Application of chalcone compound in preparation of medicine for treating cervical cancer

Abstract

The invention belongs to the technical field of disease drug treatment, and particularly relates to application of a chalcone compound in preparation of drugs for treating cervical cancer. The chalcone compound can remarkably inhibit cervical cancer cells, so that the growth of cervical cancer tumors is effectively inhibited; and the effect is better than that of the existing antitumor drug 5-fluorouracil.

Description

Technical Field

[0001] The invention belongs to the technical field of disease drug treatment, and specifically relates to the application of a chalcone compound in the preparation of a drug for treating cervical cancer. Background Art

[0002] Cervical cancer is a malignant tumor of the female reproductive tract that occurs in the cervix.

[0003] "Li GQ, Gong LQ, Xu XH, et al. FABP4 is a dependent risk factor for lymph node metastases and poor prognosis in patients with cervical cancer. Cancer cell Int. 2021, 21, 568" indicates that FABP4 may be a new target for the treatment of cervical cancer. Specifically, FABP4 is a new type of fat factor that regulates inflammation and angiogenesis. It is expressed in adipocytes, macrophages, etc. It can preferentially bind to fatty acids, enter the cytoplasm for chemical modifications such as oxidation and esterification, and be transported to various parts of the body to participate in lipid synthesis, metabolism, inflammatory response and other signal transduction; increased FABP4 levels can inhibit lipolysis, promote adipose tissue lipogenesis, and increase free fatty acid levels. Compared with normal cervical epithelium, FABP4 expression in cervical cancer tissues is significantly increased and correlated with poor survival; after knocking out FABP4, the proliferation, migration and invasion of cervical cancer cells were significantly inhibited, accompanied by increased E-cadherin expression and down-regulated N-cadherin, Vimentin and p-AKT expression. Therefore, the development of FABP4 inhibitors has great clinical significance for the treatment of cervical cancer.

[0004] Although FABP4 protein has great potential as a target in drug development, there are still two factors that restrict the development of FABP4 inhibitor drugs. On the one hand, FABP4 inhibitors have poor selectivity and there is a lack of selective small molecule inhibitors targeting FABP4; on the other hand, there are no reports of FABP4 inhibitor drugs with strong anti-cervical cancer effects. Summary of the invention

[0005] The present invention finds that natural chalcone Kuraridine (also called chalcone compound) can inhibit FABP4 activity, and can also significantly inhibit cervical cancer cells, and effectively inhibit cervical cancer tumor growth.

[0006] In order to achieve the above object, the present invention can adopt the following technical solutions:

[0007] In one aspect, the present invention provides an application of a chalcone compound in the preparation of a drug for treating cervical cancer. The structural formula of the chalcone compound is shown below:

[0008] Preferably, the above application includes one or more of the following applications: (i) application of a chalcone compound in the preparation of a drug for inhibiting Ca-Ski cell proliferation; (ii) application of a chalcone compound in the preparation of a drug for inhibiting C-33-A cell proliferation.

[0009] Preferably, in the above application, the dosage form of the drug includes injection, oral solution, patch, tablet, powder or capsule.

[0010] Another aspect of the present invention provides a use of a chalcone compound as or in the preparation of a FABP4 inhibitor. The structural formula of the chalcone compound is shown below:

[0011] The beneficial effects of the present invention include: the natural chalcone Kuraridine can significantly inhibit cervical cancer cells, thereby effectively inhibiting the growth of cervical cancer tumors; and the effect is better than the existing anti-tumor drug 5-fluorouracil. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 It is the result of ligand-protein binding between natural chalcone Kuraridine and FABP4;

[0013] Figure 2 The results of the anti-cervical cancer cell activity of the natural chalcone Kuraridine. DETAILED DESCRIPTION

[0014] The examples are provided to better illustrate the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art may make non-essential improvements and adjustments to the implementation scheme according to the above invention content, which still fall within the protection scope of the present invention.

[0015] The terms used herein are only used to describe specific embodiments and are not intended to limit the present disclosure. Unless the context has a significantly different meaning, expressions in the singular include expressions in the plural. As used herein, it should be understood that terms such as "include", "have", "include" are intended to indicate the presence of features, numbers, operations, components, parts, elements, materials or combinations. The terms of the present invention are disclosed in the specification, and are not intended to exclude the possibility that one or more other features, numbers, operations, components, parts, elements, materials or combinations thereof may exist or may be added. As used herein, " / " may be interpreted as "and" or "or", depending on the circumstances.

[0016] An embodiment of the present invention provides an application of a chalcone compound in the preparation of a drug for treating cervical cancer. The structural formula of the chalcone compound is shown below:

[0017] In some specific examples, the above applications include one or more of the following applications: (i) application of chalcone compounds in the preparation of drugs for inhibiting Ca-Ski cell proliferation; (ii) application of chalcone compounds in the preparation of drugs for inhibiting C-33-A cell proliferation.

[0018] Specifically, chalcone compounds can achieve the purpose of treating cervical cancer by inhibiting the proliferation of Ca-Ski cells and C-33-A cells.

[0019] In some specific examples, in the above applications, the dosage form of the drug includes injection, oral solution, patch, tablet, powder or capsule.

[0020] An embodiment of the present invention provides an application of a chalcone compound as or in the preparation of a FABP4 inhibitor. The structural formula of the chalcone compound is shown below:

[0021] Specifically, chalcone compounds can form ligand-FABP4 binding interactions with proteins, providing guidance for the design of FABP4 inhibitor drugs.

[0022] In order to better understand the present invention, the content of the present invention is further explained below in conjunction with specific examples, but the content of the present invention is not limited to the following examples.

[0023] Example 1 Enzyme selectivity of the above natural chalcone Kuraridine for FABP4

[0024] 1-anilinonaphthalene-8-sulfonic acid (10 μM) was mixed with FABP4 protein (10 μM, provided by MedChemExpress) in phosphate buffer solution (PBS, pH 7.4); the compound was dissolved in dimethyl sulfoxide to prepare a 10 mM compound solution, and then the compound solution was added to the above protein mixture and incubated at room temperature for 3 minutes; the fluorescence signal at an excitation wavelength of 370 nm and an emission wavelength of 470 nm was measured using a multi-mode microplate reader (Molecular Devices, CA, USA), and the IC of the compound was calculated using Prism10 software 50 In addition, FABP4 inhibitor FABP4 / 5-IN-4 was set as a control. The test results are shown in Table 1 below.

[0025] Table 1 Enzyme activity of compound Kuraridine against FABP4 and FABP5

[0026]

[0027] It can be seen from Table 1 that the compound Kuraridine has a strong inhibitory activity against FABP4, IC 50 The value was 1.35 μM, indicating that Kuraridine is an inhibitor of FABP4; however, Kuraridine has a weak inhibitory activity on FABP5, with an IC 50 The values ​​were >20 μM, thus the compound Kuraridine is a selective FABP4 inhibitor.

[0028] Example 2 Compound Kuraridine forms ligand-FABP4 binding interaction with FABP4

[0029] Download the FABP4 protein structure and conduct docking experiments (PDB: 3FR5). The compound Kuraridine can form four unique and novel hydrogen bonds with Ser53, Ala33, Glu72 and Arg106 of the FABP4 protein. The results are as follows Figure 1 As shown, the compound Kuraridine forms a ligand-FABP4 binding interaction with FABP4, which can be further optimized and designed as a drug.

[0030] Example 3 Anti-cervical cancer activity of compound Kuraridine

[0031] Cervical cancer Ca-Ski cells and C-33-A cells were seeded at appropriate densities in 96-well plates at 37 °C and 5% CO. 2 The cells were incubated under the environment of 40 °C; the compound Kuraridine was diluted with DMSO, and the final starting concentrations of the compound were 20 μM, 10 μM, 5 μM, 2.5 μM, 1.25 μM, 0.625 μM and 0.3125 μM; the compound Kuraridine was cultured in the cells for 48 hours, 20 μl of MTT solution (5 mg / ml) was added to each well, and the cells were cultured at 37 °C for 4 hours; the culture medium in each well was carefully removed, and 150 μl of DMSO was added to each well; the well plate was placed on an oscillator for 15 minutes, the absorbance was measured at a wavelength of 570 nm using an enzyme reader, and the IC of the compound was calculated using Prism10 software 50 value.

[0032] The experimental results are as follows Figure 2As shown, the results showed that compared with the control group Control, the cell survival rate of cervical cancer Ca-Ski cells and C-33-A cells treated with the compound Kuraridine was significantly reduced (*P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001), indicating that the compound Kuraridine has anti-cervical cancer cell activity and can be used as an anti-cervical cancer drug.

[0033] In addition, the IC values ​​of 5-fluorouracil, an anticancer drug, on cervical cancer Ca-Ski cells and C-33-A cells were 50 The values ​​were 19.89 μM and 14.76 μM respectively; the IC values ​​of Kuraridine on cervical cancer Ca-Ski cells and C-33-A cells were 50 The values ​​were 1.32 μM and 4.61 μM, respectively. The cell activity results are shown in Table 2. The above results show that the anti-cervical cancer cell activity of the compound Kuraridine is significantly better than that of the anti-tumor drug 5-fluorouracil.

[0034] Table 2 Antiproliferative activity of Kuraridine on cervical cancer cells

[0035]

[0036] Example 4 Anti-cervical cancer activity of compound Kuraridine in vivo

[0037] Cervical cancer Ca-Ski cells were inoculated under the skin of the right armpit of 6-week-old BALB / c-nu nude mice (provided by Beijing Huafukang Biotechnology Co., Ltd.), with 8 million cells inoculated per mouse; after 7 days, the tumor volume was close to 100mm 3 -200mm 3 The mice were randomly divided into 3 groups (n=6), including the model group (gavage with normal saline once every two days), the positive drug group (gavage with 5-fluorouracil, 50 mg / kg, once every two days), and the compound Kuraridine group (gavage with compound Kuraridine, 50 mg / kg, once every two days), and the drugs were continuously administered for 21 days (administered on the first day, then once every two days, a total of 11 times, and a total of 21 days). At the end of the drug administration, the tumor weight of each group was weighed, and the average tumor weight of each group was calculated. Tumor inhibition rate = (1-drug group tumor weight / model group tumor weight) × 100%, the results are shown in Table 3.

[0038] Table 3 Tumor inhibition rate of Kuraridine compound on cervical cancer Ca-Ski transplanted tumor in nude mice

[0039] Grouping Transplanted tumor weight (mg) Tumor inhibition rate (%) Model Group 495.37±120.63 — Kuraridine group of compounds 210.93±63.82 57.42 Positive drug 5-fluorouracil group 305.77±85.23 38.27

[0040] It can be seen from Table 3 above that the tumor inhibition rate of Kuraridine on nude mice with cervical cancer Ca-Ski transplanted tumors is 57.42%, which is much higher than the tumor inhibition rate of 5-fluorouracil on nude mice with cervical cancer Ca-Ski transplanted tumors of 38.27%, indicating that the anti-cervical cancer in vivo activity of Kuraridine is significantly better than the anti-tumor drug 5-fluorouracil, and can be used as a cervical cancer drug preparation.

[0041] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present invention, which should be covered by the scope of the claims of the present invention.

Claims

1. Use of a chalcone compound in the preparation of a drug for treating cervical cancer. The structural formula of the chalcone compound is shown below:

2. The use according to claim 1, characterized in that: Applications include one or more of the following: (i) Use of a chalcone compound in the preparation of a medicament for inhibiting Ca-Ski cell proliferation; (ii) Use of a chalcone compound in the preparation of a medicament for inhibiting the proliferation of C-33-A cells.

3. The use according to claim 1 or 2, characterized in that: The drug is available in the form of an injection, oral solution, patch, tablet, powder or capsule.

4. Use of a chalcone compound as or in the preparation of a FABP4 inhibitor, the structural formula of the chalcone compound is as follows:

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