Application of combination of ferroptosis inducer and anti-angiogenesis medicine in preparation of medicine for treating tumors
By combining ferrodysfunction inducers with antiangiogenic drugs, the problem of poor efficacy of existing antiangiogenic drugs has been solved, and significant antitumor effects and higher therapeutic persistence have been achieved.
Patent Information
- Application Number
- CN202510370670.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-27
- Publication Date
- 2025-05-16
AI Technical Summary
Existing antiangiogenic drugs are not effective in treating tumors, and a single VEGF inhibition pathway cannot effectively anti-tumor.
Ferrodysmortality inducers and antiangiogenic drugs are used in combination with antiangiogenic drugs, and ferrodysmortality inducers such as Erastin and antiangiogenic drugs such as DC101 are used to improve the tumor treatment effect.
The combination of ferrodemortem inducers and antiangiogenic drugs has significantly improved the anti-tumor effect, directly inducing tumor cell death and cutting off the nutrient supply of tumor cells, reducing tumor resistance to a single drug, and improving the effectiveness and persistence of treatment.
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Figure CN120000798A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of biomedicine, and specifically relates to the application of a ferroptosis inducer combined with an anti-angiogenic drug in the preparation of a drug for treating tumors. Background Art
[0002] The high incidence and mortality of tumors make them a key issue that threatens global public health in the long term. With the in-depth understanding of the mechanism of tumor occurrence and development, the development of targeted drugs targeting key molecules in abnormal tumor signal transduction pathways has made significant progress. Tumor angiogenesis is a necessary process for the malignant proliferation and metastasis of tumors. New blood vessels deliver necessary nutrients for tumor growth and provide channels for malignant metastasis. Angiogenesis is finely and dynamically regulated by pro-angiogenic factors and anti-angiogenic factors. VEGF is a key factor in all tumor-promoting angiogenesis. VEGF binds to VEGFR receptors on the endothelial cell membrane, activates downstream MAPK signals, maintains endothelial cell survival, and promotes endothelial cell proliferation, migration and budding. During tumor development, excessive angiogenesis promotes tumor growth and metastasis. On the other hand, the new blood vessels in the tumor present abnormal characteristics such as insufficient pericyte coverage, incomplete basement membrane, and increased permeability, which hinder drug delivery and lead to poor efficacy of clinical chemotherapy and targeted drugs. Anti-angiogenic drugs targeting VEGF signals have been widely developed and applied in clinical practice. However, clinical results show that inhibiting the VEGF pathway alone cannot have a good anti-tumor effect. Some preclinical studies have shown that combining drugs that inhibit VEGF signaling with other targeted biological agents and chemotherapy has good therapeutic effects.
[0003] Ferroptosis is a cell death mode discovered in recent years that is different from apoptosis, necrosis, and autophagy. It is mainly manifested by the depletion of intracellular glutathione (GSH) or the decrease of glutathione peroxidase 4 (GPX4) activity, which leads to the inability of lipid peroxides (LPO) to be metabolized by the GSH reduction reaction catalyzed by GPX4, and then causes the ferrous iron (Fe 2+ ) mediates lipid oxidation in a manner similar to the Fenton reaction to produce a large amount of reactive oxygen species (ROS), thereby causing cell damage. Studies have shown that in order to meet growth needs, malignant tumor cells have a higher demand for iron than non-malignant cells, and this dependence on iron makes tumor cells more susceptible to ferroptosis, which makes the induction of ferroptosis bring hope for more effective treatment of tumors. A large number of studies have shown that ferroptosis induced by ferroptosis inducers can significantly inhibit tumor growth, and the combination of ferroptosis inducers with other anti-tumor drugs may achieve more significant anti-tumor effects. At present, there are no reports on the combined use of ferroptosis inducers and anti-angiogenic drugs for tumor treatment. Summary of the invention
[0004] In view of the above-mentioned deficiencies in the prior art, the main purpose of the present invention is to provide an application of a ferroptosis inducer combined with an anti-angiogenic drug in the preparation of a drug for treating tumors, and to adopt a treatment method in which a ferroptosis inducer and an anti-angiogenic drug are administered in combination, thereby improving the tumor treatment effect, solving the problem of poor efficacy of anti-angiogenic treatment, and improving the prognosis of tumor patients.
[0005] To achieve the above object, the present invention adopts the following technical solution:
[0006] The present invention provides the use of a ferroptosis inducer combined with an anti-angiogenesis drug in the preparation of a drug for treating tumors.
[0007] Preferably, the ferroptosis inducer is selected from one or more of Erastin, RSL3, FIN56, and FIN02.
[0008] Preferably, the ferroptosis inducer is Erastin.
[0009] Preferably, the tumor includes one or more of melanoma, lung cancer, pancreatic cancer, gastric cancer, kidney cancer, colon cancer, breast cancer, and liver cancer.
[0010] Preferably, the anti-angiogenic drug refers to a drug that inhibits pro-angiogenic signals in tumors.
[0011] More preferably, the anti-angiogenic drug is DC101.
[0012] Preferably, the ferroptosis inducer Erastin in the drug is used in combination with the anti-angiogenic drug DC101.
[0013] Preferably, the drug includes a ferroptosis inducer and an anti-angiogenic drug, and further includes at least one pharmaceutically acceptable carrier, excipient or vehicle.
[0014] Preferably, the dosage of Erastin, an inducer of ferroptosis, in the drug is 1-40 mg / kg, and the dosage of DC101, an anti-angiogenic drug, is 1-20 mg / kg.
[0015] More preferably, the dosage of Erastin, an inducer of ferroptosis, in the drug is 30 mg / kg, and the dosage of DC101, an anti-angiogenic drug, is 10 mg / kg.
[0016] Preferably, the order of administration of the ferroptosis inducer and the anti-angiogenic drug is sequential administration, simultaneous administration or alternating administration.
[0017] Preferably, the drug is in the form of oral administration or injection.
[0018] The present invention also provides a pharmaceutical composition, comprising Erastin, a ferroptosis inducer, and DC101, an anti-angiogenesis drug.
[0019] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention discovers for the first time that the combination of ferroptosis inducers and anti-angiogenic drugs has a highly effective anti-tumor effect; (2) ferroptosis inducers directly induce tumor cell death, and anti-angiogenic drugs cut off the nutrient supply of tumor cells, thereby inhibiting tumor growth in many ways; (3) Tumors are prone to develop resistance to a single drug, and combined drug use can reduce resistance and improve the effectiveness and sustainability of treatment; (4) This combination therapy can overcome the shortcomings of low efficiency and limited clinical application of anti-angiogenic drugs, and has broad prospects for clinical application. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 The figures are the tumor volume detection results of tumor-bearing mice during treatment in the examples.
[0021] Figure 2 The figure is a graph showing the weight of the tumors removed from the mice in each group after the treatment in the example.
[0022] Figure 3 The images are of transplanted tumor samples peeled off from mice in each group after the treatment in the Example.
[0023] Figure 4 The following are the results of the test on the weight change of mice during the treatment process in the example. DETAILED DESCRIPTION
[0024] In order to more fully understand and demonstrate the technical solutions, purposes and advantages of the present invention, the technical effects produced by the present invention are further described in detail and completely in conjunction with the accompanying drawings and specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all. It should be pointed out that for ordinary technicians in this field, other embodiments obtained without departing from the concept of the present invention all belong to the protection scope of the present invention.
[0025] Substances used to trigger ferroptosis are collectively referred to as ferroptosis inducers, which can be roughly divided into four categories according to their mechanism of action: the first category is represented by Erastin, which mainly inhibits the activity of the cystine / glutamate antiporter (system xc-), inhibits the cell's uptake of cystine, causes GSH depletion and causes GPX4 inactivation, thereby causing the accumulation of LPO and inducing cell ferroptosis; the second category is represented by FIN56, which triggers ferroptosis by promoting GPX4 degradation; the third category is represented by RSL3, which mainly induces cell ferroptosis by inhibiting GPX4 activity; the fourth category is represented by FINO2, which causes ferroptosis by oxidizing free unstable iron in the cell. In view of the diversity of ferroptosis inducers, Erastin was selected as the ferroptosis inducer.
[0026] Anti-angiogenic drugs are diverse. The main strategies for anti-angiogenesis are to eliminate pro-angiogenic factors or inhibit the activation of downstream signals induced by pro-angiogenic factors. DC101 (Anti-Mouse VEGFR-2 Antibody) was selected as a representative anti-angiogenic drug.
[0027] Example 1
[0028] In the following examples, the ferroptosis inducer Erastin and the anti-angiogenic drug DC101 were used in combination to verify that the composition had a synergistic anti-tumor effect.
[0029] (1) Tumor cells: mouse melanoma cell line B16, mouse lung cancer cell line LLC; experimental mice: 6-8 week old C57BL / 6 mice; drugs: mouse DC101 (MCE, HY-P990106), ferroptosis inducer Erastin (Aladdin, E126853).
[0030] (2) B16 and LLC cells were cultured to the logarithmic growth phase, the cells were digested, and resuspended in ice-cold PBS. The cell density was adjusted to 5×10 5 After that, 200 μL of cell suspension was subcutaneously injected into the abdomen of the mouse near the groin using an insulin needle. It should be noted that the cells were resuspended before each injection.
[0031] (3) After injection, mice were kept in an SPF environment, and the tumor growth and mental state of the mice were observed every 3-4 days. When the tumor grew to about 3 mm, the mice were divided into four groups: control group, Erastin treatment group, DC101 treatment group, and Erastin+DC101 treatment group. DC101 and Erastin were administered by intraperitoneal injection. The dose of Erastin was 30 mg / kg, and the dose of DC101 was 10 mg / kg. The control group was injected with an equal volume of 5% DMSO+corn oil and IgG isotype control. The administration frequency was once every 3 days. At the same time, the long diameter L and short diameter W of the tumor were measured with a vernier caliper, and the tumor volume V=L×W was calculated according to the following formula 2 / 2, and recorded the body weight of mice to analyze the toxic and side effects of combined drug use.
[0032] (4) When the maximum diameter of the tumor of any mouse reached or approached 20 mm, the mouse was euthanized, and the tumor tissue was removed, weighed, and used for various subsequent analyses.
[0033] The results are as follows Figures 1 to 4 As shown in the growth curve ( Figure 1 )、Photos of peeled tumors( Figure 2 ) and tumor weight ( Figure 3 ) It can be seen that the ferroptosis inducer Erastin and the anti-angiogenic drug DC101 have a certain inhibitory effect on melanoma, but the anti-tumor effect of the combination of the two is significantly better than that of the single drug, indicating that the combination of drugs has a synergistic sensitization effect. In addition, the weight measurement results show that the combination of the two has no obvious toxic side effects ( Figure 4 ).
[0034] In summary, melanoma cell line B16 and lung cancer cell line LLC were used as representative mouse tumor cell lines to construct subcutaneous tumor models in C57BL / 6 mice. When the tumor grew to a palpable size, IgG+DMSO control treatment, DC101 treatment, Erastin treatment, and DC101 combined with Erastin treatment were given. The results showed that DC101 or Erastin alone had a certain anti-tumor effect, and the anti-tumor effect of the combination group was significantly better than that of the single treatment group, indicating that ferroptosis inducers can effectively improve the efficacy of anti-angiogenic drugs, and the combination of the two is a promising tumor treatment strategy.
[0035] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. Use of a ferroptosis inducer combined with an anti-angiogenic drug in the preparation of a drug for treating tumors, wherein the drug combines a ferroptosis inducer with an anti-angiogenic drug; The ferroptosis inducing agent is selected from one or more of Erastin, RSL3, FIN56, and FIN02; The anti-angiogenesis drug is DC101.
2. The use according to claim 1, characterized in that: The ferroptosis inducing agent is Erastin.
3. The use according to claim 1, characterized in that: The tumor includes one or more of melanoma, lung cancer, pancreatic cancer, gastric cancer, kidney cancer, colon cancer, breast cancer, and liver cancer.
4. The use according to claim 1, characterized in that: The drug includes a ferroptosis inducer and an anti-angiogenic drug, and also includes at least one pharmaceutically acceptable carrier, excipient or vehicle.
5. The use according to claim 1, characterized in that: The order of administration of the ferroptosis inducer and the anti-angiogenic drug is sequential administration, simultaneous administration or alternating administration.
6. The use according to claim 1, characterized in that: The dosage of Erastin, an ferroptosis inducer, in the medicine is 1-40 mg / kg, and the dosage of DC101, an anti-angiogenic drug, is 1-20 mg / kg.
7. The use according to claim 1, characterized in that: The drug dosage form is oral or injection.
8. A pharmaceutical composition, characterized in that It includes ferroptosis inducer Erastin and anti-angiogenic drug DC101, and the mass ratio of the two is 1-40:1-20.