CN108042545B - Application of azelastine hydrochloride in the preparation of drugs for inhibiting colon cancer tumor growth - Google Patents

Abstract

The invention discloses the application of azelastine hydrochloride as a drug for inhibiting the growth of colon cancer tumors. Azelastine hydrochloride is a 2,3-diazepine derivative, approved by the FDA for urticaria, allergic asthma, allergic rhinitis, etc., with strong and long-lasting effects. In the present invention, azelastine hydrochloride can be used for inhibiting the growth of colon cancer cells, and its inhibiting effect on tumor growth is remarkable. Most of the existing anticancer drugs are expensive, which limit the use of drugs and are accompanied by obvious toxic and side effects. The azelastine hydrochloride has small side effects and low price, and overcomes the shortcomings of the existing medicines. And azelastine hydrochloride can be used in combination with traditional anticancer drugs SN38 and Oxaliplatin, which can significantly enhance the inhibitory effect on the growth and proliferation of cancer cells.

Description

Application of azelastine hydrochloride in the preparation of drugs for inhibiting colon cancer tumor growth

technical field

The invention belongs to the technical field of medicine, in particular to the application of azelastine hydrochloride in the preparation of a drug for inhibiting the growth of colon cancer tumors.

Background technique

Azelastine HCL is a 2,3-diazepine derivative with a new structure, which has been approved by the FDA for urticaria, allergic asthma, allergic rhinitis, etc. It has a strong and long-lasting effect. 0.05% azelastine hydrochloride conventional eye drops have been approved for production, mainly for the treatment and prevention of seasonal allergic conjunctivitis.

Cancer is one of the most difficult diseases to treat in the world. Colon cancer (CRC) is the second leading cause of cancer mortality in the world. In my country, the mortality rate of colorectal cancer has been ranked fifth. Currently, the treatment of colorectal cancer is limited to radiotherapy and chemotherapy. Although radiotherapy and chemotherapy can inhibit most cancer cells, it also kills normal cells while killing cancer cells, and can also lead to toxic side effects such as gastrointestinal dysfunction and bone marrow suppression, which greatly reduces the quality of life of patients and causes long-term effects. Chemotherapy, malignant tumor cells are prone to develop drug resistance. Most of the drugs for the treatment of cancer are expensive, which also limits the application of drugs. Therefore, it is urgent to find a safe anticancer drug with less toxic and side effects, good efficacy and low price.

Azelastine hydrochloride has a variety of anti-allergic effects in addition to histamine antagonistic effects. This product has inhibitory and direct antagonistic effects on the production and release of leukotrienes and histamines that cause allergic reactions. Experimental wheezing and nasal allergies and urticaria, etc., the effect is strong and long-lasting. It has been reported earlier that azelastine can inhibit the activation of inflammatory cells (such as eosinophilic, neutrophilic, basophilic and polynuclear leukocytes and macrophages) and inhibit the release of different mediators (such as leukotrienes, Na-ptoluene) sulfonyl-1-methyl ester, superoxide anion and platelet-activating factor), decreased eosinophil migration, significantly decreased ICAM-1 expression, and decreased serum eosinophilic cation (ECP) levels. There are also reports in the literature that azelastine can enhance the anti-inflammatory effect of budesonide.

SN38 and Oxaliplatin are traditional anticancer drugs, but they are easy to cause drug resistance of cancer cells, and their inhibitory effect on the proliferation of cancer cells is not ideal. If used in combination with azelastine hydrochloride, it can play a better effect on inhibiting the growth of cancer cells.

There are no articles showing the relationship between azelastine and cancer cell proliferation. There are no reports or patent applications yet.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide the application of azelastine hydrochloride in the preparation of drugs for inhibiting the growth of colon cancer tumors.

To achieve the above object, the present invention adopts the following technical solutions:

Application of azelastine hydrochloride in the preparation of a drug for inhibiting the growth of colon cancer tumors, the active ingredient of the drug is azelastine hydrochloride, and its chemical structural formula is

Preferably, the medicine contains at least one of the azelastine hydrochloride or its pharmaceutically acceptable salts.

Preferably, the medicament contains a pharmaceutical carrier or excipient.

Preferably, the medicine is tablet, capsule, drop pill, granule or oral liquid.

For the purpose of the medicine, the azelastine hydrochloride is dissolved in water and used orally. The dosage for humans (mg/kg)=the dosage for mice (mg/kg)/(0.0026/20(g)).

Significant advantages and beneficial effects of the present invention:

(1) The present invention combines in vitro and in vivo experiments, the results show that azelastine hydrochloride can inhibit the growth of colon cancer, and provides a new drug source for the adjuvant therapy of colon cancer.

(2) Azelastine hydrochloride is an approved drug that can be used for allergic rhinitis and other diseases, with high safety, good prospects for development and utilization, low price, and small toxic and side effects.

(3) Combining azelastine hydrochloride with traditional anticancer drugs SN38 and Oxaliplatin can significantly increase the inhibitory effect on cancer cells (Figures 7-9 are experimental results).

(4) When used for oral administration, it can be prepared into conventional solid preparations such as tablets, capsules, liquid preparations, granules, etc.; when used for injection, it can be prepared into injection solutions. Azelastine hydrochloride may be administered to a patient in need of such treatment in a dosage form by intravenous injection or orally. The general dosage applied to a patient in need of treatment is: the dosage for humans (mg/kg)=the dosage for mice (mg/kg)/(0.0026/20)(g), which can also be determined according to the patient's age, condition, etc. Variety.

Description of drawings

Figure 1 is a graph showing the effect of azelastine hydrochloride on the proliferation of HCT116.

Figure 2 is a graph showing the effect of azelastine hydrochloride on DLD proliferation.

Figure 3 is a graph showing the effect of azelastine hydrochloride on the proliferation of HT29.

Figure 4 is a graph showing the results of a subcutaneous tumorigenesis experiment in nude mice.

Figure 5 is a graph showing the results of a quantitative experiment of subcutaneous tumor formation in nude mice.

Fig. 6 is a graph showing changes in body weight of nude mice.

Figure 7 is a graph showing the effect of azelastine hydrochloride combined with camptothecin derivatives (SN38) and oxaliplatin (Oxaliplatin) traditional anticancer drugs on the proliferation of HCT116.

Figure 8 is a graph showing the effect of azelastine hydrochloride combined with camptothecin derivatives (SN38) and oxaliplatin (Oxaliplatin) traditional anticancer drugs on DLD proliferation.

Figure 9 is a graph showing the effect of azelastine hydrochloride combined with camptothecin derivatives (SN38) and oxaliplatin (Oxaliplatin) traditional anticancer drugs on the proliferation of HT29.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments.

Example 1

In vitro experiments

Intestinal cancer cells (ATCC, Rockville, USA) were treated with different concentrations of azelastine hydrochloride dissolved in water for 72 hours, and then the WST-1 assay was performed using a kit for detecting cell proliferation (Beyotime Biotechnology, Shanghai, China). Cell viability, and colony formation experiments ¹ , to study the effect of different concentrations of azelastine hydrochloride on the proliferation of colorectal cancer cells. Figures 1-3 show the results of in vitro experiments, which show that azelastine hydrochloride can inhibit the proliferation of intestinal cancer cells.

1.Wang,Y.;Yu,R.Y.;Zhang,J.;Zhang,W.X.;Huang,Z.H.;Hu,H.F.;Li,Y.L.;Li,B.;He,Q.Y.,Inhibition of Nrf2enhances the anticancer effect of 6- O-angeloylenolin in lung adenocarcinoma. Biochemical pharmacology 2017, 129, 43-53.

Example 2

In vivo experiments

Twenty-one 6-week-old female nude mice (balb/c-nu/nu) were purchased from Shanghai Slack Company. 7 rats in the control group and 14 rats in the experimental group were used to construct tumor metastasis models:

(1) Each nude mouse needs to be injected with 10 ⁶ colon cancer cells HT29 (ATCC, Rockville, USA), resuspend the cells HT29 with PBS and mix with Matrigel 1:1 to obtain the resuspended cells;

(2) Anesthetize the nude mice before the experiment, evaluate the degree of anesthesia through painless and painful stimulation, and determine that the nude mice are in an anesthetized state;

(3) Use a micro-syringe with a 25G needle to take resuspended cells and subcutaneously inject nude mice, a total of 21 mice;

(4) One week after colon cancer cell HT29 was injected into 21 mice, administration by gavage was started: azelastine hydrochloride was dissolved in H ₂ O, and each mouse was fed 100 μL at a time. A total of 3 imperatorin concentration gradients were set up in this experiment, 0 mg/kg, 10 mg/kg and 20 mg/kg respectively, with 7 animals each, and they were fed once a day. The size of the transplanted tumor was measured every three days (the length and width of the transplanted tumor were measured, and the volume of the transplanted tumor was calculated according to the length×width^2/2) and the body weight of the nude mice. After 2 to 3 weeks, the nude mice were euthanized and the xenografts were removed.

Figures 4-6 are the results of in vivo experiments. Figures 4-5 show the experimental results of in vivo subcutaneous tumor formation and its quantification in nude mice. The growth curve of the tumor showed that the tumorigenic ability of intestinal cancer cells was significantly inhibited by the subcutaneous tumor formation in nude mice, especially when the experimental group received 20 mg/kg azelastine hydrochloride, the tumor growth was reduced by 74% compared with the control group. significantly inhibited. This example shows that azelastine hydrochloride can inhibit tumor growth in colon cancer. However, Figure 6 shows that there is no difference in the body weight of the mice among the three groups, indicating that the use of azelastine hydrochloride as an antitumor drug has no toxic and side effects.

Example 3

In vitro experiments

Colon cancer cells were treated with different concentrations (0, 2.5, 5, 10, 20, 40 μM) of azelastine hydrochloride and camptothecin derivative (SN38) (6 μM), Oxaliplatin (10 μM) traditionally Cells were treated with anticancer drugs for 24h, 48h, and 72h at the same time, and then the WST-1 assay was performed to detect cell activity. Figures 7-9 show the results of in vitro experiments. The results showed that the combined use of azelastine hydrochloride with camptothecin derivatives (SN38) and oxaliplatin (Oxaliplatin) can significantly inhibit the proliferation of colorectal cancer cells (HCT116, DLD, HT29).

The embodiments of the present invention are not limited to this. According to the above-mentioned content of the present invention, the present invention can also make other various forms of Modifications, substitutions or changes all fall within the scope of protection of the present invention.

Claims (4)

1. The application of azelastine hydrochloride in preparing medicine for inhibiting colon cancer tumor growth is characterized in that the active ingredient of the medicine is azelastine hydrochloride, and the chemical structural formula of the medicine is

2. The use according to claim 1, wherein said medicament comprises at least one of said azelastine hydrochloride or a pharmaceutically acceptable salt thereof.

3. The use of claim 2, wherein the medicament comprises a pharmaceutically acceptable carrier or excipient.

4. The use of claim 3, wherein the medicament is a tablet, capsule, drop pill, granule or oral liquid.

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