Application of combination of 3-indoleacetic acid and temozolomide in resisting brain glioma

Abstract

The invention provides application of 3-indoleacetic acid combined with temozolomide in resisting brain glioma, and belongs to the field of biological medicine. Wherein the 3-indoleacetic acid can significantly enhance the inhibition effect of temozolomide on brain glioma cells in a short period and a long period, and can significantly enhance the apoptosis induction effect of temozolomide on the brain glioma cells, and after the 3-indoleacetic acid and temozolomide are applied to a brain glioma animal model, the 3-indoleacetic acid and temozolomide are combined, so that the inhibition effect of temozolomide on brain glioma cells is obviously improved. The 3-indoleacetic acid and temozolomide can obviously inhibit the development of brain glioma and relieve weight loss caused by temozolomide administration, so that the 3-indoleacetic acid and temozolomide have the potential of being developed into the anti-brain glioma medicine.

Description

Technical Field

[0001] The invention relates to the technical field of biomedicine, and in particular to application of 3-indoleacetic acid combined with temozolomide in treating brain glioma. Background Art

[0002] In 2022, there will be 321,000 new confirmed cases of head and nervous system cancers and 248,000 deaths worldwide, of which malignant gliomas account for more than 80%. Patients' tumors are highly heterogeneous and have extremely poor prognosis, with a median survival of 14.6 months and a five-year survival rate of only 6.8%. According to the latest "NCCN Central Nervous System Cancer Diagnosis and Treatment Guidelines (2024 Edition)" released by the National Comprehensive Cancer Network of the United States and the "Guidelines for the Diagnosis and Treatment of Glioma (2024 Edition)" released by the Chinese Anti-Cancer Association, temozolomide is used as the first chemotherapy drug for malignant gliomas. However, the clinical efficacy of temozolomide is less than 50%, and drug resistance is serious. It is often used in combination with other treatments, and the median progression-free survival of patients is only 5.4 months. In addition to traditional MGMT-positive mutations, existing studies have shown that other biological processes in tumor tissues, such as autophagy and angiogenesis, can affect the efficacy of temozolomide. Despite this, there is currently a lack of effective means to overcome temozolomide resistance and improve its clinical efficacy.

[0003] The intestinal flora can receive signals from the external environment and food, convert them into signal molecules such as metabolites, and achieve signal transduction between the host and the circulatory system. It plays an important role in the human immune, metabolic, nutritional and nervous systems and is an indispensable component of the body. It has been confirmed that the intestinal flora can convert dietary tryptophan into tryptophan, kynurenine and indole substances. Tryptophan and its metabolites are one of the important factors affecting the immune microenvironment of glioma. Among them, tryptophan indole metabolites of intestinal flora include indole (IN, CAS: 120-72-9), indolepropionic acid (IPA, CAS: 830-96-6), indole-3-acetic acid (ILA, CAS: 832-97-3), indole-3-carboxaldehyde (I3A, CAS: 487-89-8) and 3-indoleacetic acid (IAA, CAS: 87-51-4).

[0004] At present, no studies at home or abroad have shown that tryptophan metabolites and temozolomide have synergistic anti-glioma activity, nor have there been any reports on their combined use with temozolomide. Summary of the invention

[0005] In view of the technical problems existing in the background technology, the present invention provides an application of 3-indoleacetic acid combined with temozolomide in treating brain glioma, aiming to solve the problems that temozolomide is not effective in treating brain glioma and has toxic side effects.

[0006] In the first aspect, the present invention provides the use of 3-indoleacetic acid combined with temozolomide in the preparation of an anti-glioma drug. Experiments have shown that temozolomide and 3-indoleacetic acid alone have very limited effects on glioma, but the combination of the two can play a synergistic anti-glioma effect and significantly inhibit the development of glioma.

[0007] Preferably, in the above application, the molar ratio of 3-indoleacetic acid to temozolomide in vivo is (1:5)-(5:3).

[0008] In a second aspect, the present invention provides a method for treating glioma cells with 3-indoleacetic acid in combination with temozolomide, comprising at least: 1) 3-Indoleacetic acid combined with temozolomide to prepare products for inhibiting the proliferation of brain glioma cells; 2) 3-Indoleacetic acid is combined with temozolomide to prepare a product that induces apoptosis of brain glioma cells.

[0009] Different from other tryptophan indole metabolites, 3-indoleacetic acid can significantly enhance the inhibitory effect of temozolomide on glioma cells in both the short and long term, and can significantly enhance the apoptosis-inducing effect of temozolomide on glioma cells. Therefore, 3-indoleacetic acid combined with temozolomide has the potential to be developed into a product that inhibits the proliferation of glioma cells or induces apoptosis of glioma cells.

[0010] In a third aspect, the present invention provides the use of 3-indoleacetic acid in the preparation of a drug for reducing the toxic and side effects of temozolomide. Animal experiments show that 3-indoleacetic acid can effectively alleviate the weight loss of mice caused by temozolomide administration, which shows that 3-indoleacetic acid can reduce the toxic and side effects of temozolomide on the body.

[0011] In a fourth aspect, the present invention provides a pharmaceutical composition for treating brain glioma, comprising 3-indoleacetic acid and temozolomide; preferably, the molar ratio of 3-indoleacetic acid to temozolomide in the pharmaceutical composition is (1:5)-(5:3).

[0012] It is understandable that the above-mentioned pharmaceutical composition may also contain a pharmaceutically acceptable carrier or excipient, which may be solid, semi-solid or liquid, and the dosage form of the pharmaceutical composition includes but is not limited to tablets, granules, capsules, pills, transdermal microneedle preparations, oral liquids, injections, etc.

[0013] Compared with the prior art, the present invention has the following beneficial effects: The present invention studies the potential mechanism of the low clinical efficacy of temozolomide and finds that tryptophan metabolites of intestinal flora may be an important influencing factor affecting the efficacy of temozolomide. The influence of intestinal flora indole metabolites on the anti-glioma effect of temozolomide is further screened and verified. It is found for the first time that 3-indoleacetic acid combined with temozolomide can play a synergistic anti-glioma effect, which can not only significantly inhibit the development of glioma, but also effectively alleviate the toxic and side effects caused by the administration of temozolomide, providing a new idea for the treatment of glioma. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the technical solution of the present invention, the following is a brief introduction to the drawings used in the present invention. Obviously, the drawings described below are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained based on these drawings without creative work.

[0015] Figure 1 This is a graph showing the results of the detection of the inhibitory effect (72 hours) of the same concentration of 3-indoleacetic acid combined with different concentrations of temozolomide on the proliferation of brain glioma cells GL261 in the examples of the present invention; Figure 2 This is a graph showing the results of the long-term inhibitory effect (7 days) of indole-3-acetic acid, indole-3-carboxaldehyde and 3-indoleacetic acid combined with different concentrations of temozolomide on the proliferation of brain glioma cells GL261 in the examples of the present invention; Figure 3 The figure is a result of detecting the apoptosis induction effect of indole-3-acetic acid, indole-3-formaldehyde and 3-indoleacetic acid combined with different concentrations of temozolomide on brain glioma cells GL261 in the embodiment of the present invention; Figure 4 The figure is a weight change trend diagram of each group of mice in the embodiment of the present invention; wherein, Model represents the model group, TMZ represents the temozolomide administration group, IAA represents the 3-indoleacetic acid administration group, and IAA-TMZ represents the 3-indoleacetic acid and temozolomide combined administration group; Figure 5 Statistical graphs of tumor fluorescence intensity of mice in each group in the embodiment of the present invention; wherein Model represents the model group, TMZ represents the temozolomide administration group, IAA represents the 3-indoleacetic acid administration group, and IAA-TMZ represents the 3-indoleacetic acid and temozolomide combined administration group; Figure 6 This is a graph showing the results of the detection of the inhibitory effects (72 hours) of different concentrations of indole and indolepropionic acid combined with different concentrations of temozolomide on the proliferation of brain glioma cells GL261 in the examples of the present invention; Figure 7This is a graph showing the results of the detection of the inhibitory effect (72 hours) of different concentrations of indole-3-acetic acid and indole-3-carboxaldehyde combined with different concentrations of temozolomide on the proliferation of brain glioma cells GL261 in the examples of the present invention. DETAILED DESCRIPTION

[0016] The following embodiments of the technical solution of the present invention are described in detail in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present invention, and are therefore only used as examples, and cannot be used to limit the protection scope of the present invention.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by technicians in the technical field to which the present invention belongs; the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention; the terms "including" and "having" and any variations thereof in this document are intended to cover non-exclusive inclusions.

[0018] Some specific examples are listed below. It should be noted that the examples described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be obtained commercially.

[0019] The GL261 glioma cell line used in the following examples was purchased from Shanghai Tongpai Biotechnology Co., Ltd. and cultured in a medium containing 10% FBS and 90% DMEM high glucose. The SPF-grade male C57BL / 6J mice used in the following examples were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

[0020] Example 1 This case tested the inhibitory effect of 3-indoleacetic acid combined with temozolomide on the proliferation of brain glioma cells. The specific experimental process is as follows: (1) Culture of GL261 glioma cells.

[0021] Cell recovery: Take the GL261 cells frozen in liquid nitrogen to a 37°C constant temperature water bath, shake to quickly warm them up and melt, quickly transfer them to a centrifuge tube containing 1 mL of culture medium, centrifuge at 1000 rpm for 5 min, discard the supernatant, add 1 mL of culture medium to resuspend the cells, transfer them to a T25 culture flask containing 5 mL of culture medium, shake well, and culture in a 37°C, 5% CO2 constant temperature cell culture incubator.

[0022] Cell passaging: When the healing rate of GL261 cells is 80-90%, discard the culture medium, wash twice with PBS, add 1 mL of 0.25% trypsin solution (containing EDTA), and digest at 37°C for 1 min. When the cells begin to slide like sand, quickly add 1 mL of culture medium to terminate the digestion, and gently blow to collect the cell suspension into a 5 mL centrifuge tube. Centrifuge at 800 rpm for 3 min and perform the same operation as the above "cell recovery".

[0023] (2) MTT cell proliferation assay.

[0024] GL261 cells in the logarithmic growth phase were collected after trypsin digestion and seeded in 96-well plates at a density of 800 cells / well. The temozolomide group was given different concentrations of temozolomide (TMZ: 300 / 500 μM), and the 3-indoleacetic acid group was given different concentrations of 3-indoleacetic acid (IAA: 100 / 500 μM). The drug concentrations of the combination group were set to cross the above concentrations; the solvent was the basal medium. After the cells were seeded in 96-well plates and cultured overnight at 5% CO2 and 37°C, the control group was replaced with fresh medium, and the drug-containing medium was replaced with fresh medium in the drug-treated group, and then incubated in an incubator at 5% CO2 and 37°C for 72 hours. After that, 20 μL of 5 mg / mL MTT solution was added to each well, and the wells were incubated in an incubator at 5% CO2 and 37°C for 4 hours. After that, the solution in the wells was aspirated, re-dissolved with 150 μL DMSO, and placed on a microplate oscillator at 500 rpm for 10 min. Finally, the absorbance value of each well was measured at a wavelength of 570 nm, and the inhibition rate was calculated according to the following formula: cell growth inhibition rate (%) = [1-(OD drug group-OD blank group) / (OD control group-OD blank group)] × 100%.

[0025] The inhibition rate test results are as follows Figure 1 As shown in the figure, C represents normal control, T1 represents temozolomide 300 μM, T2 represents temozolomide 500 μM, IAA represents 3-indoleacetic acid administration, IAA+T1 / T2 represents 3-indoleacetic acid and temozolomide combined administration, vs T1, # vs T2. Figure 1 It can be seen that the combination of 3-indoleacetic acid and temozolomide can inhibit the proliferation of GL261 cells.

[0026] The evaluation was conducted using the Jin Zhengjun Q value method (Jin Zhengjun's Additive Effects in Combined Use of Drugs [J]. Acta Pharmacologica Sinica, 1980), which is recognized in the art, i.e., Q=MAB / (MA+MB-MA×MB), where the numerator represents the "measured combined effect" and the denominator represents the "expected combined effect", and MA, MB, and MAB represent the inhibition rate of drug A, the inhibition rate of drug B, and the inhibition rate of the combination of the two drugs at the current dose, respectively. The drug synergy index Q is defined as follows: when the Q value is less than 0.85, the two drugs are considered to have an antagonistic effect; when the Q value is between 0.85 and 1.15, the two drugs are considered to be independent of each other and have an additive effect; when the Q value is greater than 1.15, the two drugs are considered to have a synergistic effect.

[0027] According to the above method, the average Q value of 3-indoleacetic acid combined with temozolomide is shown in Table 1, which shows that 3-indoleacetic acid and temozolomide have obvious synergistic effect on the inhibitory activity of GL261 cell proliferation (Q>1.15).

[0028] Table 1 The Q value results of Jin Zhengjun after 3-indoleacetic acid combined with temozolomide

[0029] (3) Plate cloning experiment.

[0030] GL261 cells in the logarithmic growth phase were collected after trypsin digestion and seeded in 6-well plates at a density of 800 cells / well. The temozolomide group was given different concentrations of temozolomide (TMZ: 30 / 50 μM), and the 3-indoleacetic acid group was given 3-indoleacetic acid (IAA: 500 μM). The drug concentrations of the combination group were set to the above concentrations in pairs; the solvent was used as the basal medium. After the cells were seeded in 6-well plates and cultured overnight at 5% CO2 and 37°C to adhere to the wall, the control group was replaced with fresh medium, and the drug group was replaced with fresh medium containing drugs. They were continued to be incubated in an incubator at 5% CO2 and 37°C for 7 days, and fresh medium containing drugs was replaced every 2 days. After obvious cell clones were formed, the supernatant was discarded, 1 mL PBS was added to each well for washing twice, and then 1-2 mL 4% paraformaldehyde was added for fixation for 60 min. After discarding the paraformaldehyde, 1 mL of 0.1% crystal violet solution was added to each well for staining for 3-5 min, and then each well was washed twice with PBS until the water became transparent and photographed after air drying.

[0031] The results are as follows Figure 2 As shown, C represents normal control, T1 represents 30 μM temozolomide, T2 represents 50 μM temozolomide, ILA / I3A / IAA represents administration of indole metabolites, and ILA / I3A / IAA+T1 / T2 represents combined administration of indole metabolites and temozolomide. vs T1, # vs T2. Figure 2 It can be seen that 3-indoleacetic acid can significantly enhance the inhibitory effect of temozolomide on the long-term proliferation of GL261 cells.

[0032] (4) Cell apoptosis detection.

[0033] GL261 cells in the logarithmic growth phase were collected after trypsin digestion and the cells were collected at 3×10 4 Cells were inoculated into 6-well plates at a density of 100 cells / well. The temozolomide group was given different concentrations of temozolomide (TMZ: 300 / 500 μM), the 3-indoleacetic acid group was given 3-indoleacetic acid (IAA: 500 μM), and the drug concentrations of the combination group were set to the above concentrations in pairs; the solvent was used as the basal medium. After the cells were inoculated into 6-well plates and cultured overnight at 5% CO2 and 37°C to adhere to the wall, the control group was replaced with fresh medium, and the drug-containing medium was replaced with fresh medium, and the cells were placed in an incubator at 5% CO2 and 37°C for 72 hours. The cell culture medium was collected in a 2 mL EP tube and centrifuged at 1000 rpm for 5 min, and the supernatant was discarded. Then 500 μL of trypsin solution was added to the 6-well plate, and after digestion at room temperature for 2 min, an equal amount of DMEM medium was added to terminate the digestion, and then the cell suspension was added to the above 2 mL EP tube, centrifuged at 1000 rpm for 5 min, and the supernatant was discarded. Then rinse twice with 500 μL pre-cooled PBS by centrifugation, and discard the supernatant. Add 500 μL 1× Binging Buffer to each tube to resuspend the cells, add 5 μL Annexin V-FITC and 10 μL PI to each tube, mix well, and incubate at room temperature in the dark for 5 minutes. Finally, perform flow cytometry analysis according to the experimental method.

[0034] Test results such as Figure 3 As shown in the figure, C represents the normal control, T1 represents 300 μM temozolomide, T2 represents 500 μM temozolomide, ILA / I3A / IAA represents the administration of indole metabolites, and ILA / I3A / IAA+T1 / T2 represents the combined administration of indole metabolites and temozolomide. vs T1, # vs T2. Figure 3 It can be seen that 3-indoleacetic acid can significantly enhance the apoptosis-inducing effect of temozolomide on GL261 cells.

[0035] Example 2 This case demonstrated the synergistic anti-glioma activity of 3-indoleacetic acid and temozolomide through animal experiments, as follows: Animal husbandry: C57BL / 6J mice were housed in a barrier environment IVC system with a ventilation rate of 17 times / hour, an ambient temperature of 24±2℃, a relative humidity of 50-60%, and a 12 h / 12 ​​h day and night cycle; the animals had free access to sterile tap water, cobalt-60 irradiated sterilized feed, and sterilized corn cob bedding.

[0036] Modeling: 5-6 week old male C57 BL / 6 mice (18-22 g) were anesthetized with isoflurane inhalation, and 4 μL Luci-GL261 (GL261 cells were transferred with the firefly luciferase gene-LV16-NC, so that they produce bioluminescence when injected with firefly luciferin substrate in the animal body, which is used to detect tumor development) cell suspension (about 1000 cells) was injected into the striatum. Five days after injection, the tumor formation results were detected by in vivo bioluminescence imaging system (IVIS, USA), and tumor growth was monitored by bioluminescence imaging during the experiment.

[0037] Grouping and administration: 24 mice were randomly divided into model group (Model), temozolomide group (TMZ), 3-indoleacetic acid intervention group (IAA) and 3-indoleacetic acid combined with temozolomide group (IAA-TMZ); TMZ administration method: intragastric administration of 50 mg / kg, once a day; 3-indoleacetic acid administration method: intragastric administration of 50 mg / kg, once a day.

[0038] Animal experiment results Figure 4-5 As shown in Table 2, the use of temozolomide and 3-indoleacetic acid alone could not significantly inhibit the development of mouse tumors. Compared with mice treated with 3-indoleacetic acid and temozolomide alone, the combined use of the two drugs could significantly inhibit the development of mouse brain gliomas and reduce the weight loss of mice caused by temozolomide administration, that is, the two drugs could synergistically inhibit brain gliomas and reduce the toxicity of temozolomide.

[0039] Table 2 The anti-glioma effect of IAA combined with TMZ is enhanced

[0040] Comparative Example 1 In this example, tryptophan indole metabolites indole and indolepropionic acid were used to replace 3-indoleacetic acid in Example 1, and their effects on brain glioma cell proliferation when used alone or in combination with temozolomide were detected, as follows: GL261 cells in the logarithmic growth phase (culture method is the same as in Example 1) were collected after trypsin digestion, and seeded in a 96-well plate at a density of 800 cells / well. The temozolomide group was given different concentrations of temozolomide (TMZ: 300 / 500 μM), and the indole or indolepropionic acid group was given different concentrations of indole (IN: 50 / 500 μM) or indolepropionic acid (IPA: 50 / 500 μM). The drug concentrations of the combination group were set to cross the above concentrations; the solvent was the basal culture medium. Subsequent culture and detection were completely consistent with step (2) of Example 1.

[0041] The inhibition rate test results are as follows Figure 6 As shown in the figure, C represents the normal control, T1 represents 300 μM temozolomide, T2 represents 500 μM temozolomide, IN / IPA represents the administration of indole metabolites, and IN / IPA+T1 / T2 represents the combined administration of indole metabolites and temozolomide. vs T1, # vs T2. The average Q values ​​of indole or indolepropionic acid combined with temozolomide are shown in Table 3. From these results, it can be seen that neither indole nor indolepropionic acid can synergistically enhance the inhibitory effect of temozolomide on the proliferation of GL261 cells (Q < 1.15).

[0042] Table 3 The Q value results of the combination of indole or indole propionic acid with temozolomide

[0043] Comparative Example 2 In this example, tryptophan indole metabolites indole-3-acetic acid and indole-3-carboxaldehyde were used to replace the 3-indoleacetic acid in Example 1, and their effects on the proliferation of brain glioma cells when used alone or in combination with temozolomide were detected, as follows: (1) Cultivation of brain glioma GL261 cells is the same as step (1) of Example 1.

[0044] (2) MTT cell proliferation assay.

[0045] GL261 cells in the logarithmic growth phase (culture method is the same as in Example 1) were collected after trypsin digestion, and seeded in a 96-well plate at a density of 800 cells / well. The temozolomide group was given different concentrations of temozolomide (TMZ: 300 / 500 μM), and the indole-3-acetic acid or indole-3-formaldehyde group was given different concentrations of indole-3-acetic acid (ILA: 100 / 800 μM) or indole-3-formaldehyde (I3A: 100 / 500 μM). The drug concentrations of the combination group were set to be crossed in pairs; the solvent was the basal medium. Subsequent culture and detection were completely consistent with step (2) of Example 1.

[0046] The inhibition rate test results are as follows Figure 7 As shown in the figure, C represents the normal control, T1 represents 300 μM temozolomide, T2 represents 500 μM temozolomide, ILA / I3A represents the administration of indole metabolites, and ILA / I3A / +T1 / T2 represents the combined administration of indole metabolites and temozolomide. vs T1, # vs T2. The average Q values ​​of Jin Zheng after indole-3-acetic acid or indole-3-carboxaldehyde combined with temozolomide are shown in Table 4. From these results, it can be seen that indole-3-acetic acid (ILA), indole-3-carboxaldehyde (I3A) and temozolomide (TMZ) have obvious synergistic effects on the inhibitory activity of GL261 cell proliferation (Q>1.15).

[0047] Table 3 The Q value results of the combination of indole or indole propionic acid with temozolomide

[0048] (3) Plate cloning experiment.

[0049] GL261 cells in the logarithmic growth phase were collected after trypsin digestion and seeded in a 6-well plate at a density of 800 cells / well. The temozolomide group was given different concentrations of temozolomide (TMZ: 30 / 50 μM), and the indole-3-acetic acid or indole-3-formaldehyde group was given indole-3-acetic acid (ILA: 800 μM) or indole-3-formaldehyde (I3A: 500 μM). The drug concentrations of the combination group were set to be crossed with the above concentrations; the solvent was the basal medium. Subsequent culture and detection were completely consistent with step (3) of Example 1.

[0050] Results Figure 2 Although high concentrations of indole-3-acetic acid or indole-3-carboxaldehyde can also enhance the inhibitory effect of temozolomide on the long-term proliferation of GL261 cells, the effect is significantly inferior to that of 3-indoleacetic acid.

[0051] (4) Cell apoptosis detection.

[0052] GL261 cells in the logarithmic growth phase were collected after trypsin digestion and the cells were collected at 3×10 4 The cells were inoculated into 6-well plates at a density of 100 cells / well. The temozolomide group was given different concentrations of temozolomide (TMZ: 300 / 500 μM), the indole-3-acetic acid or indole-3-carboxaldehyde group was given indole-3-acetic acid (ILA: 800 μM) or indole-3-carboxaldehyde (I3A: 500 μM), and the drug concentrations of the combination group were set to be crossed with the above concentrations; the solvent was the basal medium. Subsequent culture and detection were completely consistent with step (4) of Example 1.

[0053] The results are as follows Figure 3 As shown in the results, indole-3-formaldehyde could not enhance the apoptosis-inducing effect of TMZ on GL261 cells, while indole-3-acetic acid could enhance its apoptosis-inducing effect to a certain extent, but the effect was significantly weaker than that of IAA.

[0054] In summary, the combination of 3-indoleacetic acid and temozolomide can exert a synergistic anti-glioma effect and alleviate the weight loss of mice caused by temozolomide. It can be seen that 3-indoleacetic acid combined with temozolomide has the potential to be developed into an anti-glioma drug.

[0055] It should be noted that the present invention is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and the embodiments having the same structure as the technical idea and exerting the same effect within the scope of the technical solution of the present invention are all included in the technical scope of the present invention. In addition, without departing from the scope of the main purpose of the present invention, various modifications that can be thought of by those skilled in the art to the embodiments and other methods of combining some of the constituent elements in the embodiments are also included in the scope of the present invention.

Claims

Application of 1.3-indoleacetic acid combined with temozolomide in the preparation of anti-glioma drugs.

2. The use according to claim 1, characterized in that: The molar ratio of 3-indoleacetic acid to temozolomide is (1:5)-(5:3).

3. The use according to claim 1, characterized in that: The anti-glioma drug also contains a pharmaceutically acceptable carrier or excipient, and its dosage form is any one of tablets, granules, capsules, pills, transdermal microneedle preparations, oral liquids or injections. 4.3-Application of indoleacetic acid combined with temozolomide in the preparation of products for inhibiting the proliferation of brain glioma cells. 5.3-Application of indoleacetic acid combined with temozolomide in the preparation of products for inducing apoptosis of brain glioma cells. 6.3-Application of indoleacetic acid in the preparation of drugs for reducing the toxic and side effects of temozolomide.

7. A pharmaceutical composition for treating brain glioma, characterized in that: Contains 3-indoleacetic acid and temozolomide.

8. The pharmaceutical composition according to claim 7, characterized in that The molar ratio of 3-indoleacetic acid to temozolomide is (1:5)-(5:3).

9. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition contains pharmaceutically acceptable carriers or excipients.

10. The pharmaceutical composition according to claim 7, characterized in that The dosage form of the pharmaceutical composition is any one of tablets, granules, capsules, pills, transdermal microneedle preparations, oral liquids or injections.

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