumor volume of mice with gastric cancer tumor xenograft models, and prolong the survival time of mice, showing significant anti-tumor effects.

[0010] As a preferred embodiment of the application of the present invention, the tumor includes non-small cell lung cancer, colorectal cancer or gastric cancer.

[0011] In a second aspect, the present invention provides use of stiripentol in the preparation of a drug for reducing and / or reversing tumor drug resistance.

[0012] The present invention has found through research that stiripentol can reduce the drug resistance of tumor cells such as non-small cell lung cancer, colorectal cancer, and gastric cancer that are resistant to chemotherapy drugs (such as cisplatin).

[0013] As a preferred embodiment of the application of the present invention, the tumor includes non-small cell lung cancer, colorectal cancer or gastric cancer.

[0014] As a preferred embodiment of the application of the present invention, the chemotherapy drug is a DNA damaging chemotherapy drug.

[0015] As a preferred embodiment of the application of the present invention, the DNA damaging chemotherapy drugs include cisplatin, oxaliplatin, doxorubicin, fluorouracil or cyclophosphamide.

[0016] As a preferred embodiment of the application of the present invention, the tumor drug resistance refers to the resistance of the tumor to chemotherapy drugs.

[0017] In a third aspect, the present invention provides the use of stiripentol in the preparation of a drug for enhancing the effect of tumor radiotherapy.

[0018] The present invention has found through research that the combination of stiripentol and radiotherapy can significantly inhibit the tumor volume of tumor-bearing mice and significantly prolong the survival time of tumor-bearing mice. The combination of the two has a synergistic effect on the treatment of tumors and has the effect of significantly enhancing the effect of tumor radiotherapy.

[0019] As a preferred embodiment of the application of the present invention, the radiotherapy method includes ionizing radiation, X-knife or gamma knife.

[0020] In a fourth aspect, the present invention provides the use of stiripentol in combination with chemotherapy drugs in the preparation of anti-tumor drugs.

[0021] The present invention has found through research that stiripentol can reverse the resistance of tumor cells to chemotherapy drugs. The combination of stiripentol and chemotherapy drugs can significantly reduce the survival percentage of tumor cells, and has a more significant effect in treating tumors. Compared with the use of stiripentol and chemotherapy drugs alone, the combination of stiripentol and chemotherapy drugs has a synergistic effect on the treatment of tumors.

[0022] As a preferred embodiment of the application of the present invention, the chemotherapy drug is a DNA damaging chemotherapy drug.

[0023] As a preferred embodiment of the application of the present invention, the DNA damaging chemotherapy drugs include cisplatin, oxaliplatin, doxorubicin, fluorouracil or cyclophosphamide.

[0024] As a preferred embodiment of the application of the present invention, the stiripentol is used in combination with a chemotherapy drug, and the dosage of stiripentol is 150 mg / kg / day.

[0025] In a fifth aspect, the present invention provides an anti-tumor combination drug comprising stiripentol and a chemotherapy drug.

[0026] As a preferred embodiment of the application of the present invention, the chemotherapy drug is a DNA damaging chemotherapy drug.

[0027] As a preferred embodiment of the application of the present invention, the DNA damaging chemotherapy drugs include cisplatin, oxaliplatin, doxorubicin, fluorouracil or cyclophosphamide.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention has discovered that stiripentol, used to treat epilepsy, can reduce the activity of tumor cells in non-small cell lung cancer, colorectal cancer, gastric cancer, and other diseases, reduce tumor volume, and prolong the survival of mice bearing tumors, demonstrating significant anti-tumor effects. Stiripentol, when used in combination with chemotherapy drugs or radiotherapy, can significantly enhance the anti-tumor effect, and the combination of stiripentol with chemotherapy drugs or radiotherapy has a synergistic effect. The present invention has discovered new uses for stiripentol and expanded its application range. Furthermore, stiripentol has good clinical safety and is free of toxic side effects, providing a new option for clinical treatment of tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 shows the cell viability and IC values ​​of each tumor cell line before and after treatment with cisplatin in Example 1 of the present invention. 50 result;

[0031] FIG2 shows the effects of stiripentol and cisplatin alone or in combination on the survival percentage of cisplatin-resistant tumor cell lines in Example 1 of the present invention;

[0032] FIG3 shows the ATP activity test results of 5 organoids in Example 2 of the present invention;

[0033] FIG4 shows the effects of stiripentol and cisplatin alone or in combination on the cell survival percentage of cisplatin-resistant organoids in Example 2 of the present invention;

[0034] Figure 5 shows the effects of stiripentol and cisplatin alone or in combination on PDX-R model mice in Example 3 of the present invention; Control is a normal saline control group, Cisplatin is a cisplatin alone treatment group, Stiripentol is a stiripentol alone treatment group, and Stiripentol+Cisplatin is a stiripentol and cisplatin combined treatment group;

[0035] Figure 6 shows the effects of stiripentol and ionizing radiation (IR) alone or in combination on PDX-R model mice in Example 3 of the present invention; wherein Control is a normal saline control group, IR is an ionizing radiation alone treatment group, Stiripentol is a stiripentol alone treatment group, and Stiripentol+IR is a stiripentol and ionizing radiation combined treatment group;

[0036] Figure 7 shows the effects of four LDHA inhibitors and cisplatin in the comparative examples of the present invention, used alone or in combination, on the survival percentage of PDX-R model mice; wherein Control is a normal saline control group, Cisplatin is a cisplatin single-treatment group, FX11 is an FX11 single-treatment group, NHI-2 and NHI-2 single-treatment groups, Quinoline-3-Sulfonamide is a 3-quinolinesulfonamide single-treatment group, Oxamate is an oxamate single-treatment group, Cisplatin+FX11 is a FX11 and cisplatin combined treatment group, Cisplatin+NHI-2 is a NHI-2 and cisplatin combined treatment group, Cisplatin+Quinoline-3-Sulfonamide is a 3-quinolinesulfonamide and cisplatin combined treatment group, and Cisplatin+Oxamate is an oxamate and cisplatin combined treatment group. DETAILED DESCRIPTION

[0037] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0038] Unless otherwise specified, other materials and reagents used in the examples can be obtained from commercial sources.

[0039] Example 1 Effect of Stiripentol Combined with Cisplatin on the Efficacy of Tumor Cells

[0040] The efficacy of stiripentol combined with cisplatin was tested using a cisplatin (chemotherapeutic drug)-resistant tumor cell line model. The inventors first used the drug concentration escalation method to construct a cisplatin-resistant tumor cell line.

[0041] 1. Construction of cisplatin-resistant tumor cell lines

[0042] Tumor cell lines sensitive to the chemotherapy drug cisplatin were selected: non-small cell lung cancer cell line A549 (A549-P), colorectal cancer cell line HCT116 (HCT116-P), gastric cancer cell line AGS (AGS-P) and MGC803 cell line (MGC803-P), and the IC values ​​of each tumor cell line were tested. 50 The tumor cell lines were then plated on 10 cm culture dishes at a density of approximately 70-80%, and then a 5-well plate containing cisplatin at a concentration of IC 2 for each cell line was added. 50 One tenth (10% IC 50 The cells were treated with medium containing 10% FBS and double antibody for 48 h, and then replaced with medium without drug for 48 h; then the culture medium containing drug and medium without drug were repeatedly used to continue the culture, and the concentration of cisplatin in the medium containing drug was gradually increased (20% IC 50 , 40%IC 50、60%IC 50 , 80%IC 50 , 100% IC 50 , 200%IC 50 400% IC 50 ), cisplatin treatment time was 6 months. After 6 months, the IC 50 The tumor cell lines after treatment with A549-P, HCT116-P, AGS-P, and MGC803-P were designated as A549-R, HCT116-R, AGS-R, and MGC803-R, respectively.

[0043] Cell viability and IC of each tumor cell line before and after treatment with cisplatin 50 The results are shown in Figure 1. The results show that the IC of each tumor cell line after treatment with cisplatin 50 All reached the IC values ​​of each tumor cell line before cisplatin treatment 50 The results showed that the cisplatin-resistant tumor cell line was successfully constructed. A549-R, HCT116-R, AGS-R and MGC803-R are all cisplatin-resistant tumor cell lines.

[0044] 2. Testing the efficacy of stiripentol combined with cisplatin on cisplatin-resistant tumor cell lines

[0045] The above-mentioned successfully constructed cisplatin-resistant tumor cell lines (A549-R, HCT116-R, AGS-R and MGC803-R) were used to test the therapeutic effects of stiripentol alone, cisplatin alone and stiripentol combined with cisplatin.

[0046] A549-R, HCT116-R, AGS-R and MGC803-R were cultured in culture medium (1640 culture medium + 10% FBS + double antibody) containing different concentrations (0, 1, 5, 10, 20, 40, 80 μM) of stiripentol. After 48 hours of culture, CCK-8 drug sensitivity test was performed, the absorbance was tested, and the cell survival percentage under each culture condition was calculated.

[0047] A549-R, HCT116-R, AGS-R and MGC803-R were cultured in culture medium (1640 culture medium + 10% FBS + double antibody) containing different concentrations (0, 10, 20, 40, 80, 120, 160 μM) of cisplatin. After 48 hours of culture, CCK-8 drug sensitivity test was performed, the absorbance was tested, and the cell survival percentage under each culture condition was calculated.

[0048] Different concentrations of stiripentol and cisplatin were used together to culture A549-R, HCT116-R, AGS-R and MGC803-R cells, respectively. After 48 h of culture, CCK-8 drug sensitivity test was performed, the absorbance was tested, and the cell survival percentage under each culture condition was calculated.

[0049] The results of the effects of stiripentol and cisplatin used alone or in combination on the cell survival percentage of cisplatin-resistant tumor cell lines are shown in Figure 2. The results show that stiripentol and cisplatin used alone can significantly inhibit the survival of cisplatin-resistant tumor cell lines, and the cell survival percentage is significantly reduced, which has a significant tumor inhibitory effect and can reverse the cisplatin resistance of tumor cells; the combined use of stiripentol and cisplatin has a synergistic inhibitory effect on cisplatin-resistant tumor cell lines and can significantly reverse the cisplatin resistance of tumor cells.

[0050] Example 2 Effect of Stiripentol Combined with Cisplatin on the Efficacy of Organoid Models Derived from Tumor Patients

[0051] 1. Screening of cisplatin-resistant organoids

[0052] The inventors selected organoids from five gastric cancer patients at the Seventh Affiliated Hospital of Sun Yat-sen University and named them PDO#1, PDO#2, PDO#3, PDO#4, and PDO#5. Each of these five organoids was passaged and seeded into 96-well plates. The plates were then cultured in cisplatin-containing medium (1640 medium + 10% FBS + dual-antibody) for 72 hours, followed by ATP activity assays. The effects of drugs on organoid activity were assessed using the organoid drug-sensitive ATP activity assay.

[0053] Figure 3 shows the results of ATP activity assays in five organoids. The results show that the cell viability of organoids PDO#4 and PDO#5 treated with different concentrations of cisplatin was significantly higher than that of organoids PDO#1, PDO#2, and PDO#3, indicating that organoids PDO#4 and PDO#5 are significantly more cisplatin-resistant than those of organoids PDO#1, PDO#2, and PDO#3. Organoids PDO#4 and PDO#5 are cisplatin-resistant organoids.

[0054] 2. Testing the efficacy of stiripentol combined with cisplatin on cisplatin-resistant organoids

[0055] The screened organoids PDO#4 and PDO#5 were used to test the therapeutic effects of stiripentol alone, cisplatin alone, and the combination of stiripentol and cisplatin, respectively.

[0056] Organoids PDO#4 and PDO#5 were cultured in culture medium (1640 culture medium + 10% FBS + double antibody) containing different concentrations (0, 5, 10, 20, 40, 80, 120 μM) of stiripentol. ATP activity detection experiments were performed after 72 hours of culture, the luminescence intensity was tested, and the cell survival percentage under each culture condition was calculated.

[0057] Organoids PDO#4 and PDO#5 were cultured in culture medium (1640 culture medium + 10% FBS + double antibodies) containing different concentrations (0, 20, 40, 60, 80, 100, 120 μM) of cisplatin. ATP activity detection experiments were performed after 72 hours of culture, the luminescence intensity was tested, and the cell survival percentage under each culture condition was calculated.

[0058] Different concentrations of stiripentol and cisplatin were used together to culture organoids PDO#4 and PDO#5, respectively. ATP activity detection experiments were performed after 72 hours of culture, the luminescence intensity was tested, and the cell survival percentage under each culture condition was calculated.

[0059] The results of the effects of stiripentol and cisplatin, used alone or in combination, on the cell survival percentage of cisplatin-resistant organoids are shown in Figure 4. The results show that stiripentol and cisplatin, used alone, can significantly inhibit the survival of cisplatin-resistant organoids, and the cell survival percentage is significantly reduced, which has a significant inhibitory effect on tumor organoids and can reverse the cisplatin resistance of organoids; the combined use of stiripentol and cisplatin has a synergistic inhibitory effect on cisplatin-resistant organoids and can significantly reverse the cisplatin resistance of organoids.

[0060] Example 3 Effect of Stiripentol Combined with Cisplatin on the Efficacy of NSG Mouse Transplanted Tumor Model

[0061] The inventors collected fresh cisplatin-resistant tumor tissue from gastric cancer patients from the Seventh Affiliated Hospital of Sun Yat-sen University, transplanted the tumor tissue into immunodeficient mice (NSG mice), and then constructed a patient-derived tumor xenograft (PDX) model derived from gastric cancer patients; the cisplatin-resistant tumor tissue from gastric cancer patients, i.e., the patient-derived xenograft (PDX), was named PDX-R.

[0062] 1. Testing the efficacy of stiripentol combined with cisplatin on PDX-R model

[0063] Fresh cisplatin-resistant tumor tissues collected from gastric cancer patients were transplanted into the backs of NSG mice to obtain the PDX-R mouse model. Subsequently, stiripentol (150 mg / kg, once a day for 5 consecutive days a week) and cisplatin (2 mg / kg, once a week) were used for treatment alone or in combination (6 mice per group). The tumor volume, survival percentage, and body weight of the mice were tested after different treatment times, and the ratio of the body weight after treatment to the body weight before treatment (body weight ratio) was calculated.

[0064] The effects of stiripentol and cisplatin, alone or in combination, on PDX-R model mice are shown in Figure 5. Control represents the saline control group, Cisplatin represents the cisplatin-only treatment group, Stiripentol represents the stiripentol-only treatment group, and Stiripentol+Cisplatin represents the stiripentol-Cisplatin-combination treatment group. The results show that both stiripentol and cisplatin, when used alone, can inhibit tumor volume and significantly prolong survival in PDX-R model mice, demonstrating a significant tumor-suppressing effect. The combination of stiripentol and cisplatin exhibits a synergistic inhibitory effect on cisplatin-resistant PDX-R model mice, significantly inhibiting tumor volume and prolonging survival. There was no significant change in the body weight of PDX-R model mice with either stiripentol or cisplatin alone or in combination, indicating that stiripentol and cisplatin do not cause serious toxic side effects in mice and are therefore safe.

[0065] 2. Testing the efficacy of stiripentol combined with ionizing radiation (IR) on the PDX-R model

[0066] Combine stiripentol with ionizing radiation and other radiotherapy methods to study the therapeutic effect of stiripentol combined with radiotherapy on tumors.

[0067] Fresh cisplatin-resistant tumor tissues collected from gastric cancer patients were transplanted into the backs of NSG mice to obtain the PDX-R mouse model. Subsequently, stiripentol (150 mg / kg, once a day for 5 consecutive days a week) and ionizing radiation (IR, 2 Gy each time, once a day for 4 consecutive days a week) were used for treatment alone or in combination (6 mice per group). The tumor volume, survival percentage, and body weight of the mice were tested after different treatment times, and the ratio of the body weight after treatment to the body weight before treatment (body weight ratio) was calculated.

[0068] The effects of stiripentol and ionizing radiation (IR) alone or in combination on PDX-R model mice are shown in Figure 6, where Control is the normal saline control group, IR is the ionizing radiation alone treatment group, Stiripentol is the stiripentol alone treatment group, and Stiripentol+IR is the stiripentol and ionizing radiation combined treatment group; the results showed that stiripentol and ionizing radiation alone could inhibit the tumor volume of PDX-R model mice, significantly prolong the survival time of PDX-R model mice, and had a significant tumor inhibitory effect; the combined use of stiripentol and ionizing radiation had a synergistic effect on the inhibitory effect of cisplatin-resistant PDX-R model mice, which could more significantly inhibit the tumor volume and prolong the survival time of mice; there was no significant change in the body weight of PDX-R model mice when stiripentol and ionizing radiation were used alone or in combination, indicating that stiripentol and ionizing radiation did not cause serious toxic side effects on mice and had good safety.

[0069] The above NSG mouse transplant tumor model experiments showed that the combination of stiripentol and cisplatin can significantly reverse tumor cisplatin resistance and is safe.

[0070] Comparative test of the efficacy of different LDHA inhibitors combined with cisplatin on PDX-R model

[0071] The inventors selected four other LDHA inhibitors besides stiripentol: oxamate, FX11 (molecular formula C 22 H 22 O4), 3-quinolinesulfonamide (Quinoline-3-Sulfonamide), NHI-2 (C 17 H 12 F3NO3), respectively, were used in combination with cisplatin to test the therapeutic effects of different LDHA inhibitors in combination with cisplatin on tumors. The tumor model used was the PDX-R model constructed in Example 3.

[0072] Freshly collected cisplatin-resistant gastric cancer tumor tissue was transplanted into the backs of NSG mice to generate the PDX-R mouse model. The mice were then treated with the four LDHA inhibitors and cisplatin, either alone or in combination (n=6 mice per group), and the survival percentage of the mice was measured after different treatment durations. The LDHA inhibitor and cisplatin treatment doses were: FX11 (50 mg / kg once daily for 5 consecutive days per week), NHI-2 (25 mg / kg once daily for 5 consecutive days per week), 3-quinolinesulfonamide (30 mg / kg once daily for 5 consecutive days per week), oxamate (750 mg / kg once daily), and cisplatin (2 mg / kg once weekly).

[0073] The effects of four LDHA inhibitors and cisplatin alone or in combination on the survival percentage of PDX-R model mice are shown in Figure 7, where Control is the normal saline control group, Cisplatin is the cisplatin alone treatment group, FX11 is the FX11 alone treatment group, NHI-2 is the NHI-2 alone treatment group, Quinoline-3-Sulfonamide is the 3-quinolinesulfonamide alone treatment group, Oxamate is the oxamate alone treatment group, Cisplatin+FX11 is the FX11 and cisplatin combination treatment group, Cisplatin+NHI-2 is the NHI-2 and cisplatin combination treatment group, Cisplatin+Quinoline-3-Sulfonamide is the 3-quinolinesulfonamide and cisplatin combination treatment group, and Cisplatin+Oxamate is the oxamate and cisplatin combination treatment group;

[0074] The results showed that (1) the survival time of mice treated with FX11 alone and FX11 combined with cisplatin was significantly lower than that of the control group and the cisplatin alone group, indicating that FX11 alone could not effectively inhibit tumors, and the combination of FX11 and cisplatin could not effectively inhibit tumors, and there was no synergistic effect; the mice in the cisplatin alone group and the control group were still alive at 30 days, and the lines corresponding to the survival percentages of the two groups overlapped;

[0075] (2) The survival time of mice treated with NHI-2 alone and NHI-2 combined with cisplatin was significantly lower than that of the control group and the cisplatin alone group, indicating that NHI-2 alone could not effectively inhibit tumors, and the combination of NHI-2 and cisplatin could not effectively inhibit tumors, and there was no synergistic effect; the mice in the cisplatin alone group and the control group were still alive at 30 days, and the lines corresponding to the survival percentages of the two groups overlapped;

[0076] (3) The survival time of mice treated with 3-quinolinesulfonamide alone or in combination with cisplatin was significantly lower than that of the control group and the cisplatin alone group, indicating that 3-quinolinesulfonamide alone could not effectively inhibit tumors, and the combination of 3-quinolinesulfonamide and cisplatin could not effectively inhibit tumors, and there was no synergistic effect. Among them, the mice in the cisplatin alone group and the control group were still alive at 30 days, and the lines corresponding to the survival percentages of the two groups overlapped;

[0077] (4) The survival time of mice treated with oxamate alone or in combination with oxamate and cisplatin was significantly lower than that of the control group and the cisplatin alone group, indicating that oxamate alone could not effectively inhibit tumors, and the combination of oxamate and cisplatin could not effectively inhibit tumors, and there was no synergistic effect; among them, the mice in the cisplatin alone group and the control group were still alive at 30 days, and the lines corresponding to the survival percentages of the two groups overlapped.

[0078] In summary, the four LDHA inhibitors, oxamate, FX11, 3-quinolinesulfonamide, and NHI-2, have serious toxic side effects, causing rapid death in mice (all causing death in mice within 20 days), significantly shortening the survival time of mice, and having no obvious inhibitory effect on tumors. In addition, they also have no obvious inhibitory effect on tumors when used in combination with the chemotherapy drug cisplatin, let alone synergistic effects. This shows that not all LDHA inhibitors have the effect of inhibiting tumors, and not all LDHA inhibitors and chemotherapy drugs have a synergistic effect of inhibiting tumors.

[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. Application of stiripentol in the preparation of anti-tumor drugs.

2. Use of stiripentol in the preparation of drugs for reducing and / or reversing tumor drug resistance.

3. The use according to claim 2, characterized in that The tumor drug resistance refers to the resistance of the tumor to chemotherapy drugs.

4. The application of stiripentol in the preparation of drugs for enhancing the effect of tumor radiotherapy.

5. The use according to claim 4, characterized in that The radiotherapy methods include ionizing radiation, X-knife or gamma knife.

6. The application of stiripentol in combination with chemotherapy drugs in the preparation of anti-tumor drugs.

7. The use according to any one of claims 1 to 6, characterized in that The tumor includes non-small cell lung cancer, colorectal cancer or gastric cancer.

8. The use according to claim 3 or 6, characterized in that The chemotherapy drug is a DNA damaging chemotherapy drug.

9. The use according to claim 8, characterized in that The DNA damaging chemotherapy drugs include cisplatin, oxaliplatin, doxorubicin, fluorouracil or cyclophosphamide.

10. An anti-tumor combination drug, characterized in that: These include stiripentol and chemotherapy drugs.

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