Anti-tumor composition and application thereof
By combining mitochondrial autophagy agonists with chemotherapeutic drugs to regulate mitochondrial autophagy, the problem of low sensitivity of chemotherapy to tumors has been solved, achieving effective inhibition and apoptosis promotion of malignant tumors such as liver cancer, and enhancing the effect of chemotherapy.
Patent Information
- Application Number
- CN202511130832.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-28
- Publication Date
- 2025-11-07
AI Technical Summary
Existing chemotherapy methods are not very sensitive to tumors, and there is a lack of effective chemotherapy sensitizers, resulting in poor chemotherapy effects, especially in the treatment of malignant tumors such as liver cancer, where it is difficult to effectively inhibit the growth of tumor cells and promote their apoptosis.
Combinations of mitophagy agonists with chemotherapy drugs, including epirubicin, platinum-based chemotherapy drugs, or pentafluorouracil in combination with CCCP, olaparib, or ketoconazole, are used to enhance the efficacy of chemotherapy by modulating the mitophagy process.
It significantly enhanced the inhibitory effect on tumor cells, especially in liver cancer cells, achieving a synergistic effect with chemotherapy and improving the sensitivity and efficacy of chemotherapy.
Smart Images
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Abstract
Description
[0001] This application claims priority to the Chinese Patent Application No. 202411193408.5, filed on August 28, 2024, and entitled "Anti-tumor composition and application thereof", the content of which is incorporated herein by reference in its entirety. TECHNICAL FIELD
[0002] The present application relates to the field of medicine, in particular to an anti-tumor composition and application thereof. BACKGROUND
[0003] Tumor is a new organism formed by abnormal proliferation and differentiation of cells in the body, including benign tumor and malignant tumor (cancer). Benign tumors usually grow slowly, have clear boundaries, do not invade surrounding tissues, and have no metastasis ability, while malignant tumors grow rapidly, can invade surrounding tissues and organs, and have distant metastasis. Malignant tumor is one of the main diseases that threaten human health, and its occurrence is related to many factors such as genetics, environment, and living habits.
[0004] The treatment plan for tumor mainly includes: surgical treatment, chemotherapy, radiotherapy, targeted therapy and immunotherapy. With the continuous progress of medical technology, new treatment methods and means are constantly emerging, bringing more hope and choices for tumor patients.
[0005] Mitophagy is one of the pathways of autophagy in cells, which selectively self-degrades damaged mitochondria, helps cells to remove senescent and pathological mitochondria under normal physiological conditions, and is a conservative biological self-defense mechanism to maintain the homeostasis of the cell. When mitochondria are damaged or diseased due to various factors, the mitochondrial membrane permeability and potential change, PTEN-induced kinase 1 (PINK1) and Parkin E3 ubiquitin ligase are induced and activated downstream biochemical response. Under normal physiological conditions, PINK1 can be rapidly degraded after targeting mitochondria, but when the mitochondria are damaged and diseased, the mitochondrial membrane permeability and potential change, PINK1 cannot enter the mitochondria, but is riveted to the outer membrane of the mitochondria, and through its phosphorylase activity, the ubiquitin and Parkin ubiquitin-like domain are phosphorylated and activated and enriched around the mitochondria, and further recruit autophagy-related receptors such as NDP52 and optineurin (OPTN), the latter two activate Microtubule-Associated Protein 1 Light Chain 3 (LC3), especially LC3B-I is converted to lipidized LC3B-II. At the same time, autophagy-related receptors also promote the formation of a large number of mitochondrial autophagosomes, which are the main sites of contact and fusion between mitochondria and organelles such as endoplasmic reticulum and lysosomes, and affect the final outcome of mitochondrial autophagosomes.
[0006] Appropriate level of mitochondrial autophagy is one of the survival strategies of tumors. In extreme cases such as resistance to chemotherapy drugs, anti-tumor immunity, high oxygen free radical (ROS) level leading to apoptosis, nutritional deficiency, hypoxia and other causes of tumor death, appropriate mitochondrial autophagy is a self-protection mechanism for tumor cells to utilize limited energy to remove harmful or damaged mitochondria, thereby reducing apoptotic cell death caused by excessive mitochondrial damage. However, excessive mitochondrial autophagy is a process of depleting mitochondria, which is not conducive to the survival of tumor cells. At the same time, the mitochondrial autophagy signaling pathway of tumor cells presents an abnormal state, and is closely related to mitochondrial-induced apoptosis and other events. When the killing effect of drugs on cells, DNA damage, inflammation, hypoxia and nutritional deficiency lead to metabolic stress exceeding a certain threshold or triggering abnormal mitochondrial autophagy switch, mitochondrial autophagy can be intensified, which in turn causes cell death. Under the action of chemotherapy drugs, targeted molecular drugs and the like, irreversible process of mitochondrial autophagy can be caused, which eventually leads to cell death. Therefore, appropriate mitochondrial autophagy is an important pathway for tumor cell survival and drug resistance, while excessive mitochondrial autophagy can cause excessive mitochondrial damage, leading to apoptosis and even cell death.
[0007] Targeting mitochondrial autophagy process is a new direction of research and development of chemosensitizing drugs, but it is still limited to basic research. Therefore, finding drugs with mitochondrial autophagy regulation in clinical drugs as a combination regimen of chemosensitization can be expected to quickly convert basic research ideas into clinical applications. SUMMARY
[0008] Therefore, the technical problem to be solved by the present application is to provide an antitumor composition and its application.
[0009] The composition provided by the present application consists of a mitochondrial autophagy agonist and a chemotherapeutic drug,
[0010] The chemotherapeutic drug is at least one selected from epirubicin, platinum-based chemotherapeutic drugs or 5-fluorouracil;
[0011] The mitochondrial autophagy agonist is at least one selected from CCCP, olaparib or ketoconazole.
[0012] The platinum-based chemotherapeutic drugs include cisplatin and other platinum-derived chemotherapeutic drugs; and their same name salts or derivatives. For example, cisplatin, carboplatin or oxaliplatin. The present application finds that the combination of mitochondrial autophagy agonists and chemotherapeutic drugs (epirubicin / cisplatin and 5-fluorouracil / 5-Fu) has an inhibitory effect on hepatocellular carcinoma Figure 1 ), and it is proved that the combination of the two drugs can produce significant synergistic effect. In the present application, the two drugs in the composition can exist in mixture or independently, which is not limited by the present application.
[0013] In the present application, the mass ratio of the mitochondrial autophagy agonist and the chemotherapeutic drug is 1:(0.0005-1000). As a preferred, the mass ratio of the mitochondrial autophagy agonist and the chemotherapeutic drug is 1:(0.0025-500). For example, the mass ratio of the mitochondrial autophagy agonist and the chemotherapeutic drug is (0.62-26):(0.1-1.6).
[0014] In some embodiments, the composition consists of epirubicin and CCCP, wherein the mass ratio of epirubicin to CCCP is (0.1-1.6):(0.62-10) or (0.4-1.6):(0.62-10) or (0.8-1.6):(0.62-10) or 1.6:(0.62-10) or 1.6:(2.5-10) or 1.6:(5-10); in some specific embodiments, the mass ratio of epirubicin to CCCP is 0.1:0.62, 0.1:1.25, 0.1:2.5, 0.1:5, 0.1:10, 0.2:0.62, 0.2:1.25, 0.2:2.5, 0.2:5, 0.2:10, 0.4:0.62, 0.4:1.25, 0.4:2.5, 0.4:5, 0.4:10, 0.8:0.62, 0.8:1.25, 0.8:2.5, 0.8:5, 0.8:10, 1.6:0.62, 1.6:1.25, 1.6:2.5, 1.6:5, or 1.6:10.
[0015] In other embodiments, the composition consists of epirubicin and olaparib, wherein the mass ratio of epirubicin to olaparib is (0.1-1.6):(1.25-20) or (0.1-1.6):(5-20) or 1.6:(1.25-2.5) or (0.4-1.6):(5-20) or (0.1-1.6):20 or 0.4:(5-20) or 0.4:(5-10); in some specific embodiments, the mass ratio of epirubicin to olaparib is 0.1:1.25, 0.1:2.5, 0.1:5, 0.1:10, 0.1:20, 0.2:1.25, 0.2:2.5, 0.2:5, 0.2:10, 0.2:20, 0.4:1.25, 0.4:2.5, 0.4:5, 0.4:10, 0.4:20, 0.8:1.25, 0.8:2.5, 0.8:5, 0.8:10, 0.8:20, 1.6:1.25, 1.6:2.5, 1.6:5, 1.6:10, or 1.6:20.
[0016] In some embodiments, the composition consists of epirubicin and ketoconazole, wherein the mass ratio of epirubicin and ketoconazole is (0.1-1.6):(1.62-26) or (0.4-1.6):(1.62-26) or (0.4-1.6):(6.5-26) or (0.8-1.6):(6.5-26) or 1.6:(6.5-26) or 1.6:(13-26). In some specific embodiments, the mass ratio of epirubicin and ketoconazole is 0.1:1.62, 0.1:3.25, 0.1:6.5, 0.1:13, 0.1:26, 0.2:1.62, 0.2:3.25, 0.2:6.5, 0.2:13, 0.2:26, 0.4:1.62, 0.4:3.25, 0.4:6.5, 0.4:13, 0.4:26, 0.8:1.62, 0.8:3.25, 0.8:6.5, 0.8:13, 0.8:26, 1.6:1.62, 1.6:3.25, 1.6:6.5, 1.6:13 or 1.6:26.
[0017] The present application also provides use of the composition as any one of the preceding embodiments in the preparation of an anti-tumor drug.
[0018] In some embodiments, the tumor is a liver cancer, a gallbladder cancer, a pancreatic cancer, a small intestine tumor, a large intestine cancer / colorectal cancer, an esophageal cancer, a stomach cancer, a digestive system tumor, a bladder cancer, a hematological tumor, a bone tumor, a cartilage tumor, a lung cancer, a trachea tumor, a glottis cancer, a brain cancer, a central nervous system tumor, a peripheral nervous system tumor, a head and neck tumor, a kidney cancer, a laryngeal cancer, a nasopharyngeal cancer, a lung cancer, a muscle tissue cancer, a cancer of oral or nasal mucosa, an ovarian cancer, a breast cancer, a prostate cancer, a cervical cancer, an endometrial cancer, an exogenous genital tumor, a urogenital tract tumor, an adrenal gland tumor, a skin cancer, a spleen tumor, a testicular cancer and / or a thyroid cancer. In some specific embodiments, the tumor is a liver cancer. More specifically, the tumor is a primary liver cancer. More specifically, the tumor is a hepatocellular liver cancer.
[0019] In some embodiments, the anti-tumor comprises inhibiting tumor cell activity and / or promoting tumor cell apoptosis.
[0020] In some specific embodiments, in the anti-tumor, the tumor cell is a liver cancer cell, and more specifically, the liver cancer cell is MHCC97H and / or Bel-7402.
[0021] Further, the present application also provides an anti-tumor drug, which comprises the composition as described above and a pharmaceutically acceptable excipient.
[0022] The pharmaceutically acceptable adjuvant includes one or more than one mixture of a flavoring agent, a filler, a lubricant, a preservative, a suspending agent, a food color, a diluent, an emulsifying agent, a disintegrating agent or a plasticizer.
[0023] The dosage form of the medicine of the present application is a gastrointestinal administration dosage form and / or a non-gastrointestinal administration dosage form.
[0024] The gastrointestinal administration dosage form is a powder, a tablet, a granule, a capsule, a solution, an emulsion or a suspension.
[0025] The non-gastrointestinal administration dosage form is an injection administration dosage form, a respiratory administration dosage form, a skin administration dosage form, a mucous membrane administration dosage form or a cavity administration dosage form.
[0026] The content of the composition in the medicine of the present application is not limited, and the dosage of each administration is not limited, preferably, the administration dosage is not less than an effective dosage. The dosage of the composition in the medicine is also not less than an effective amount.
[0027] The medicine also includes other therapeutic agents with anti-tumor activity, which are selected from Mitomycin, Gemcitabine, Capecitabine, Irinotecan, Oxaliplatin, Cyclophosphamide, Methotrexate, Adriamycin, Vincristine, Sorafenib, Sunitinib, Bevacizumab, Erlotinib, Lenvatinib Mesylate, Regorafenib, Lenvima, Entecavir, Peginterferon Alfa-2a, Interferon, Lamivudine, Acriflavine (Icariin), Cinobufacitin Capsule, Kanglaite Injection, Cidan Capsule, Sodium Cantharidate Vitamin B6 Injection, Jinlong Capsule, Biejiajian Pill, Huai'er Granule, Elemene Injection, Kana Injection, Aidi Injection, Ganfule Capsule, Oils of Calophyllum Inophyllum Soft Capsule, Compound Cantharides Capsule, Transfer Factor, various immune checkpoint drugs (PD-1 antibody, PD-L1 antibody, TIGIT antibody, CTLA4 antibody, etc.), Gamma Globulin, various Chinese medicine mixtures, such as Chaihu Shugan San of Jingyue Quanshu, Daxia Yuyu Decoction of Yilin Gaicuo, Xiaoyao San of Taiping Huimin Heji, Yinchenhao Decoction and Wuling San of Shanghan Lun, Yiganjian Decoction of Liuzhou Yihua, etc.
[0028] The present application also provides an anti-tumor method, which comprises administering the medicine as described above or the composition as described above.
[0029] In the anti-tumor method, two or more active ingredients are administered simultaneously or sequentially, and the present application does not limit the administration sequence. The interval between the administration of the two active ingredients is any time interval within 30 days, preferably any time interval within 3 days, preferably not longer than 24 hours, preferably not longer than 12 hours, preferably not longer than 6 hours, preferably not longer than 5 hours, more preferably not longer than 4 hours, even more preferably not longer than 3 hours, more preferably not longer than 2 hours and most preferably not longer than 1 hour and / or not longer than 6 hours, preferably not longer than 5 hours, more preferably not longer than 4 hours, even more preferably not longer than 3 hours, more preferably not longer than 2 hours and most preferably not longer than 1 hour after the administration of the other therapeutic agent.
[0030] In the anti-tumor method of the present application, the administration of the drugs includes, but is not limited to, sublingual administration, oral administration, subcutaneous injection, intradermal injection, intramuscular injection, intravenous injection, intravenous infusion, intraperitoneal administration, transanal administration, transairway administration, transcutaneous or other mucosal administration, etc.
[0031] In the anti-tumor method of the present application, the administration frequency of two or more drugs can be the same or different, which is not limited by the present application. For example, the administration frequency of two or more drugs is independently selected from 1 month / time, 15 days / time, 7 days / time, once every other day, 1 time / day, 2 times / day, 3 times / day or 4 times / day.
[0032] The present application provides that the combination of mitochondrial autophagy agonists and chemotherapeutic drugs can produce more effective inhibition on tumors, and experiments have shown that the combination of the two drugs can produce significant synergistic effect. In particular, the combination of the two drugs has good therapeutic effect on liver cancer, which solves the problem of low sensitivity of liver cancer to chemotherapy and no clinically available chemosensitizing agent. BRIEF DESCRIPTION OF DRAWINGS
[0033] Figure 1 Schematic diagram: mitochondrial autophagy agonists (CCC, Olaparib, Ketoconazole) combined with chemotherapeutic drugs (epirubicin, cisplatin and 5-Fu) for treating liver cancer;
[0034] Figure 2 Transmission electron microscopy (TEM) verification of three mitochondrial autophagy agonists inducing mitochondrial autophagy in liver cancer cells: (A) TEM verification of three mitochondrial autophagy activators (CCC, Ketoconazole and Olaparib) inducing mitochondrial autophagy in HCC cancer cell line (Bel-7402); (B) Transmission electron microscopy showing statistical analysis of liver cancer cell (Bel-7402) mitochondria autophagosomes (n=50 in each group, 10 in each group); (C) TEM verification of three mitochondrial autophagy activators (CCC, Ketoconazole and Olaparib) inducing mitochondrial autophagy in HCC cancer cell line (MHCC97H); (D) Transmission electron microscopy showing statistical analysis of liver cancer cell (MHCC97H) mitochondria autophagosomes (n=50 in each group, 10 in each group);
[0035] Figure 3To enhance the effect of chemotherapeutic drug epirubicin in hepatocellular carcinoma as a mitochondrial autophagy activator, analysis was performed by Syngerfinder platform, wherein (A) was the drug synergy analysis of epirubicin and CCCP, and a dose-response matrix and 2D and 3D drug synergy model (ZIP synergy score 7.109±2.73) were obtained; (B) was the drug synergy effect analysis of epirubicin and olaparib, and a dose-response matrix and 2D and 3D drug synergy model (ZIP synergy score 5.884±3.32) were obtained; (C) was the drug synergy effect analysis of epirubicin and ketoconazole, and a dose-response matrix and 2D and 3D drug synergy model (ZIP synergy effect score 3.423±1.24) were obtained.
[0036] Figure 4 Analysis was performed by Syngerfinder platform, and the Bliss synergy score of epirubicin and CCCP was 6.995±2.73; the Bliss synergy score of epirubicin and olaparib was 5.884±3.32; and the Bliss synergy score of epirubicin and ketoconazole was 3.342±1.24.
[0037] Figure 5 Analysis was performed by DrugComb platform, and the LOEWE synergy score of epirubicin and CCCP was (9.61, 18.68, 8.84); the LOEWE synergy score of epirubicin and olaparib was (5.60, 9.25, 8.85); and the LOEWE synergy score of epirubicin and ketoconazole was (6.72, 7.68, 6.13).
[0038] Figure 6 Analysis was performed by DrugComb platform, and the HSA synergy score of epirubicin and CCCP was (13.39, 12.74, 11.65); the HSA synergy score of epirubicin and olaparib was (11.97, 9.35, 14.17); and the HSA synergy score of epirubicin and ketoconazole was (9.60, 10.90, 9.95). DETAILED DESCRIPTION
[0039] The present application provides an anti-tumor composition and its application, and those skilled in the art can refer to the content herein to appropriately improve the process parameters. It is particularly pointed out that all similar substitutions and changes are obvious to those skilled in the art, and they are considered to be included in the present application. The methods and applications of the present application have been described by preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications herein without departing from the content, spirit and scope of the present application, to realize and apply the present application technology.
[0040] Unless otherwise defined, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art.
[0041] Further, as used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Specifically, as used herein, the singular forms "a" (or "an"), "the" and "said" include plural referents unless the context clearly dictates otherwise.
[0042] The terms "comprises", "comprising", "includes", "including" and "has" or "having", as used herein, are specifically intended to be construed as inclusive or open ended and not exclusive or limiting, unless explicitly stated to the contrary. As used herein, the term "comprises" and variations thereof, such as "comprising" and "comprise", are used throughout to mean, and are interpreted to mean, that the named steps, elements and / or components can be present or combined, but are not limited to, the steps, elements and / or components listed.
[0043] The term "and / or", when used in the context of "A and / or B" or the like, means that A or B or both A and B can be present. The term "and / or" is used in this disclosure to mean "and", "or", "and / or" and "one or the other" and "one and the other" and "one but not the other".
[0044] In this application, "at least one", "one or more" means one or more, and "plurality" means two or more. "At least one of the following (items)" or the like means any combination of these items, including a single item (or a plurality of items).
[0045] In this application, numerical ranges and parameters are approximations. Although the exact numerical values are inherently approximations, they are provided to give a general idea of the range of values that the parameters can take on. Unless otherwise stated, it is intended that the numerical ranges and parameters set forth herein are to be read as being open-ended ranges. Thus, for example, a range of "1% to 50%" is intended to be interpreted to include not only the explicitly stated range of "1% to 50%" but also the range of "about 1% to about 50%" (such as within 10% of the stated range at either end) and sub-ranges thereof (such as 1% to 49.9% or 2.3% to 45.7%). In an embodiment, the numerical values are in the range of ±10%, ±5%, ±1%, or ±0.5%.
[0046] In the embodiments of the present application, by taking propofol combined with epirubicin as an example, it is found that propofol combined with chemotherapy drugs can effectively inhibit liver cancer. In fact, propofol combined with various chemotherapy drugs can achieve the effect of treating liver cancer, not limited to propofol combined with epirubicin, propofol combined with cisplatin, propofol combined with 5-Fu, and other combined drug regimens, and the administration mode is not limited to simultaneous administration, asynchronous administration, sequential administration, and administration of various mixtures.
[0047] In the present application, the implementation object of inhibiting liver cancer is a human or a mammal, and the mammal includes bovine, equine, ovine, porcine, canine, feline, rodent, and primate.
[0048] The test materials used in the present application are all ordinary commercially available products and can be purchased in the market.
[0049] Among them, CCCP / Carbonyl Cyanide m-Chlorophenylhydrazone, also known as: Carbonyl cyanide 3-chlorophenylhydrazone; Carbonyl Cyanide m-Chlorophenylhydrazone
[0050] Olaparib, also known as Olaparib, is an English name.
[0051] Ketoconazole, also known as Ketoconazole, is an English name.
[0052] Epirubicin, also known as Epirubicin, is an English name for Epidoxorubicin.
[0053] Cisplatin / cisplatin also includes other platinum-derived chemotherapy drugs; and its same name salt or derivative.
[0054] 5-Fu, also known as 5-Fluorouracil, is also known as 5-Fluorouracil, and the fluorouracil also includes its same name salt or derivative.
[0055] It should be understood that in various embodiments of the present application, the size of the sequence number of the above-mentioned processes does not mean the order of execution, and part or all of the steps can be executed in parallel or in sequence, and the execution order of each process should be determined according to its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.
[0056] Some cases are described in the embodiments of the present application. Among them, the embodiments show some implementation ways of the present application. However, this does not mean that the effect of the present application can only be achieved in these cases. In fact, any concentration of each component between the two endpoint values shown in the embodiments can achieve good antitumor effect, in addition, many attempts have been made in the development process, such as using different chemotherapy drugs or analogues of propofol, using different proportions to carry out tumor cell inhibition experiments, but the effect of these attempts is not as good as the effect described in the embodiments, which will not be described here.
[0057] The present application will be further described below in conjunction with the embodiments:
[0058] Examples
[0059] The drug concentrations shown in the following examples were subjected to preliminary safety experiments (IC50) in pre-experiments, and the combination scheme for treating liver cancer models in vivo and in vitro was determined by joint drug experiments and re-detection of IC50 concentrations. The selected combination drug concentrations are lower than the IC50 of the above-mentioned single drug, and in the scheme described in this case, the drug dose is much lower than the median lethal concentration (IC50, 0.1 ug / ml or 0.17 uM) of non-tumor cells HEK293T cells or the highest clinical dose recorded in the existing literature (see J Nat Prod. 2016 Sep 23; 79(9): 2397-402. doi: 10.1021 / acs.jnatprod.6b00639.).
[0060] The combination drug test was performed on liver cancer cell lines (HepG2) using the above-mentioned mitochondrial autophagy agonists and epirubicin. We used the online combination drug analysis platform Syngerfinder (https: / / synergyfinder.fimm.fi) and DrugComb (https: / / drugcomb.fimm.fi) platform to analyze the synergistic effect of drug combinations.
[0061] Drug dosage:
[0062] Epirubicin: 0.1 ug / ml, 0.2 ug / ml, 0.4 ug / ml, 0.8 ug / ml, 1.6 ug / ml;
[0063] CCCP: 0.62 ug / ml, 1.25 ug / ml, 2.5 ug / ml, 5 ug / ml, 10 ug / ml;
[0064] Ketoconazole: 1.62 ug / ml, 3.25 ug / ml, 6.5 ug / ml, 13 ug / ml, 26 ug / ml;
[0065] Olaparib: 1.25 ug / ml, 2.5 ug / ml, 5 ug / ml, 10 ug / ml, 20 ug / ml.
[0066] The results are shown in Figures 2 to 6
[0067] 1. Three mitochondrial autophagy activators (CCCP, ketoconazole and olaparib) can induce mitochondrial autophagy in liver cancer cells;
[0068] 2、Through Syngerfinder platform analysis, the ZIP synergy score of epirubicin and CCCP is 7.109±2.73; the ZIP synergy score of epirubicin and olaparib is 5.912±3.32; the ZIP synergy score of epirubicin and ketoconazole is 3.423±1.24. It is shown that epirubicin can produce synergistic effect with three kinds of mitochondrial autophagy activators Figure 3 ).
[0069] 3、Through Syngerfinder platform analysis, the Bliss synergy score of epirubicin and CCCP is 6.995±2.73; the Bliss synergy score of epirubicin and olaparib is 5.884±3.32; the Bliss synergy score of epirubicin and ketoconazole is 3.342±1.24. It is shown that epirubicin can produce synergistic effect with three kinds of mitochondrial autophagy activators Figure 4 ).
[0070] 4、Through DrugComb platform analysis, the LOEWE synergy score of epirubicin and CCCP is (9.61, 18.68, 8.84); the LOEWE synergy score of epirubicin and olaparib is (5.60, 9.25, 8.85); the LOEWE synergy score of epirubicin and ketoconazole is (6.72, 7.68, 6.13). It is shown that epirubicin can produce synergistic effect with three kinds of mitochondrial autophagy activators Figure 5 ).
[0071] 5、Through DrugComb platform analysis, the HSA synergy score of epirubicin and CCCP is (13.39, 12.74, 11.65); the HSA synergy score of epirubicin and olaparib is (11.97, 9.35, 14.17); the HSA synergy score of epirubicin and ketoconazole is (9.60, 10.90, 9.95). It is shown that epirubicin can produce synergistic effect with three kinds of mitochondrial autophagy activators Figure 6 ).
[0072] The above is only the preferred embodiment of the present application, it should be noted that for those skilled in the art, without departing from the principles of the present application, can make a number of improvements and refinements, these improvements and refinements should also be considered as the protection scope of the present application.
Claims
1. Composition, characterized in that, Consists of a chemotherapeutic drug and a mitochondrial autophagy agonist, the chemotherapeutic drug is epirubicin, and the mitochondrial autophagy agonist is ketoconazole.
2. The composition of claim 1, wherein The mass ratio of epirubicin and ketoconazole is (0.1-1.6):(1.62-26).
3. The composition of claim 1, wherein The mass ratio of epirubicin and ketoconazole is 0.1:1.62, 0.1:3.25, 0.1:6.5, 0.1:13, 0.1:26, 0.2:1.62, 0.2:3.25, 0.2:6.5, 0.2:13, 0.2:26, 0.4:1.62, 0.4:3.25, 0.4:6.5, 0.4:13, 0.4:26, 0.8:1.62, 0.8:3.25, 0.8:6.5, 0.8:13, 0.8:26, 1.6:1.62, 1.6:3.25, 1.6:6.5, 1.6:13, or 1.6:
26.
4. Use of the composition of any one of claims 1 to 3 in the preparation of a drug for resisting liver cancer.
5. The use according to claim 4, wherein the compound is ###0002### The resisting liver cancer includes inhibiting liver cancer cell activity.
6. The use according to claim 4, wherein the compound is ###0002### The resisting liver cancer includes promoting liver cancer cell apoptosis.
7. Use according to claim 5 or 6, characterized in that, The liver cancer cells include at least one of MHCC97H, Bel-7402, and HepG2.
8. A medicament, characterized by, It also includes other therapeutic agents with anti-tumor activity, the therapeutic agents are selected from mytomycin, gemcitabine, capecitabine, irinotecan, oxaliplatin, cyclophosphamide, methotrexate, doxorubicin, vincristine, sorafenib, sunitinib, bevacizumab, erlotinib, lenvatinib mesylate capsule, regorafenib, linifanib, entecavir, long-acting polyethylene glycol, interferon, lamivudine, acoradin, cinobufacine capsule, kanglaite injection, cidan capsule, sodium cantharidate vitamin B6 injection, jinlong capsule, biejia decoction, sophora fl avescens granules, elemene injection, kana injection, aidi injection, ganfule capsule, brucea javanica oil soft capsule, compound cantharidin capsule, transfer factor, immune checkpoint drugs, gamma globulin, chaihu shugan powder, dixia zhuyu decoction, xiaoyao powder, yinchenhao decoction combined with wulingsan, yiguan decoction.
9. The medicament according to claim 8, characterized in that, The dosage form is a gastrointestinal administration dosage form and / or a non-gastrointestinal administration dosage form; 10. The medicament according to claim 8 or 9, characterized in that, The gastrointestinal administration dosage form is a powder, a tablet, a granule, a capsule, a solution, an emulsion, or a suspension; The non-gastrointestinal administration dosage form is an injection administration dosage form, a respiratory administration dosage form, a skin administration dosage form, a mucosa administration dosage form, or a cavity administration dosage form.