Cabotegravir for inhibiting tumors and application of Cabotegravir

Abstract

The invention relates to the technical field of biological medicines, in particular to application of categravir or medicinal salt thereof in preparation of tumor treatment medicines. The applicant discovers that the categravir can enable chromatin of tumor cells to be more open, so that DNA of the tumor cells is more easily attacked by chemotherapeutic drugs, more DNA damage is generated, genome instability is caused, the apoptosis number of the tumor cells is further increased, and the development of tumors is inhibited. The mechanism can reduce the dosage of chemotherapeutic drugs, thereby reducing the non-selective damage of the chemotherapeutic drugs to normal tissues and improving the treatment safety. And a new treatment choice is provided for patients who are ineffective in traditional chemotherapy, and the compound is especially suitable for chromatin accessibility abnormality mediated drug-resistant tumors.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceutical technology, and particularly to the inhibition of tumors by Cabotegravir and its applications. Background Art

[0002] With the continuous increase in the global cancer incidence rate, cancer has become one of the major diseases seriously threatening human health and life. Surgical resection combined with radiotherapy and chemotherapy is currently the main means of tumor treatment. Although radiotherapy and chemotherapy play a central role in tumor treatment, their clinical applications still face many bottlenecks. First, the non-selective damage of radiotherapy and chemotherapy to normal tissues leads to serious adverse reactions, such as myelosuppression (the incidence rate of grade 3-4 hematological toxicity is as high as 35% - 90%), gastrointestinal mucositis, and immune system function decline, significantly affecting the quality of life of patients and limiting the dose intensity. Second, tumor cells rapidly develop resistance to radiotherapy and chemotherapy by activating DNA damage repair pathways and remodeling the immune microenvironment, resulting in local recurrence and distant metastasis, which become the main cause of patient death. According to statistics, more than 50% of patients with locally advanced tumors experience recurrence within 5 years after radical treatment, and although traditional sensitization strategies (such as the combination of platinum drugs) can improve the efficacy, they further exacerbate the toxic reactions.

[0003] Cabotegravir is an HIV-1 integrase strand transfer inhibitor (INSTI), which has been approved for pre-exposure prophylaxis (PrEP) of HIV and exerts a long-acting inhibitory effect by blocking the integration of viral DNA into the host genome. Its core advantage lies in the once-monthly intramuscular injection administration mode, which can significantly improve patient compliance. However, existing studies have all focused on its antiviral properties, and there is no public evidence indicating its direct effect on tumor treatment. Summary of the Invention

[0004] The applicant has found that Cabotegravir can make the chromatin of tumor cells more open, thereby making the DNA of tumor cells more vulnerable to the attack of chemotherapeutic drugs, generating more DNA damage, causing genomic instability, and further increasing the number of apoptotic tumor cells and inhibiting tumor progression. Based on this, the present invention provides the application of Cabotegravir or its pharmaceutically acceptable salts in the preparation of tumor treatment drugs.

[0005] The technical solutions provided by the present invention are specifically as follows:

[0006] The present invention provides the application of Cabotegravir or its pharmaceutically acceptable salts in the preparation of tumor treatment drugs.

[0007] In some embodiments of the present invention, the tumor is a tumor with abnormal chromatin accessibility; and / or, the tumor is a chemotherapy-resistant tumor.

[0008] In some embodiments of the present invention, the tumor is one or more of breast cancer, liver cancer, gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, acute leukemia, lymphoma, lung cancer, osteosarcoma, pancreatic cancer, and retinoblastoma.

[0009] In some embodiments of the present invention, in the tumor treatment drug, carfilavir is used as the sole active ingredient.

[0010] In some embodiments of the present invention, the tumor treatment drug comprises a first active ingredient for opening the chromatin of tumor cells and a second active ingredient for damaging DNA.

[0011] In some embodiments of the present invention, the first active ingredient is carfilavir or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments of the present invention, the pharmaceutically acceptable salt of carfilavir is carfilavir sodium.

[0013] In some embodiments of the present invention, the second active ingredient is one or more of platinum compounds, alkylating agents, antibiotics, PARP inhibitors, and anthracycline drugs.

[0014] In some embodiments of the present invention, the platinum compound is one or more of cisplatin, carboplatin, and oxaliplatin; and / or, the alkylating agent is one or more of cyclophosphamide, nitrogen mustard, chlorambucil, and busulfan; and / or, the antibiotic is one or more of bleomycin, mitomycin, and pingyangmycin; and / or, the PARP inhibitor is one or more of olaparib, rucaparib, and niraparib; and / or, the anthracycline drug is one or more of daunorubicin, doxorubicin, and epirubicin.

[0015] In some embodiments of the present invention, the dosage form of the tumor treatment drug is one or more of oral dosage forms, injection dosage forms, implant dosage forms, suppository dosage forms, inhalation dosage forms, and coating dosage forms.

[0016] Compared with the prior art, the present invention has at least the following beneficial effects:

[0017] Carfilavir opens the chromatin structure of tumor cells, making DNA more vulnerable to chemotherapy drugs, causing more DNA damage and inducing apoptosis. When combined with DNA-damaging drugs such as cisplatin and doxorubicin, it can produce a synergistic effect. This mechanism can reduce the dosage of chemotherapy drugs, thereby reducing their non-selective damage to normal tissues and improving treatment safety. In particular, for chemotherapy-resistant tumors, carfilavir reverses the tolerance mechanism of tumor cells to chemotherapy drugs by disrupting the abnormal chromatin structure, providing a new treatment option for patients who are ineffective with traditional chemotherapy, especially suitable for tumors with drug resistance mediated by abnormal chromatin accessibility. Description of the Drawings

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention, the following will briefly introduce the accompanying drawings required for the description of the embodiments. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other accompanying drawings can be obtained based on these drawings.

[0019] Figure 1 : The effect of Cabotegravir on chromatin transcription level; A: The staining results of breast cancer cells treated with Cabotegravir; B: The statistical results of Figure A; C: The results of Western-Blot detection of histone 3 methylation level.

[0020] Figure 2 : The effect of Cabotegravir on the growth of tumor cells.

[0021] Figure 3 : The effect of Cabotegravir on tumor growth and chromatin accessibility; A: The size change of liver cancer organoids before and after treatment with Cabotegravir; B: The statistical results of Figure A; C: The immunofluorescence detection results of the organoid growth marker Ki67 and the heterochromatin marker H3K9me3; D: The statistical results of Ki67 in Figure C; E: The statistical results of H3K9me3 in Figure C.

[0022] Figure 4 : The effect of Cabotegravir on tumor chromatin accessibility and growth in vivo; A: Analysis of the difference in tumor volume changes between the Cabotegravir intervention group and the control group in hydrodynamics-based liver cancer model mice; B: The comparison results of liver weights between the Cabotegravir intervention group and the control group in hydrodynamics-based liver cancer model mice; C: The comparison results of liver weight / body weight between the Cabotegravir intervention group and the control group in hydrodynamics-based liver cancer model mice; D: The immunohistochemistry (IHC) detection results of the tumor growth marker Ki67 and the heterochromatin marker H3K9me3; E: The statistical results of Ki67 in Figure D; F: The statistical results of H3K9me3 in Figure D; G: The tumor cell apoptosis results of the Cabotegravir intervention group and the control group in hydrodynamics-based liver cancer model mice detected by immunofluorescence; H: The statistical results of Figure G; I: The changes in body weights of mice in the Cabotegravir intervention group and the control group during the experiment.

[0023] Figure 5: Effects of Cabotegravir on the growth of chemotherapy-resistant tumor cells; A: Proliferation results of non-doxorubicin-tolerant human breast cancer cells MDA-MB-231 and doxorubicin-tolerant breast cancer cells MDA-MB-231-ADR under Cabotegravir intervention; B: Proliferation results of non-doxorubicin-tolerant human breast cancer cells MCF7 and doxorubicin-tolerant breast cancer cells MCF7-ADR under Cabotegravir intervention.

[0024] Figure 6 : Efficacy of Cabotegravir in combination with chemotherapy drugs for the treatment of breast cancer; A: Effects of Cabotegravir and doxorubicin (ADR) alone and in combination on the growth of human breast cancer cells MDA-MB-231 detected by CCK8; B: Effects of Cabotegravir and doxorubicin alone and in combination on the growth of human breast cancer cells MDA-MB-231 detected by CCK8; C: Effects of Cabotegravir and cisplatin alone and in combination on the size of human breast cancer tumors; D: Effects of Cabotegravir and cisplatin alone and in combination on the weight of human breast cancer tumors; E: Immunohistochemical detection results of tumor growth marker Ki67 and heterochromatin marker H3K9me3; F: Statistical results of H3K9me3 in Figure E; G: Statistical results of Ki67 in Figure E; H: Results of apoptosis of human breast cancer tumor cells detected by immunofluorescence with Cabotegravir and cisplatin alone and in combination; I: Statistical results of Figure H. Detailed implementation manners

[0025] To make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are some, rather than all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0026] In recent years, more and more studies have shown that abnormal chromatin accessibility plays an important role in the process of tumor chemotherapy resistance. In tumors, abnormal chromatin accessibility regulation causes abnormal expression of genes such as DNA damage repair on the one hand, leading to rapid repair of DNA damage in tumors and tolerance to chemotherapy; on the other hand, by changing the chromatin structure, it enables rapid response to DNA damage caused by endogenous and exogenous factors, maintaining genome stability, thereby promoting tumor growth and tolerance to radiotherapy and chemotherapy.

[0027] The applicant has found that catiravir can promote the sensitivity of DNA to chemotherapeutic drugs, increase DNA damage and genomic instability by making the chromatin of tumor cells more open, thereby increasing the apoptosis rate of tumor cells and inhibiting tumor progression. Based on this, the present invention provides the use of catiravir or a pharmaceutically acceptable salt thereof in the preparation of a tumor therapeutic drug, which can synergistically enhance the effect by combining the approved drug catiravir with a DNA damage drug, reduce the dosage of the DNA damage drug, thereby reducing chemotherapy toxicity, and has important clinical transformation value. As a salt form of an approved HIV therapeutic drug, the safety and pharmacokinetic properties of catiravir sodium have been fully verified (such as a long-acting dosing mode of once-monthly injection), and the existing clinical data can be directly used for tumor treatment to reduce the development risk.

[0028] In some embodiments of the present invention, the tumor is a tumor with abnormal chromatin accessibility; and / or, the tumor is a chemotherapy-resistant tumor. Experimental verification shows that catiravir can reverse the abnormally compact state of chromatin by reducing the level of heterochromatin marker H3K9me3 (such as a significant decrease in the level of H3K9me3 in a liver cancer organoid model), thereby improving the chemotherapy-resistant phenotype (such as the proliferation of doxorubicin-resistant breast cancer cells is significantly inhibited after treatment with catiravir).

[0029] In some embodiments of the present invention, the tumor is one or more of breast cancer, liver cancer, gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, acute leukemia, lymphoma, lung cancer, osteosarcoma, pancreatic cancer, retinoblastoma. The in vivo and in vitro experiments of this application (such as an orthotopic breast cancer model, a hydrodynamic liver cancer model, Figures 3 to 6 ) confirm that catiravir shows significant proliferation inhibitory effects on the above-mentioned breast cancer and liver cancer (such as a decrease in the tumor weight of mice and a decrease in the Ki67 positive rate); the cell experiments of this application show that catiravir has obvious growth inhibitory effects on human breast cancer cells MDA-MB-231, human gastric cancer cells SGC-7901, and colorectal cancer cells WiDR ( Figure 2 ). Inhibit their proliferation. Ovarian cancer (especially BRCA mutant type) relies on homologous recombination to repair DNA damage. After catiravir opens chromatin, it can increase the binding probability of platinum drugs (such as cisplatin) to DNA and synergistically induce apoptosis. Abnormal chromatin accessibility in tumors such as lung cancer, osteosarcoma, pancreatic cancer, and retinoblastoma is often associated with chemotherapy resistance (such as lung cancer being resistant to cisplatin and osteosarcoma being resistant to doxorubicin). Catiravir can restore the sensitivity of tumor cells to DNA damage drugs by reversing the chromatin compaction state and achieve proliferation inhibition.

[0030] In some embodiments of the present invention, in the tumor therapeutic drug, catiravir is used as the only active ingredient. When used alone, catiravir can directly induce apoptosis of tumor cells by opening chromatin (such as Figure 3, the apoptotic signal is enhanced in the liver cancer organoid model), which is suitable for patients who are insensitive to traditional chemotherapy or require monotherapy maintenance treatment.

[0031] In some embodiments of the present invention, the tumor treatment drug comprises a first active ingredient for opening chromatin of tumor cells and a second active ingredient for damaging DNA. The first active ingredient and the second active ingredient are packaged independently or together. In the tumor treatment drug, the first active ingredient and the second active ingredient can significantly enhance the anti-tumor effect through the synergistic mechanism of "opening chromatin - damaging DNA" (for example, in the orthotopic breast cancer model, the tumor volume of the combination group of cidofovir and cisplatin is significantly smaller than that of the single drug group).

[0032] In some embodiments of the present invention, the first active ingredient is cidofovir or a pharmaceutically acceptable salt thereof. It increases chromatin accessibility (such as enhanced chromatin opening signal shown by Tunel staining), making DNA more vulnerable to attack by the second active ingredient, thereby achieving synergistic enhancement of efficacy.

[0033] In some embodiments of the present invention, the pharmaceutically acceptable salt of cidofovir is cidofovir sodium. As a marketed salt form of an HIV treatment drug, its safety and pharmacokinetic properties have been fully verified (such as the long-acting administration mode of once-monthly injection). When used for tumor treatment, existing clinical data can be directly referred to, reducing the development risk.

[0034] In some embodiments of the present invention, the second active ingredient is one or more of platinum compounds, alkylating agents, antibiotics, PARP inhibitors, anthracycline drugs. Experiments have confirmed that the combination of cidofovir and cisplatin (platinum compound), doxorubicin (anthracycline drug), etc. can significantly increase DNA damage (such as increased apoptotic level shown by immunofluorescence), and synergistically inhibit tumor growth.

[0035] In some embodiments of the present invention, the platinum compound is one or more of cisplatin, carboplatin, oxaliplatin; and / or, the alkylating agent is one or more of cyclophosphamide, nitrogen mustard, chlorambucil, busulfan; and / or, the antibiotic is one or more of bleomycin, mitomycin, pingyangmycin; and / or, the PARP inhibitor is one or more of olaparib, rucaparib, niraparib; and / or, the anthracycline drug is one or more of daunorubicin, doxorubicin, epirubicin. These drugs all act by directly or indirectly damaging DNA, and the combination with cidofovir can optimize the treatment plan for different tumor types (such as cisplatin is preferred for breast cancer, and oxaliplatin is preferred for colorectal cancer).

[0036] In some embodiments of the present invention, the dosage form of the tumor therapeutic drug is one or more of oral preparations, injections, implants, suppositories, inhalants, and coatings. For example, long-acting injections (such as intramuscular injection once a month) can improve patient compliance; oral preparations are suitable for maintenance treatment; implants can achieve local slow release, reduce systemic toxicity, and meet the needs of different clinical scenarios.

[0037] The technical solutions provided by the present invention will be described in detail below in conjunction with the embodiments.

[0038] Example 1

[0039] In this example, Tunel staining and Western Blot were used to detect the effect of Cabotegravir on chromatin accessibility, EU was used to detect the effect of Cabotegravir on chromatin transcription level, and the effect of Cabotegravir on tumor cell growth was detected by CCK8 experiment. Western Blot experiment and CCK8 experiment used conventional commercially available kits and were carried out according to the experimental steps in the instructions.

[0040] 1. Cell treatment:

[0041] Control group: Human breast cancer cells MDA-MB-231, human gastric cancer cells SGC-7901, and colorectal cancer cells WiDR were treated with DMSO respectively.

[0042] Cabotegravir treatment group: Cabotegravir was dissolved in DMSO with the same volume as the control group to prepare Cabotegravir working solutions with Cabotegravir concentrations of 10 μM, 20 μM, and 40 μM respectively, and human breast cancer cells MDA-MB-231, human gastric cancer cells SGC-7901, and colorectal cancer cells WiDR were treated under the same conditions as the control group.

[0043] 2. Detection of chromatin accessibility level by Tunel staining

[0044] The human breast cancer cells MDA-MB-231 treated with Cabotegravir were permeabilized with PBS buffer (Invitrogen) containing 0.5% Triton X-100 for 15 minutes, and then digested with 0.2 units / ml of DNase I (NEB). After the cells were fixed with 4% paraformaldehyde (PFA), TUNEL detection (DeadEnd TM Fluorescent TUNEL detection system, Promega) was carried out according to the instructions. The nuclear region was defined according to DAPI DNA staining, images were collected using an Olympus FV1000 confocal microscope, and the intensity of nuclear TUNEL signal was quantitatively analyzed by Image J software.

[0045] 3. Detection of nascent RNA levels by EU staining

[0046] After culturing Cabotegravir-treated human breast cancer cells MDA-MB-231 on pre-coated slides for 24 hours, the detection of nascent RNA synthesis labeling was performed using the Click-It RNA Imaging Kit (Invitrogen, catalog number C10329) according to the instructions. Experimental images were collected by an Olympus FV1000 confocal microscope, and the intensity of the labeling signal was quantitatively analyzed using Image J software.

[0047] Figure 1 (A) Detection of chromatin openness by Tunel staining (the higher the chromatin openness, the stronger the Tunel signal), and detection of nascent RNA levels by EU staining (after chromatin opening, transcriptional activity is enhanced, and the nascent RNA signal is stronger); Figure 1 (B-C) are the statistics of the signal intensity in Figure A, and the results show that both Tunel (chromatin opening) and EU (nascent RNA) signals are significantly enhanced after Cabotegravir treatment. Figure 1 (D) Western Blot was used to detect the histone 3 methylation level. After Cabotegravir treatment, the histone 3 methylation level decreased. Usually, histone methylation is associated with chromatin compaction, and a decrease in methylation level indicates chromatin opening. The above Tunel and Western Blot results show that Cabotegravir treatment increases the accessibility of chromatin in human breast cancer cells MDA-MB-231, making the chromatin of human breast cancer cells MDA-MB-231 more open.

[0048] Figure 2 The CCK8 detection results after treating tumor cells with DMSO and different concentrations of Cabotegravir working solution are shown. The results show that the higher the Cabotegravir concentration, the lower the concentration of human breast cancer cells MDA-MB-231, human gastric cancer cells SGC-7901, and colorectal cancer cells WiDR, indicating that Cabotegravir has an obvious growth inhibitory effect on various tumor cells.

[0049] Example 2

[0050] (1) Construction of a hydrodynamic liver cancer model in mice

[0051] To construct a mouse model of liver cancer development, the present invention performs hydrodynamic transfection through the Sleeping Beauty (SB) transposon system. Briefly, 25 μg of AKT1 and 25 μg of N-RasV12 are dissolved together with 2 μg of SB transposase in 2.5 ml of normal saline and rapidly injected into wild-type C57BL / 6 mice (8 - 12 weeks old) through the lateral tail vein within 5 - 7 seconds. Three weeks after hydrodynamic transfection, Cabotegravir is intraperitoneally injected. The mice are sacrificed 2 weeks after drug administration, and liver tissues are collected for the analysis of hepatocellular carcinoma tumorigenesis.

[0052] Figure 3 (A) Observation of the size change of liver cancer organoids before and after Cabotegravir treatment through a microscope (the smaller the volume of liver cancer organoids, the more obvious the inhibition of proliferation); Figure 3 (B) Quantitative statistics of the size of liver cancer organoids in Figure A, and the results show that the volume of liver cancer organoids significantly decreases after Cabotegravir treatment. Figure 3 (C) Detection of the levels of the growth marker Ki67 (the higher the positive rate of Ki67, the more active the cell proliferation) and the heterochromatin marker H3K9me3 (the higher the level of H3K9me3, the higher the degree of chromatin compaction) in liver cancer organoids by immunofluorescence; Figure 3 (D) Statistics of the positive rate of Ki67 in Figure C, and the results show that the positive rate of Ki67 significantly decreases after Cabotegravir treatment; Figure 3 (E) Statistics of the level of H3K9me3 in Figure C, and the results show that the level of H3K9me3 significantly decreases after Cabotegravir treatment (the reduction of heterochromatin indicates that chromatin tends to be open). The above microscopic observation, immunofluorescence detection and statistical results show that Cabotegravir treatment can inhibit the proliferation of liver cancer organoids and make the chromatin of liver cancer organoids more open by reducing the level of the heterochromatin marker H3K9me3.

[0053] Figure 4 (A) Observation of the change in tumor volume of mice in the Cabotegravir intervention group and the control group through a hydrodynamic liver cancer model (the smaller the tumor volume, the more significant the inhibition of the development of liver cancer); Figure 4 (B) Direct comparison results of the liver weights of the two groups of mice, showing that the liver weight of the Cabotegravir intervention group is significantly lower than that of the control group; Figure 4 (C) Comparison results of the ratio of liver weight to body weight of the two groups of mice, further verifying that the relative liver weight significantly decreases after Cabotegravir intervention (indicating a reduction in tumor burden). Figure 4(D) Detect the levels of tumor growth marker Ki67 (the higher the Ki67 positive rate, the more active the proliferation of tumor cells) and heterochromatin marker H3K9me3 (the higher the H3K9me3 level, the higher the degree of chromatin compaction) by immunohistochemistry (IHC); Figure 4 (E) It is the statistics of the Ki67 positive rate in Figure D. The results show that the Ki67 positive rate in the Cabotegravir intervention group is significantly lower than that in the control group (tumor proliferation is inhibited); Figure 4 (F) It is the statistics of the H3K9me3 level in Figure D. The results show that the H3K9me3 level in the Cabotegravir intervention group decreases significantly (heterochromatin decreases, indicating that chromatin tends to be open). Figure 4 (G) Detect the apoptosis level of tumor cells in the hydrodynamic liver cancer model mice by immunofluorescence (the stronger the apoptosis signal, the more tumor cells die); Figure 4 (H) It is the statistics of the apoptosis signal in Figure G. The results show that the apoptosis level of tumor cells in the Cabotegravir intervention group is significantly higher than that in the control group (promote tumor cell death). Figure 4 (I) Record the body weight changes of mice in the Cabotegravir intervention group and the control group during the experiment. The results show that there is no significant difference in the body weights of the two groups of mice (indicating that Cabotegravir has no obvious systemic toxicity). The above model construction, immunohistochemistry, immunofluorescence detection and statistical results show that Cabotegravir can effectively inhibit the occurrence and development of liver cancer in mice by inhibiting tumor cell proliferation (reducing the Ki67 positive rate), promoting tumor cell apoptosis, and reducing the level of heterochromatin marker H3K9me3 (making chromatin more open), and has no significant systemic toxicity.

[0054] Example 3

[0055] (1) Construction of mouse orthotopic breast cancer model

[0056] Prepare single cell suspensions of non-doxorubicin-tolerant human breast cancer cells MDA-MB-231, MCF7 and doxorubicin-tolerant breast cancer cells MDA-MB-231-ADR, MCF7-ADR at a concentration of 5×10 6 cells / mL respectively; Select 6-8-week-old female BALB / c mice. After 1 week of adaptive feeding in the SPF environment, anesthetize the mice by intraperitoneal injection of 1% sodium pentobarbital (45 mg / kg). Shave the hair in the fourth pair of mammary gland regions and disinfect with iodophor. Incise the skin 1 cm along the midline of the abdomen, bluntly separate the muscle layer to expose the mammary fat pad, use a 29G insulin needle to pierce the fat pad at a 45° angle, slowly inject 20 μL of the cell suspension (stay for 30 seconds to prevent reflux), and then suture the muscle layer and the skin; After the operation, place the mice on a warming pad to wake up, disinfect the wound continuously for 3 days and observe the status.

[0057] (2) Group intervention

[0058] Seven days after surgery, the mice were randomly divided into a Cabotegravir intervention group, a cisplatin intervention group, a combined Cabotegravir and cisplatin application group, and a control group. Cabotegravir or cisplatin was injected intraperitoneally every two days for 14 consecutive days, after which the mice were sacrificed and the tumor tissues were removed for photographing, weighing, and subsequent index detection. The control group was injected intraperitoneally with DMSO, the Cabotegravir intervention group was injected intraperitoneally with Cabotegravir, the cisplatin intervention group was injected intraperitoneally with cisplatin, and the combined Cabotegravir and cisplatin application group was injected intraperitoneally with a mixture of cisplatin and Cabotegravir.

[0059] Figure 5 (A) Detect the proliferation levels of doxorubicin-naive human breast cancer cells MDA-MB-231 and doxorubicin-resistant breast cancer cells MDA-MB-231-ADR under Cabotegravir intervention by CCK8 (the higher the CCK8 absorbance value, the more active the cell proliferation); the results showed that the absorbance value of doxorubicin-resistant breast cancer cells MDA-MB-231-ADR was significantly lower than that of doxorubicin-naive human breast cancer cells MDA-MB-231, indicating that doxorubicin-resistant breast cancer cells MDA-MB-231-ADR were more sensitive to Cabotegravir.

[0060] Figure 5 (B) Detect the proliferation levels of doxorubicin-naive human breast cancer cells MCF7 and doxorubicin-resistant breast cancer cells MCF7-ADR under Cabotegravir intervention by CCK8 (the higher the CCK8 absorbance value, the more active the cell proliferation); the results showed that the absorbance value of doxorubicin-resistant breast cancer cells MCF7-ADR was significantly lower than that of doxorubicin-naive human breast cancer cells MCF7, indicating that doxorubicin-resistant breast cancer cells MCF7-ADR were more sensitive to Cabotegravir.

[0061] The above CCK8 detection and comparison results showed that Cabotegravir could not only inhibit the proliferation of ordinary breast cancer cells, but also had a more significant inhibitory effect on doxorubicin-resistant chemoresistant breast cancer cells, indicating its potential therapeutic value for chemoresistant tumors.

[0062] Figure 6It shows the effect of cabotegravir in combination with chemotherapeutic drugs in the treatment of breast cancer; A: The effects of cabotegravir and doxorubicin alone and in combination on the growth of human breast cancer cells MDA-MB-231 were detected by CCK8. The results showed that although cabotegravir and doxorubicin alone had obvious inhibitory effects on human breast cancer cells MDA-MB-231, they could not reverse the trend of cell proliferation. However, the combination of cabotegravir and doxorubicin could cause all human breast cancer cells MDA-MB-231 to apoptose within 3 days, showing a significant inhibitory effect; Figure 6 (B) It shows the effects of cabotegravir and doxorubicin alone and in combination on the growth of doxorubicin-resistant breast cancer cells MDA-MB-231-ADR detected by CCK8 experiment. The combination of cabotegravir and doxorubicin could significantly inhibit the proliferation of MDA-MB-231-ADR cells; Figure 6 (C) It shows the effects of cabotegravir and cisplatin alone and in combination on the size of human breast cancer tumors. The results showed that compared with the use of cisplatin and cabotegravir alone, the combination of cabotegravir and cisplatin had a stronger ability to inhibit the growth of human breast cancer tumor volume; Figure 6 (D) It shows the effects of cabotegravir and cisplatin alone and in combination on the weight of human breast cancer tumors. The results showed that compared with the use of cisplatin and cabotegravir alone, the combination of cabotegravir and cisplatin had a stronger ability to inhibit the growth of human breast cancer tumor weight; Figure 6 (E), (F) It shows the immunohistochemistry (IHC) detection results of tumor growth marker Ki67 and heterochromatin marker H3K9me3 in breast cancer tumor tissues. Compared with the use of cisplatin and cabotegravir alone, the combination of cabotegravir and cisplatin resulted in lower expression levels of Ki67 and H3K9me3; Figure 6 (H), (I) It shows the results of immunofluorescence detection of the apoptosis of human breast cancer tumor cells by cabotegravir and cisplatin alone and in combination, showing the apoptosis of tumor cells under different treatments. The results showed that compared with the use of cisplatin and cabotegravir alone, the combination of cabotegravir and cisplatin caused more apoptosis of tumor cells. The above results comprehensively indicate that the combination of cabotegravir and chemotherapeutic drugs has a certain synergistic effect in the treatment of breast cancer.

[0063] In the description of this specification, the descriptions with reference to terms such as "one embodiment / way", "some embodiments / ways", "example", "specific example" or "some examples" etc. mean that the specific features, structures, materials or characteristics described in connection with the embodiment / way or example are included in at least one embodiment / way or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment / way or example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more embodiments / ways or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments / ways or examples described in this specification and the features of different embodiments / ways or examples.

[0064] It should be noted that in the present invention, relational terms such as "first" and "second" etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising one..." does not exclude the existence of another identical element in the process, method, article or device comprising the said element. In the present invention, the meaning of "a plurality" is at least two, such as two, three, etc., unless otherwise specifically defined.

[0065] The above are only specific embodiments of the present invention, enabling those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be obvious to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments shown herein, but rather to the broadest scope consistent with the principles and novel features claimed herein.

Claims

1. Use of catiravir or a pharmaceutically acceptable salt thereof in the preparation of a tumor therapeutic agent.

2. The application according to claim 1, wherein: The tumor is a tumor with abnormal chromatin accessibility; and / or, the tumor is a chemotherapy-resistant tumor.

3. The application according to claim 1, wherein: The tumor is one or more of breast cancer, liver cancer, gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, acute leukemia, lymphoma, lung cancer, osteosarcoma, pancreatic cancer, retinoblastoma.

4. The application according to claim 1, wherein: In the tumor therapeutic agent, catiravir is used as the only active ingredient.

5. The application according to claim 1, characterized in that: The tumor therapeutic agent comprises a first active ingredient for opening the chromatin of tumor cells and a second active ingredient for damaging DNA.

6. The application according to claim 5, wherein: The first active ingredient is catiravir or a pharmaceutically acceptable salt thereof.

7. The application according to claim 1 or 6, characterized in that: The pharmaceutically acceptable salt of catiravir is catiravir sodium.

8. The application according to claim 6, wherein: The second active ingredient is one or more of platinum compounds, alkylating agents, antibiotics, PARP inhibitors, anthracycline drugs.

9. The application according to claim 4, wherein: The platinum compound is one or more of cisplatin, carboplatin, oxaliplatin; and / or, The alkylating agent is one or more of cyclophosphamide, nitrogen mustard, chlorambucil, busulfan; and / or, The antibiotic is one or more of bleomycin, mitomycin, pingyangmycin; and / or, The PARP inhibitor is one or more of olaparib, rucaparib, niraparib; and / or, The anthracycline drug is one or more of daunorubicin, doxorubicin, epirubicin.

10. The application according to claim 1, characterized in that: The dosage form of the tumor therapeutic agent is one or more of oral dosage form, injection, implant, suppository, inhalant, coating agent.

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