Use of a pharmaceutical composition comprising GL-V9 and a chemotherapeutic agent as active ingredients for treating tumors

Abstract

The application discloses application of a pharmaceutical composition taking GL-V9 and a chemotherapeutic drug as active ingredients in treatment of tumors. When GL-V9 is combined with a classical chemotherapeutic drug to treat tumors, a drug synergistic effect can be obviously achieved, and the effect is obviously superior to combination of similar drugs and the chemotherapeutic drug. The chemotherapeutic drugs include 5-fluorouracil; and the tumor types include leukemia, colorectal cancer and lung cancer.

Description

Technical Field

[0001] This invention is a divisional application of application number 202311421137.X, entitled "Use of a pharmaceutical composition with GL-V9 and a chemotherapy drug as active ingredients in the treatment of tumors". This invention relates to the application of a pharmaceutical composition, specifically to the use of a pharmaceutical composition with GL-V9 and a chemotherapy drug as active ingredients in the treatment of tumors. Background Technology

[0002] Due to their potential for clinical application in cancer treatment, HSP90 inhibitors are not only constantly being developed into new drugs, but their combined use with chemotherapy drugs to improve the efficacy of cancer treatment is also an important aspect of research and application. Currently, the following combinations of HSP90 inhibitors have been disclosed: onalespib combined with a PARP1 inhibitor for the treatment of breast cancer [Reference: PMID: 34887522], 17-AAG combined with cisplatin for the treatment of ovarian cancer [Reference: PMID: 33331136], etc. However, the research on these HSP90 inhibitors has limited their clinical application due to certain limitations. For example, the research progress on 17-AAG has been slowed due to its poor water solubility and low bioavailability; and the research on Ganetespib has even been considered futile. Therefore, the development of novel HSP90 inhibitors is of great significance for advancing their clinical treatment and application.

[0003] GL-V9 is a novel flavonoid compound that has shown good therapeutic effects on various tumors and has been identified as a novel HSP90 inhibitor [Reference: PMID: 33143000]. However, no studies have yet revealed whether GL-V9, as an HSP90 inhibitor, can have a synergistic effect with chemotherapy drugs. Therefore, this invention, based on the aforementioned existing research techniques on HSP90, compares the application of GL-V9 in combination with chemotherapy drugs in various tumors, revealing its effectiveness and superiority. Summary of the Invention

[0004] Objective of the Invention: The objective of this invention is to provide a compound pharmaceutical composition with GL-V9 and commonly used clinical chemotherapy drugs as active ingredients. Another objective of this invention is to provide the application of the said pharmaceutical composition in leukemia, lung cancer, and colorectal cancer.

[0005] Technical solution: A pharmaceutical composition with HSP90 inhibitors and chemotherapy drugs as active ingredients.

[0006] The pharmaceutical composition wherein the HSP90 inhibitor is GL-V9, Onalespib, Luminespib, 17-AAG, or Ganetespib; and the chemotherapeutic agent is a PARP1 inhibitor, capecitabine, irinotecan, sorafenib, cisplatin, or 5-fluorouracil.

[0007] The pharmaceutical composition wherein the GL-V9 comprises a GL-V9 compound or a pharmaceutically acceptable salt thereof.

[0008] The application of the pharmaceutical composition in the preparation of a drug for treating tumors, wherein the tumors are leukemia, lung cancer, and colorectal cancer.

[0009] The application of GL-V9 in combination with chemotherapy drugs in the preparation of drugs for treating leukemia. The chemotherapy drugs are PARP1 inhibitors, capecitabine, irinotecan, sorafenib, cisplatin, or 5-fluorouracil.

[0010] The application of GL-V9 in combination with chemotherapy drugs in the preparation of drugs for treating lung cancer. The chemotherapy drugs are PARP1 inhibitors, capecitabine, irinotecan, sorafenib, cisplatin, or 5-fluorouracil.

[0011] The application of GL-V9 in combination with chemotherapy drugs in the preparation of drugs for treating colorectal cancer. The chemotherapy drugs are PARP1 inhibitors, capecitabine, irinotecan, sorafenib, cisplatin, or 5-fluorouracil.

[0012] Application of Ganetespib and 5-fluorouracil in the preparation of drugs for treating colon cancer.

[0013] The use of 17-AGG in combination with cisplatin, Ganettespib and 5-fluorouracil, Luminespib and capecitabine, PARP1 inhibitors and Onelespib, Luminespib and irinotecan, and Luminespib and sorafenib in the preparation of drugs for the treatment of leukemia.

[0014] Application of 17-AGG in combination with cisplatin, PARP1 inhibitors and Onelespib in the preparation of drugs for treating lung cancer.

[0015] The pharmaceutical composition according to claim 1 is formulated by adding pharmaceutically acceptable excipients.

[0016] The pharmaceutical composition, wherein the dosage form of the preparation includes tablets, capsules, powders, powder for injection, granules, powders, oral liquids, and syrups.

[0017] Preferably, a pharmaceutical composition comprises GL-V9 and a chemotherapeutic drug as active ingredients. The chemotherapeutic drug is a PARP1 inhibitor, capecitabine, irinotecan, sorafenib, cisplatin, or 5-fluorouracil.

[0018] Application of GL-V9 in the preparation of chemotherapy drug enhancers.

[0019] Beneficial Effects: Compared with existing technologies, this invention has the following advantages: GL-V9, when used in combination with several chemotherapeutic drugs (PARP1 inhibitors, capecitabine, irinotecan, sorafenib, cisplatin, or 5-fluorouracil), can exert a synergistic effect in the treatment of leukemia, colorectal cancer, and lung cancer. At concentrations / doses where GL-V9 or other HSP90 inhibitors are ineffective or have only mild effects on tumors when used alone, the synergistic effect of GL-V9 with the aforementioned chemotherapeutic drugs is significantly stronger than that of other HSP90 inhibitors. Compound drug compositions with GL-V9 and chemotherapeutic drugs as active ingredients show promising application prospects. Detailed Implementation

[0020] 1.1 Experimental Materials 1.1.1 Reagents and Materials ① Compounds GL-V9, provided by China Pharmaceutical University, is a pale yellow powder with a purity >95%. Before use, the compound powder should be prepared into a 0.01 M stock solution using dimethyl sulfoxide and stored at -80°C. When using, dilute to the required concentration using the appropriate cell culture medium. The structural formula of GL-V9 is as follows:

[0021] HSP90 inhibitors: Onalespib, Luminespib, 17-AAG and Ganetspib were purchased from MedChemExpress.

[0022] Chemotherapy drugs: PARP1 inhibitors, capecitabine, irinotecan, sorafenib, cisplatin, and 5-fluorouracil were purchased from MedChemExpress.

[0023] MTT: Yellow powder, purchased from Yisheng Biotechnology.

[0024] ② Cell lines Human leukemia cell lines Jurkat, ME1 and THP1, colorectal cancer cell line (HCT116) and lung cancer cell line (H1975) were all purchased from the Shanghai Institute of Cell Biology, Chinese Academy of Sciences.

[0025] ③ Cell culture reagents RPMI-1640, IMDM, and DMEM liquid culture media were purchased from Jiangsu Kaiji Biotechnology Co., Ltd. Fetal bovine serum (GIBCO, Carlsbad, CA, USA) was stored at -20°C. Before use, it was inactivated in a 56°C water bath for 35 min, then aliquoted and stored at 4°C for one week. When using, the fetal bovine serum was mixed with the culture medium at a ratio of 1:10.

[0026] 1.1.2 Experimental Apparatus YJ-875 Medical Clean Bench (Clean Equipment Factory, Suzhou, China); 3111 Water-jacketed CO2 Incubator (ThermoFisher Scientific, Waltham, MA, USA); 702 Ultra-low Temperature Freezer (ThermoFisher Scientific); Electronic Balance (Sartorius Instrument Systems Co., Ltd., Beijing, China); QIUJING Hemocytometer (Qiujing Biochemical Reagent Instrument Co., Ltd., Shanghai, China); LD4-2 General Centrifuge (Medical Centrifuge Factory, Shanghai, China); 5417R Benchtop Refrigerated High-Speed ​​Centrifuge (Eppendorf AG, Hamburg, Germany); Research Single-Channel Adjustable Pipette (Eppendorf AG); THZ-312 Benchtop Thermostatic Shaker (Jinghong Test Equipment Co., Ltd., Shanghai, China); Varioskan Full-Wavelength Microplate Reader (ThermoFisher Scientific).

[0027] 1.2 Experimental Methods 1.2.1 Cell Viability Assay: The principle is that MTT can be reduced by mitochondrial dehydrogenases in cells to form blue-purple formazan crystals. The optical density (OD) value at 570 nm is measured and compared to reflect the relative level of cell viability. The procedure is as follows: 100 µL of cell suspension (5000 cells / well) is uniformly cultured in 96-well plates. For suspension cells, 50 µL of a specific concentration of HSP90 inhibitor / GL-V9 and 50 µL of a specific concentration of chemotherapeutic agent are added immediately after cell addition; for adherent cells, the two drugs are added after cell adhesion and growth, finally reaching the final therapeutic concentration. Cells are cultured in a 37°C, 5% CO2 incubator; after 48 h of drug treatment, 15 µL of MTT solution is added to each well. After incubation for 3 h, the OD value at 570 nM is measured using a microplate reader to calculate cell viability before and after drug administration.

[0028] 1.2.2 Combination Index CI Analysis: The principle of medium efficiency was adopted, and calculations were performed using Compusyn software. Average CI The evaluation of the intervals and interactions is shown in Table 1.

[0029]

[0030] Example 1

[0031] Taking three highly representative leukemia cells, Jurkat, THP1, and ME1, as the research objects, comparing the combination of the publicly disclosed HSP90 inhibitor 17-AGG and cisplatin, and studying the therapeutic effect of the combination of GL-V9 and cisplatin on inhibiting leukemia. As shown in Table 2, it is the inhibition level (0 < Effect < 1) of GL-V9, 17-AGG, and cisplatin on leukemia cells when acting alone. As shown in Table 3, it is the inhibition rate and combination index of the combination of 17-AGG and cisplatin on leukemia cells; as shown in Table 4, it is the inhibition rate and combination index of the combination of GL-V9 and cisplatin on leukemia cells.

[0032]

[0033]

[0034] As shown in Table 3, when 17-AAG and cisplatin are used in combination to treat leukemia, with cisplatin at 1.0 μM, 17-AAG has strong or relatively strong synergistic effects at 0.01563 - 0.125 μM. With cisplatin at 2.0 μM, 17-AAG has relatively strong synergistic effects at 0.01563 - 0.125 μM. With cisplatin at 4.0 μM, 17-AAG has moderate or relatively strong synergistic effects at 0.01563 - 0.0625 μM.

[0035]

[0036] As shown in Table 4, when GL-V9 and cisplatin are used in combination to treat leukemia, with cisplatin at 1.0 - 4.0 μM, GL-V9 has synergistic effects at 0.25 - 4.0 μM.

[0037] In summary, the results confirm that the combination of GL-V9 and cisplatin can have strong or relatively strong synergistic effects on leukemia cells Jurkat, and the overall combined effect is stronger than that of the combination of 17-AAG and cisplatin, proving the advantage of the combination of GL-V9 and cisplatin in preparing a pharmaceutical composition for treating leukemia.

[0038] Example 2

[0039] Taking three highly representative leukemia cells, Jurkat, THP1, and ME1, as the research objects, and comparing the combination of the publicly available technology HSP90 inhibitor Ganetespib and 5-fluorouracil, the therapeutic effect of the combination of GL-V9 and 5-fluorouracil in inhibiting leukemia was studied. As shown in Table 5, it is the inhibition level (0 < Effect < 1) of leukemia cells under the individual action of GL-V9, Ganetespib, and 5-fluorouracil. As shown in Table 6, it is the inhibition rate and combination index of leukemia cells after the combined use of Ganetespib and 5-fluorouracil; as shown in Table 7, it is the inhibition rate and combination index of leukemia cells after the combined use of GL-V9 and 5-fluorouracil.

[0040]

[0041]

[0042] As shown in Table 6, when Ganetespib and 5-fluorouracil are used in combination to treat leukemia, at 5-fluorouracil 2.0 μM, Ganetespib has a strong or moderate synergistic effect at 0.03125 - 0.125 μM. At 5-fluorouracil 4.0 μM, Ganetespib has a strong synergistic effect at 0.03125 - 0.125 μM. At 5-fluorouracil 8.0 μM, Ganetespib has a moderate synergistic effect at 0.03125 - 0.125 μM.

[0043]

[0044] As shown in Table 7, when GL-V9 and 5-fluorouracil are used in combination to treat leukemia, there is a synergistic effect when GL-V9 is 0.25 - 4.0 μM and 5-fluorouracil is 2.0 - 8.0 μM.

[0045] In summary, the results confirm that the combination of GL-V9 and 5-fluorouracil in the treatment of leukemia can play a good synergistic effect, with strong, relatively strong, and moderate synergistic effects, while the combination of Ganetespib and 5-fluorouracil cannot achieve the same effect. This result shows the advantage of the combination of GL-V9 and 5-fluorouracil in the preparation of a drug composition for treating leukemia.

[0046] Example 3

[0047] Taking three highly representative leukemia cells, Jurkat, THP1, and ME1, as the research objects, comparing the combination of the publicly available HSP90 inhibitor Luminespib and capecitabine, and studying the therapeutic effect of the combination of GL-V9 and capecitabine in inhibiting leukemia. As shown in Table 8, the inhibitory levels (0 < Effect < 1) of GL-V9, Luminespib, and capecitabine alone on leukemia cells are presented. As shown in Table 9, the inhibition rates and combination indices of the combination of Luminespib and capecitabine on leukemia cells are shown; as shown in Table 10, the inhibition rates and combination indices of the combination of GL-V9 and capecitabine on leukemia cells are shown.

[0048]

[0049]

[0050] As shown in Table 9, when Luminespib and capecitabine are used in combination to treat leukemia, with capecitabine at 32.0 μM, Luminespib has a synergistic effect at 0.01563 - 0.125 μM. When capecitabine is 64.0 μM, Luminespib has a strong or relatively strong synergistic effect at 0.01563 - 0.03125 μM. When capecitabine is 128.0 μM, Luminespib has a strong or relatively strong synergistic effect at 0.01563 - 0.0625 μM.

[0051]

[0052] As shown in Table 10, when GL-V9 and capecitabine are used in combination to treat leukemia, with GL-V9 at 0.25 μM, capecitabine has a very strong synergistic effect at 64.0 - 128.0 μM. When GL-V9 is 0.5 μM, capecitabine has a very strong or strong synergistic effect at 64.0 - 128.0 μM. When GL-V9 is 1.0 μM, capecitabine has a very strong or moderate synergistic effect at 64.0 - 128.0 μM. When GL-V9 is 2.0 μM, capecitabine has a strong synergistic effect at 128.0 μM. When GL-V9 is 4.0 μM, capecitabine has a synergistic effect at 32.0 - 128.0 μM.

[0053] In summary, the results confirm that the combination of GL-V9 and capecitabine can produce a very strong synergistic effect within a certain range ratio, and this synergistic strength is significantly better than the therapeutic effect of the combination of Luminespib and capecitabine on leukemia, indicating the advantage of the combination of GL-V9 and capecitabine in preparing a pharmaceutical composition for treating leukemia.

[0054] Example 4

[0055] Taking three highly representative leukemia cells, Jurkat, THP1, and ME1, as the research objects, comparing the combination of the publicly available technology HSP90 inhibitor Onelespib and PARP1 inhibitor Olaparib, and studying the therapeutic effect of the combination of GL-V9 and Olaparib on inhibiting leukemia. As shown in Table 11, it is the inhibition levels (0 < Effect < 1) of GL-V9, Onelespib, and Olaparib on leukemia cells when acting alone. As shown in Table 12, it is the inhibition rate and combination index of Onelespib and Olaparib after combined treatment on leukemia cells; as shown in Table 13, it is the inhibition rate and combination index of GL-V9 and Olaparib after combined treatment on leukemia cells.

[0056]

[0057]

[0058] As shown in Table 12, when Onelespib and Olaparib are used in combination to treat leukemia, Olaparib at 4.0 - 16.0 μM and Onelespib at 0.01563 - 0.25 μM both have a synergistic effect.

[0059]

[0060] As shown in Table 13, when GL-V9 and Olaparib are used in combination to treat leukemia, GL-V9 at 0.25 - 4.0 μM and Olaparib at 4.0 - 16.0 μM both have a synergistic effect.

[0061] In summary, the results confirm that both the combination of GL-V9 or Onelespib with Olaparib can achieve good synergistic effects. It shows the feasibility of the application of these two drug combination methods in the preparation of drug compositions for treating leukemia.

[0062] Example 5

[0063] Taking three highly representative leukemia cells, Jurkat, THP1, and ME1, as the research objects, comparing the combination of the publicly available technology HSP90 inhibitor Luminespib and irinotecan, and studying the therapeutic effect of the combination of GL-V9 and irinotecan on inhibiting leukemia. As shown in Table 14, the inhibition levels (0 < Effect < 1) of leukemia cells by GL-V9, Luminespib, and irinotecan alone are presented. As shown in Table 15, the inhibition rates and combination indices of leukemia cells after the combination of Luminespib and irinotecan are shown; as shown in Table 16, the inhibition rates and combination indices of leukemia cells after the combination of GL-V9 and irinotecan are shown.

[0064]

[0065]

[0066] As shown in Table 15, when Luminespib and irinotecan are combined to treat leukemia, at Luminespib 0.01563 μM, the synergy is stronger when irinotecan is at 4.0 - 8.0 μM. At Luminespib 0.03125 μM, the synergy is strong or stronger when irinotecan is at 4.0 - 8.0 μM. At Luminespib 0.0625 μM, the synergy is strong or stronger when irinotecan is at 4.0 - 8.0 μM. At Luminespib 0.125 μM, the synergy is stronger or moderate when irinotecan is at 4.0 - 8.0 μM.

[0067]

[0068] As shown in Table 16, when GL-V9 and irinotecan are combined to treat leukemia, at irinotecan 4.0 μM, the synergy is stronger or moderate when GL-V9 is at 0.25 - 2.0 μM. At irinotecan 8.0 μM, the synergy is stronger or moderate when GL-V9 is at 0.25 - 2.0 μM.

[0069] In summary, compared with the strong antagonistic effect produced by the combination of Luminespib and irinotecan at a relatively large concentration ratio, the combination of GL-V9 and irinotecan does not produce a strong or very strong antagonistic effect within the concentration range of single-drug screening. According to the experimental results, a synergistic effect of inhibiting leukemia can be produced within the range of the GL-V9:irinotecan molar ratio of 1:0.0625 to 1:0.25.

[0070] Example 6

[0071] Taking three highly representative leukemia cells, Jurkat, THP1, and ME1, as the research objects, comparing the combination of the publicly available HSP90 inhibitor Luminespib and sorafenib, and studying the therapeutic effect of the combination of GL-V9 and sorafenib in inhibiting leukemia. As shown in Table 17, it is the inhibition level (0 < Effect < 1) of leukemia cells under the individual action of GL-V9, Luminespib, and sorafenib. As shown in Table 18, it is the inhibition rate and combination index of leukemia cells after the combined use of Luminespib and sorafenib; as shown in Table 19, it is the inhibition rate and combination index of leukemia cells after the combined use of GL-V9 and sorafenib.

[0072]

[0073]

[0074] As shown in Table 18, when Luminespib and sorafenib are used in combination to treat leukemia, Luminespib is 0.01563 μM and sorafenib is 4.0 μM, with moderate synergistic effect.

[0075]

[0076] As shown in Table 19, when GL-V9 and sorafenib are used in combination to treat leukemia, sorafenib is 4.0 - 16.0 μM and GL-V9 has a synergistic effect at 0.25 - 4.0 μM.

[0077] In summary, the results confirm that compared with the antagonistic effect produced by the combination of Luminespib and sorafenib in treating leukemia, the combination of GL-V9 and sorafenib can exert a good synergistic effect, demonstrating the advantage of the combination of GL-V9 and sorafenib in preparing a pharmaceutical composition for treating leukemia.

[0078] Example 7

[0079] Taking the highly representative lung cancer cell H1975 as the research object, comparing the combination of the publicly available HSP90 inhibitor 17-AGG and cisplatin, and studying the therapeutic effect of the combination of GL-V9 and cisplatin in inhibiting lung cancer. As shown in Table 20, it is the inhibition level (0 < Effect < 1) of lung cancer cells under the individual action of GL-V9, 17-AGG, and cisplatin. As shown in Table 21, it is the inhibition rate and combination index of lung cancer cells after the combined use of 17-AGG and cisplatin; as shown in Table 22, it is the inhibition rate and combination index of lung cancer cells after the combined use of GL-V9 and cisplatin.

[0080]

[0081]

[0082] As shown in Table 21, when 17-AAG and cisplatin are used in combination to treat lung cancer, with 17-AAG at 0.0625 μM and cisplatin at 1.0 - 2.0 μM, the synergistic effect is strong or moderate.

[0083]

[0084] As shown in Table 22, when GL-V9 and cisplatin are used in combination to treat lung cancer, with cisplatin at 1.0 - 2.0 μM and GL-V9 at 0.5 - 4.0 μM, the synergistic effect is strong, relatively strong or moderate. When cisplatin is at 4.0 μM and GL-V9 is at 1.0 μM, the synergistic effect is slight.

[0085] In summary, the results confirm that within the screened concentration range, the combination of GL-V9 and cisplatin can produce a relatively obvious synergistic effect on lung cancer cells, while the combination of 17-AAG and cisplatin mainly produces an additive or antagonistic effect on lung cancer cells. These results indicate the application value of preparing a lung cancer drug composition by combining GL-V9 and cisplatin.

[0086] Example 8

[0087] Taking the colorectal cancer representative cell HCT116 cells as the research object, comparing the combination of the publicly available HSP90 inhibitor Ganetespib and 5-fluorouracil, the therapeutic effect of the combination of GL-V9 and 5-fluorouracil in inhibiting colorectal cancer was studied. As shown in Table 23, the inhibition levels (0 < Effect < 1) of GL-V9, Ganetespib and 5-fluorouracil on colorectal cancer cells alone are shown. As shown in Table 24, the inhibition rate and combination index of Ganetespib and 5-fluorouracil after combined use on colorectal cancer cells are shown; as shown in Table 25, the inhibition rate and combination index of GL-V9 and 5-fluorouracil after combined use on colorectal cancer cells are shown.

[0088]

[0089]

[0090] As shown in Table 24, when Ganetespib and 5-fluorouracil are used in combination to treat colorectal cancer, with 5-fluorouracil at 2.0 μM and Ganetespib at 0.01563 - 0.125 μM, the synergistic effect is strong or relatively strong. When 5-fluorouracil is at 4.0 μM and Ganetespib is at 0.01563 - 0.125 μM, the synergistic effect is strong or relatively strong. When 5-fluorouracil is at 8.0 μM and Ganetespib is at 0.01563, 0.0625 - 0.125 μM, the synergistic effect is relatively strong or moderate.

[0091]

[0092] As shown in Table 25, when GL-V9 and 5-fluorouracil are combined for the treatment of colorectal cancer, the concentration of 5-fluorouracil is 2.0 μM, and the concentrations of GL-V9 are 0.5 - 2.0 μM and 8.0 μM, and the synergistic effect is strong or very strong. When the concentration of 5-fluorouracil is 4.0 - 8.0 μM and the concentration of GL-V9 is 0.5 - 8.0 μM, the synergistic effect is strong.

[0093] In summary, compared with the combination of Ganetespib and 5-fluorouracil, the combination of GL-V9 and 5-fluorouracil mainly produces a synergistic effect, and the synergistic effect is very strong, strong and relatively strong, showing advantages in the preparation of drug compositions for colorectal cancer.

[0094] Example 9

[0095] Taking the colorectal cancer representative cell HCT116 cells as the research object, comparing the combination of the publicly available HSP90 inhibitor Luminespib and capecitabine, the therapeutic effect of the combination of GL-V9 and capecitabine in inhibiting colorectal cancer was studied. As shown in Table 26, it shows the inhibition levels (0 < Effect < 1) of GL-V9, Luminespib and capecitabine on colorectal cancer cells when acting alone. As shown in Table 27, it shows the inhibition rate and combination index of the combination of Luminespib and capecitabine on colorectal cancer cells; as shown in Table 28, it shows the inhibition rate and combination index of the combination of GL-V9 and capecitabine on colorectal cancer cells.

[0096]

[0097]

[0098] As shown in Table 27, when Luminespib and capecitabine are combined for the treatment of colorectal cancer, the concentration of capecitabine is 1.0 μM, and the concentrations of Luminespib are 0.01563 - 0.125 μM, and the synergistic effect is strong or relatively strong. When the concentration of capecitabine is 2.0 μM and the concentration of Luminespib is 0.01563 - 0.125 μM, the synergistic effect is relatively strong. When the concentration of capecitabine is 4.0 μM and the concentration of Luminespib is 0.01563 - 0.0625 μM, the synergistic effect is relatively strong or moderate.

[0099]

[0100] As shown in Table 28, when GL-V9 and capecitabine are combined for the treatment of colorectal cancer, when the concentration of capecitabine is 1 - 4.0 μM and the concentration of GL-V9 is 0.25 - 4.0 μM, there is a synergistic effect.

[0101] In summary, the results confirm that, compared with the combination drug prepared by Luminespib and capecitabine for the treatment of colorectal cancer, GL-V9 combined with capecitabine has strong and relatively strong synergistic effects on colorectal cancer cells, showing the advantages of GL-V9 combined with capecitabine in the preparation of drug compositions for the treatment of colorectal cancer.

[0102] Example 10

[0103] Taking the highly representative lung cancer cell line H1975 as the research object, comparing the combination of the publicly available HSP90 inhibitor onelespib and the PARP1 inhibitor olaparib, and studying the therapeutic effect of the combination of GL-V9 and olaparib on inhibiting lung cancer. As shown in Table 29, the inhibitory levels (0 < Effect < 1) of GL-V9, onelespib and olaparib on lung cancer cells alone are presented. As shown in Table 30, the inhibition rate and combination index of the combination of onelespib and olaparib on lung cancer cells are shown; as shown in Table 31, the inhibition rate and combination index of the combination of GL-V9 and olaparib on lung cancer cells are shown.

[0104]

[0105]

[0106] As shown in Table 30, when onelespib and Olaparib are combined to treat lung cancer, with Olaparib at 4.0 μM and Onelespib at 0.125 μM, the synergistic effect is relatively strong. When Olaparib is at 8.0 μM and Onelespib is at 0.01563 - 0.125 μM, the synergistic effect is relatively strong. When Olaparib is at 16.0 μM and Onelespib is at 0.03125 - 0.125 μM, the synergistic effect is moderate.

[0107]

[0108] As shown in Table 31, when GL-V9 and Olaparib are combined to treat lung cancer, with GL-V9 at 0.5 - 4.0 μM and Olaparib at 4.0 - 16.0 μM, both show synergistic effects.

[0109] In summary, the results confirm that, compared with the combination drug prepared by onelespib and olaparib for the treatment of lung cancer, GL-V9 combined with olaparib has strong and relatively strong synergistic effects on lung cancer cells, showing the advantages of GL-V9 combined with the PARP1 inhibitor olaparib in the preparation of drug compositions for the treatment of lung cancer.

Claims

1. A pharmaceutical composition, characterized in that, The active ingredients are GL-V9 and a chemotherapy drug; the chemotherapy drug is 5-fluorouracil.

2. The pharmaceutical composition according to claim 1, characterized in that, The GL-V9 includes the GL-V9 compound or a pharmaceutically acceptable salt thereof.

3. The use of the pharmaceutical composition according to any one of claims 1 to 2 in the preparation of a drug for treating tumors, wherein the tumor is leukemia, lung cancer, or colorectal cancer.

4. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, The pharmaceutical composition is formulated by adding pharmaceutically acceptable excipients.

5. The pharmaceutical composition according to claim 4, characterized in that, The dosage forms of the preparations include tablets, capsules, powders, powder injections, granules, powdered drinks, oral liquids, and syrups.

6. Application of GL-V9 in the preparation of chemotherapeutic drug enhancers; wherein the chemotherapeutic drug is 5-fluorouracil.

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