A Chinese medicine composition for preventing and treating lung cancer

Abstract

The present invention relates to a Chinese medicine composition for preventing and treating lung cancer, which is prepared by using Chinese medicines such as polygonatum, astragalus, scutellaria, peach kernel, atractylodes and liquorice as raw materials. The Chinese medicine composition uses Chinese medicines for strengthening the body and strengthening the body as immunomodulators, giving full play to the multi-pathway, multi-target and multi-link effect advantages of Chinese medicines, and as a medicine for treating lung tumors, it can improve the anti-tumor immune function of lung cancer patients, inhibit the formation, proliferation, invasion and metastasis of tumors, and shows a very good lung cancer inhibition effect on the basis of lung carcinoma in situ models, subcutaneous tumors and in vitro cytological experiments, and can significantly improve the tumor immune microenvironment.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicines, and relates to a traditional Chinese medicine for preventing the progression of lung cancer and treating lung cancer, which is prepared using Chinese herbal medicines as raw materials. Background Art

[0002] Lung cancer is the most common cause of cancer-related death worldwide, with 1.8 million people diagnosed with lung cancer and 1.6 million dying from the disease each year. In the 11 years from 2000 to 2011, the incidence and mortality of lung cancer in Chinese men ranked first among all cancers. Lung cancer patients have a poor prognosis, with a 5-year survival rate of only 18%.

[0003] The main reason for the high mortality rate of lung cancer is that most patients are already in the advanced stage with metastasis when diagnosed. The standard treatment of lung cancer is mainly surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc., and has achieved remarkable clinical results. But it also causes various adverse reactions. For example, chemotherapy can easily cause bone marrow suppression, gastrointestinal reactions and damage to organ functions, resulting in symptoms such as nausea, vomiting, fatigue, etc., thus affecting the normal chemotherapy cycle. Targeted therapy and immunotherapy are the embodiment of precision treatment of lung cancer, but their toxic side effects are also very common, such as rash, diarrhea, fatigue, bleeding and other symptoms, which not only affect the quality of life of patients, but may even force them to stop taking the medicine.

[0004] In current clinical practice, there is a lack of effective prevention and treatment methods for precancerous lesions and early tumors, and most of them are in the stage of observation and follow-up or resection of new lesions. Therefore, a non-invasive and non-significant toxic and side-effect lung tumor prevention and treatment program is urgently needed.

[0005] As a cultural treasure of the Chinese nation, traditional Chinese medicine has a unique theoretical basis and rich clinical practice experience. It emphasizes the concept of "people-oriented, living with tumors" and plays an indispensable role in the comprehensive prevention and treatment system of tumors by improving the human body's tumor-susceptible constitution and inhibiting the regrowth of tumors to the greatest extent.

[0006] The recurrence and metastasis of lung cancer is the main cause of death. Clinical practice has confirmed that the early intervention of traditional Chinese medicine in tumor patients after surgery can help restore the body's positive energy, promote the body's recovery after trauma, improve immune function, relieve postoperative complications, and effectively prevent postoperative recurrence and metastasis, thereby prolonging survival time.

[0007] In clinic, many patients have no drugs to use after multiple rounds of treatment such as surgery, radiotherapy and chemotherapy due to drug resistance; or some patients with advanced tumors are not suitable for radiotherapy and chemotherapy due to their advanced age and poor physical condition. At this time, according to the specific situation of the patient's evil and the rise and fall of the positive and negative forces, the corresponding treatment principles and methods are formulated, and the use of traditional Chinese medicine alone can also stabilize the lesions, prevent recurrence and metastasis, improve the quality of life, and achieve the goal of living with tumors. Summary of the invention

[0008] The purpose of the present invention is to provide a Chinese medicine composition for preventing and treating lung cancer, using Chinese medicine for strengthening the body and strengthening the root as an immunomodulator, giving full play to the multi-pathway, multi-target and multi-link advantages of Chinese medicine, so as to improve the anti-tumor immune function of lung cancer patients and inhibit the formation, proliferation, invasion and metastasis of tumors.

[0009] The traditional Chinese medicine composition for preventing and treating lung cancer of the present invention is prepared by taking traditional Chinese medicines polygonatum, astragalus, scutellaria, peach kernel, atractylodes and liquorice as raw materials.

[0010] Furthermore, in the traditional Chinese medicine composition for preventing and treating lung cancer described in the present invention, the weight proportions of the raw materials are: 50-200 parts of polygonatum, 20-80 parts of astragalus, 10-50 parts of scutellaria, 10-50 parts of peach kernel, 15-60 parts of atractylodes, and 5-20 parts of liquorice.

[0011] Furthermore, the weight proportions of the raw materials are: 50-100 parts of polygonatum, 30-50 parts of astragalus, 15-30 parts of scutellaria, 15-30 parts of peach kernel, 20-40 parts of atractylodes, and 5-10 parts of liquorice.

[0012] More specifically, the weight proportions of the raw materials are: 100 parts of polygonatum, 40 parts of astragalus, 20 parts of scutellaria, 20 parts of peach kernel, 30 parts of atractylodes, and 10 parts of liquorice.

[0013] The specific preparation method of the Chinese medicine composition of the present invention is to mix the Chinese medicine raw materials according to the weight proportions, add water and boil, filter to obtain an extract, and concentrate and dry to obtain the active pharmaceutical ingredient.

[0014] Preferably, the Chinese medicine composition of the present invention is any oral preparation prepared by adding pharmaceutically acceptable excipients or carriers to the active ingredients of the medicine. The oral dosage form can be any one of tablets, capsules, pills, syrups, granules, powders, pastes, pellets, suspensions or emulsions.

[0015] Furthermore, the Chinese medicine composition of the present invention can also be prepared into a sustained-release preparation or a controlled-release preparation.

[0016] Furthermore, the present invention also provides the use of the traditional Chinese medicine composition for preventing and treating lung cancer in preparing medicine for treating lung tumors.

[0017] The method of "supporting the positive and cultivating the root" is the essence of traditional Chinese medicine and the main feature of Chinese medicine in preventing and treating tumors. "Fuzheng" means to support the positive energy, and "cultivating the root" means to cultivate the root. The treatment of supporting the positive and cultivating the root has a multi-link and multi-target overall regulatory effect on tumors, and is the most important principle in Chinese medicine tumor treatment.

[0018] Clinical practice experience shows that the occurrence of early lung cancer is closely related to deficiency of vital energy, imbalance of qi and blood, and dysfunction of organs such as the lungs, spleen, and kidneys. The basic pathogenesis is based on deficiency of vital energy and symptomed by excess of pathogenic factors. Therefore, treatment should take into account both strengthening the vital energy and eliminating the pathogenic factors.

[0019] The Chinese medicine composition of the present invention is based on the treatment principle of "strengthening the body", with polygonatum, astragalus and scutellaria as the main medicines, wherein polygonatum nourishes the liver and kidney, nourishes yin and blood, and studies have shown that it can inhibit the cell cycle and induce cell apoptosis to play an anti-tumor effect; astragalus can strengthen the spleen and replenish the middle, raise yang and lift the sunken, benefit the defense and consolidate the exterior, and its anti-tumor mechanism is mainly to inhibit tumor cell proliferation and metastasis, promote tumor cell apoptosis, block tumor cell cycle, regulate tumor cell autophagy, target tumor microenvironment, resist tumor angiogenesis, and enhance the body's immune function; scutellaria has the functions of clearing away heat, detoxifying and purging fire, can effectively remove pathological products that damage mitochondria, improve the internal environment of mitochondria, promote mitochondrial repair, provide sufficient energy for the body, and prevent inflammation and cancer transformation. The above "three yellows" are used together to nourish the lungs and replenish qi, detoxify and disperse knots, and give equal importance to strengthening the body and eliminating evil.

[0020] Peach kernel, as a ministerial drug, mainly plays the role of breaking blood stasis, moistening the intestines, and removing blood stasis and promoting new growth. When used in combination with the monarch drug, it can inhibit the proliferation of tumor cells by inhibiting the cell cycle protein B1, causing the tumor cell division to remain in the G2 phase. At the same time, it can also inhibit the expression of mitochondrial related genes and interfere with the tumor cell power station to exert an anti-tumor effect. The effective ingredients of Atractylodes lancea have an inhibitory effect on the growth of various tumor cells including lung cancer, cervical cancer, and melanoma. Using it as an adjuvant can significantly improve the inhibitory effect of the monarch drug on tumor cell proliferation. Licorice has anti-inflammatory, anti-allergic, analgesic and anti-tumor effects. Especially in terms of anti-tumor, licorice has the effect of protecting normal cells and regulating the body's immunity. It is used as a ministerial drug for the prevention and treatment of tumors, and can jointly improve the energy of immune cells in sub-healthy people, inhibit oxidative stress and chronic inflammatory reactions, and inhibit tumor cell growth, which may make a breakthrough in the prevention and treatment of tumors.

[0021] The Chinese medicine composition for preventing and treating lung cancer provided by the present invention targets the common low immune function in tumor patients, uses Chinese medicine mainly for strengthening the body and restoring the root as an immunomodulator, and gives full play to the multi-pathway, multi-target and multi-link advantages of the Chinese medicine compound, thereby improving the anti-tumor immune function of lung cancer patients and inhibiting the formation, proliferation, invasion and metastasis of tumors.

[0022] Dampness, especially damp-heat pathogens, is mostly an inflammatory response caused by pathogens infecting the body or the body's autoimmune diseases. The inflammatory response damages the electron transport chain on the inner membrane of the mitochondria, ATP synthesis is damaged, and the regulation of oxidative stress and energy metabolism is weakened. The Chinese medicine composition of the present invention can achieve the clinical effects of replenishing essence and increasing energy, moving the spleen and eliminating dampness, detoxifying and activating blood circulation, and playing a role in strengthening the body, eliminating evil, repairing and dispersing nodules. It can fundamentally and effectively repair the body's damaged mitochondria, increase ATP, effectively eliminate tumors, regulate the body's immunity, inhibit the remaining nodules from developing into second primary cancer foci, and rebalance the internal environment.

[0023] The Chinese medicine composition of the present invention shows a very good lung cancer inhibition effect on the basis of lung carcinoma in situ models, subcutaneous tumors and in vitro cytological experiments, and can significantly improve the tumor immune microenvironment. It can be used for the prevention of lung cancer and for the late conditioning of early lung nodules, postoperative radiotherapy and chemotherapy of lung cancer, and immune targeted therapy, and has the effect of improving prognosis. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 These are the results of pharmacodynamic experiments on carcinoma in situ in animals using different Chinese medicine compositions.

[0025] Figure 2 These are the quantitative results of CK19 immunohistochemistry by different Chinese medicine compositions.

[0026] Figure 3 The invention relates to the effect of different Chinese medicine compositions in inhibiting the proliferation of subcutaneous tumors.

[0027] Figure 4 It is the effect of different Chinese medicine compositions on tumor-associated macrophages and T cells.

[0028] Figure 5 The effect of different Chinese medicine compositions on the mitochondrial ATP production capacity of tumor-associated macrophages and T cells.

[0029] Figure 6 The invention discloses an inhibitory effect of the Chinese medicinal composition on different lung cancer tumor cells. Implementation

[0030] The specific implementation of the present invention is further described in detail below in conjunction with the accompanying drawings and examples. The following examples are only used to more clearly illustrate the technical solution of the present invention so that those skilled in the art can well understand and utilize the present invention, rather than limiting the scope of protection of the present invention.

[0031] The production processes, experimental methods or detection methods involved in the embodiments and comparative examples of the present invention are all conventional methods in the prior art unless otherwise specified, and their names and / or abbreviations are all conventional names in the field and are very clear and unambiguous in the relevant application fields. Those skilled in the art can understand the conventional process steps based on the names and apply the corresponding equipment to implement them according to conventional conditions or the conditions recommended by the manufacturer.

[0032] The various instruments, equipment, raw materials or reagents used in the embodiments of the present invention are not particularly limited in terms of their sources, and are all conventional products that can be purchased through regular commercial channels, or can be prepared according to conventional methods well known to those skilled in the art. Example

[0033] Example 1

[0034] Prepare the raw materials according to the following formula ratio: 100 parts by weight of polygonatum, 40 parts by weight of astragalus, 20 parts by weight of scutellaria, 20 parts by weight of peach kernel, 30 parts by weight of atractylodes, and 10 parts by weight of liquorice.

[0035] Put the above raw materials into an extraction tank, add 12 times the amount of water, boil for 2 hours, filter out the decoction, add 10 times the amount of water, boil for 1.5 hours, filter out the decoction. Combine the two decoctions, filter, and concentrate into a clear paste with a relative density of 1.20-1.24, dry, crush into 80 mesh fine powder, add appropriate amount of auxiliary materials, and encapsulate to make capsules.

[0036] Example 2

[0037] Prepare the raw materials according to the following formula ratio: 80 parts by weight of polygonatum, 40 parts by weight of astragalus, 20 parts by weight of scutellaria, 30 parts by weight of peach kernel, 40 parts by weight of atractylodes, and 10 parts by weight of liquorice.

[0038] The preparation method is the same as that of Example 1.

[0039] Example 3

[0040] Prepare the raw materials according to the following formula ratio: 100 parts by weight of polygonatum, 30 parts by weight of astragalus, 30 parts by weight of scutellaria, 30 parts by weight of peach kernel, 20 parts by weight of atractylodes, and 10 parts by weight of liquorice.

[0041] The preparation method is the same as that of Example 1.

[0042] Comparative Example 1

[0043] On the basis of Example 1, without adding the auxiliary drug peach kernel, the raw materials are prepared according to the following formula ratio: 100 parts by weight of polygonatum, 40 parts by weight of astragalus, 20 parts by weight of scutellaria, 30 parts by weight of atractylodes, and 10 parts by weight of liquorice, and the preparation method is the same as that of Example 1.

[0044] Comparative Example 2

[0045] On the basis of Example 1, without adding the auxiliary drug peach kernel and the guiding drug liquorice, the raw materials are prepared according to the following formula ratio: 100 parts by weight of polygonatum, 40 parts by weight of astragalus, 20 parts by weight of scutellaria, and 30 parts by weight of atractylodes, and the preparation method is the same as that of Example 1.

[0046] Comparative Example 3

[0047] The other raw materials are the same, except that the ministerial drug peach kernel is replaced with the same amount of Atractylodes macrocephala, and the raw materials are prepared according to the following formula ratio: 100 parts by weight of Polygonatum sibiricum, 40 parts by weight of Astragalus membranaceus, 20 parts by weight of Scutellaria baicalensis, 20 parts by weight of Atractylodes macrocephala, 30 parts by weight of Atractylodes lancea, and 10 parts by weight of Licorice, and the preparation method is the same as Example 1.

[0048] Comparative Example 4

[0049] On the basis of Comparative Example 3, one of the main herbs, Astragalus, was removed, and the raw materials were prepared according to the following formula ratio: 100 parts by weight of Polygonatum sibiricum, 20 parts by weight of Scutellaria baicalensis, 20 parts by weight of Atractylodes macrocephala, 30 parts by weight of Atractylodes lancea, and 10 parts by weight of Licorice. The preparation method was the same as that in Example 1.

[0050] Comparative Example 5

[0051] On the basis of Comparative Example 3, the adjuvant Atractylodes was removed and the raw materials were prepared according to the following formula ratio: 100 parts by weight of Polygonatum sibiricum, 40 parts by weight of Astragalus membranaceus, 20 parts by weight of Scutellaria baicalensis, 20 parts by weight of Atractylodes macrocephala, and 10 parts by weight of Licorice. The preparation method was the same as that in Example 1.

[0052] Comparative Example 6

[0053] On the basis of Comparative Example 3, the guiding drug licorice was removed, and the raw materials were prepared according to the following formula ratio: 100 parts by weight of polygonatum, 40 parts by weight of astragalus, 20 parts by weight of scutellaria, 20 parts by weight of atractylodes, and 30 parts by weight of atractylodes. The preparation method was the same as that of Example 1.

[0054] Comparative Example 7

[0055] On the basis of comparative example 3, two main herbs, Astragalus and Scutellaria, were removed, and the adjuvant Atractylodes was removed. The raw materials were prepared according to the following formula ratio: 100 parts by weight of Polygonatum sibiricum, 20 parts by weight of Atractylodes macrocephala, and 10 parts by weight of Licorice. The preparation method was the same as that in Example 1.

[0056] Application Example 1: Pharmacodynamics experiment of different Chinese medicine compositions on carcinoma in situ in animals

[0057] In this application example, 6-week-old male SPF-grade C57 model mice with Kras and p53 double gene knockout (C57BL / 6 LSL-KrasG12D / p53flox / flox) provided by Southern Model Animal Company were used as experimental animals.

[0058] The model mice were randomly divided into 9 groups, namely, blank group, Example 1 administration group and Comparative Examples 1 to 7 administration groups, with 6 mice in each group, and the Comparative Examples 1 to 7 administration groups were used as the control group.

[0059] After the mice in each experimental group were given ether inhalation and fell into deep sleep, they inhaled 0.5×10 7 pfu, and simultaneously initiated Kras mutation and p53 tumor suppressor gene knockout to initiate lung carcinoma in situ modeling. The blank group was not given any medication, and each medication group was given feed containing each drug at the same time as modeling was initiated.

[0060] After 8 weeks of administration, the lung tissues were fixed with 4% paraformaldehyde, embedded in paraffin, and immunohistochemically stained for CK-19, a cancer marker, to observe the pathological morphological changes of the lung tissues in each test group. Figure 1 Image J software was used to scan and quantify the stained CK-19 (brown area), and the results are listed in Tables 1 and Figure 2 middle.

[0061]

[0062] The results showed that compared with the blank group, the drug in Example 1 had a statistically significant inhibitory effect on lung carcinoma in situ tumors, while the drugs in Comparative Examples 1 to 7 had no obvious inhibitory effect.

[0063] Application Example 2: Pharmacodynamics experiment on the inhibition of subcutaneous tumor proliferation in animals by different Chinese medicine compositions

[0064] Four-week-old C57L mice were divided into four groups: blank group, Example 1 group, Comparative Example 1 group and Comparative Example 3 group, with 4 mice in each group. 2×10 6 LLC (mouse lung cancer cell) cells were used to establish subcutaneous tumor models in mice.

[0065] Except for the blank group, the other groups were given the corresponding drugs on the day of inoculation. The weight and tumor size of the mice were recorded every two days. The experiment was terminated 14 days after the drug administration. The mice were killed by dislocation, the tumor tissue was completely removed, and the tumor volume was recorded. The results are as follows: Figure 3 As shown, compared with the blank group, the drug in Example 1 has a significant inhibitory effect on subcutaneous tumors, while the two comparative examples have no significant inhibitory effect on subcutaneous tumors in mice.

[0066] Application Example 3: Effects of different Chinese herbal medicine compositions on tumor-associated macrophages and cytotoxic T cells in subcutaneous tumors

[0067] Generally, there are two types of macrophages in the tumor microenvironment. Among them, M1 macrophages have the function of antigen presentation, which can enhance the function of CD8 cytotoxic T cells (CD8T), and CD8T can further kill tumor cells, while M2 macrophages have the function of promoting tumor cell proliferation. If M2 macrophages increase and CD8T weakens, the tumor will grow larger and become invasive. Therefore, the immunotherapy strategy for tumors is to increase CD8T while suppressing the proportion of M2 macrophages.

[0068] Single cell suspensions were prepared from subcutaneous tumor tissues of each experimental group in Application Example 2, and flow cytometry was used to count and sort the cells. The ratio of immune cells M2 (CD45, CD11B, F4 / 80, CD86+, CD206+) and CD8T (CD45, CD3+, CD8+) in the tumor tissues, as well as the ability of mitochondria to produce ATP, were detected. The results are as follows: Figure 4 and Figure 5 .

[0069] Figure 4 In the experiment, the drug in Example 1 can reduce the proportion of M2 macrophages in the tumor microenvironment of subcutaneous tumors. Compared with the blank group, the proportion of M2 macrophages can be reduced by one time. Correspondingly, the drug in Example 1 has a significant effect on promoting cytotoxic T cells. Compared with the blank group, the drug in Example 1 can increase the TC cells in tumor cells by 3 times.

[0070] However, the control drug not only had no effect on CD8T cells, but also had no inhibitory effect on M2 cells.

[0071] Furthermore, the mitochondrial function of the CD8T cells and M2 macrophages separated by flow cytometry was tested ( Figure 5 ), Example 1 can enhance the ability of CD8T mitochondria to produce ATP and reduce the ability of M2 to produce ATP, while the control group has no effect on the ATP production capacity of immune cells.

[0072] Application Example 4: Inhibitory effects of different Chinese medicine compositions on lung cancer cell lines

[0073] In order to prove the therapeutic effect of the Chinese medicine composition of the present invention on lung cancer, the lung cancer cell lines A549, H1299 and PC9 tumor cells were treated in vitro with the drug in Example 1 for 48 hours, and then CCK8 experiments were performed. The results are as follows: Figure 6 .

[0074] from Figure 6 It can be seen that the Chinese medicine composition of the present invention inhibits tumor cell proliferation in a concentration-dependent manner. The IC 50 The concentrations were 4.7 mg / mL, 4.8 mg / mL and 2.8 mg / mL respectively.

[0075] After a series of formulation explorations, the present invention adds peach kernel as a ministerial drug, takes Atractylodes macrocephala as an adjuvant, and traditional liquorice as a guiding drug, based on the three main drugs of polygonatum, scutellaria baicalensis and astragalus which have anti-tumor and immune regulation, to obtain a traditional Chinese medicine composition for preventing and treating lung cancer with significant effects.

[0076] However, the formula of Comparative Example 3, which only replaces the ministerial drug peach kernel with white surgery, does not have the effect of inhibiting lung carcinoma in situ in mice. Similarly, whether it is Comparative Example 1 and Comparative Example 2 that delete any drug based on the Chinese medicine composition of the present invention, or Comparative Examples 4, 5, 6 and 7 that delete any drug based on Comparative Example 3, there is no significant effect of inhibiting lung carcinoma in situ in mice. Compared with these comparative examples, the Chinese medicine composition of the present invention has obvious anti-lung carcinoma in situ efficacy, which is specifically manifested in the expression of tumor marker CK19 in immunohistochemical analysis, which has obvious statistical differences compared with the comparative examples ( P >0.05).

[0077] Similarly, mouse subcutaneous tumor and in vitro cytology experiments also verified that the Chinese medicine composition of the present invention has a significant inhibitory effect on subcutaneous tumors compared with other comparative formulas. Further immune cell analysis proved that it can inhibit M2 cells, enhance immune killer T cells, and play a role in enhancing tumor immunity.

[0078] The above embodiments of the present invention do not describe all the details in detail, nor limit the present invention to the above embodiments. Various changes, modifications, substitutions and variations made by ordinary technicians in this field without departing from the principles and purpose of the present invention should be included in the protection scope of the present invention.

Claims

1. A Chinese medicine composition for preventing and treating lung cancer, wherein the Chinese medicine composition is prepared using Chinese medicines polygonatum, astragalus, scutellaria, peach kernel, atractylodes and liquorice as raw materials, and the weight proportions of each raw material are: 50 to 200 parts of polygonatum, 20 to 80 parts of astragalus, 10 to 50 parts of scutellaria, 10 to 50 parts of peach kernel, 15 to 60 parts of atractylodes, and 5 to 20 parts of liquorice.

2. The Chinese medicine composition according to claim 1, characterized in that The weight proportions of the raw materials are as follows: 50-100 parts of polygonatum, 30-50 parts of astragalus, 15-30 parts of scutellaria, 15-30 parts of peach kernel, 20-40 parts of atractylodes, and 5-10 parts of liquorice.

3. The Chinese medicine composition according to claim 1, characterized in that The weight proportions of the raw materials are as follows: 100 parts of polygonatum, 40 parts of astragalus, 20 parts of scutellaria, 20 parts of peach kernel, 30 parts of atractylodes, and 10 parts of liquorice.

4. Use of the Chinese medicine composition according to any one of claims 1 to 3 in the preparation of a medicine for treating lung tumors.

5. The method for preparing the Chinese medicine composition according to claim 1 is to mix the Chinese medicine raw materials according to the weight proportions, add water and boil, filter to obtain an extract, and concentrate and dry to obtain the active pharmaceutical ingredient.

6. The method for preparing the Chinese medicine composition according to claim 5, characterized in that The active pharmaceutical ingredient is added with pharmaceutically acceptable adjuvants or carriers to prepare any oral preparation.

7. The method for preparing the Chinese medicine composition according to claim 6, characterized in that The oral preparation is a tablet, capsule, pill, syrup, granule, powder, paste, suspension or emulsion.

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