Application of Licofelone and Taxane Combination in Treating Solid Tumors

Abstract

The present invention relates to the field of biomedicine technology, and discloses the use of a composition of licofelone and taxanes in the treatment of solid tumors; the present invention proposes for the first time that the combination of licofelone and taxanes can be used for the treatment of pan-solid tumors, and the present invention proves that licofelone can significantly improve the tumor killing effect of low-concentration taxanes. In addition to cell lines, the present invention uses a PTCs model to simulate the tumor microenvironment, and the drug screening results highly simulate the clinic and are credible. The results show that licofelone combined with paclitaxel can effectively inhibit the progression of various solid tumors, suggesting that the dose of paclitaxel can be appropriately reduced in the pharmaceutical composition, effectively inhibiting tumor progression while reducing adverse reactions, so the present invention has considerable application potential in the clinic.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to application of a combination of Licofelone and taxane drugs in treating solid tumors. Background Art

[0002] Paclitaxel is a broad-spectrum anti-tumor drug that is clinically used to treat a variety of solid tumors, such as lung cancer, breast cancer, and ovarian cancer. In order to improve the bioavailability of paclitaxel, a variety of dosage forms, including albumin-bound paclitaxel and lipoprotein paclitaxel, have been developed. These paclitaxel preparations can effectively increase the effect of paclitaxel, but still have obvious toxic side effects. In addition, the commonly used combination regimens of paclitaxel in clinical practice, including anthracyclines, platinum drugs, targeted drugs or immunotherapy drugs, also have obvious adverse reactions, so it is very necessary to develop a drug combination that can reduce toxic side effects while improving the efficacy of taxanes.

[0003] In recent years, with the advancement of drug screening technology, the concept of new uses of old drugs has received more attention. Many studies have shown that cyclooxygenase (COX) inhibitors can inhibit tumor progression or increase the anti-tumor efficacy of other chemotherapy drugs to a certain extent.

[0004] The present application found that the combination of COX inhibitor Licofelone and paclitaxel can significantly increase the anti-tumor efficacy of paclitaxel, and has broad application prospects. Summary of the invention

[0005] The purpose of the present invention is to provide a combination of Licofelone and taxane drugs for use in treating solid tumors, so as to solve the problem that the existing paclitaxel combination regimen has multiple toxic and side effects.

[0006] To achieve the above object, the present invention provides the following technical solution: use of a combination of Licofelone and taxanes in the treatment of solid tumors.

[0007] In a specific embodiment, the solid tumor includes lung cancer, brain cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, liver cancer, kidney cancer, stomach cancer, head and neck cancer, ovarian cancer, esophageal cancer, pancreatic cancer, and osteosarcoma.

[0008] In a specific embodiment, the taxane is paclitaxel.

[0009] In a specific embodiment, the concentration ratio of the taxane to Licofelone is 1:1-1000.

[0010] Licofelone was purchased from MCE Company with a CAS number of 107902-67-0, and paclitaxel was purchased from Selleck Company with a CAS number of 33069-62-4.

[0011] In a specific embodiment, the dosage form of the composition is one of capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment and suppository.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] The present invention proposes for the first time that Licofelone combined with taxanes can be used for the treatment of pan-solid tumors. The present invention proves that Licofelone can significantly improve the tumor killing effect of low-concentration taxanes. In addition to cell lines, the present invention uses PTCs models to simulate tumor microenvironment, and the drug screening results are highly simulated and credible. The results show that Licofelone combined with paclitaxel can effectively inhibit the progression of various solid tumors, suggesting that the dose of paclitaxel can be appropriately reduced in the pharmaceutical composition, effectively inhibiting tumor progression while reducing adverse reactions, so the present invention has considerable application potential in the clinic. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is a schematic diagram of the inhibition rate of A549 activity after 24 hours of treatment with different drugs in Example 1 of the present invention;

[0015] Figure 2 This is a schematic diagram of the normalized results of the ratio of the PTCs area on the 7th day after drug treatment to that without treatment in Example 2 of the present invention;

[0016] Figure 3 This is a schematic diagram of the normalized results of ATP signal values ​​after 7 days of drug treatment in Example 2 of the present invention.

[0017] In the figure, ns means that there is no significant difference between the two groups after statistical analysis; * or # means that there is a significant difference between the two groups after statistical analysis, P<0.05; ** or ## means that there is a significant difference between the two groups after statistical analysis, P<0.01; *** means that there is a significant difference between the two groups after statistical analysis, P<0.001; **** means that there is a significant difference between the two groups after statistical analysis, P<0.0001. DETAILED DESCRIPTION

[0018] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0019] Patient-Derived Tumor-Like Cell Cluster (PTC), referred to as microtumor or microtumor PTC, is a new type of primary 3D tumor model. The model maintains a high degree of similarity with the original tumor tissue in terms of pathological histological characteristics and molecular genetic characteristics. At the same time, the model retains the fibroblasts and immune cells in the original tumor tissue during the culture process, thereby highly restoring the microenvironment characteristics of the original tumor tissue. The microtumor PTC model can be widely used in the fields of basic scientific research on tumors, precision treatment, and new drug development.

[0020] Example 1

[0021] The application of the combination of licofelone and taxanes in the treatment of solid tumors is as follows:

[0022] (1) Grouping and treatment: A549 cells were evenly spotted in a 96-well plate (purchased from Thermo Fisher Scientific), with 10,000 cells spotted in each well. After the cells were completely attached to the plate, drug treatments were performed, including a negative control group, a licofelone alone group (0.02, 0.2, 2, 20, and 100 μM), and a paclitaxel (7.5 nM) + licofelone group, for a total of 24 h.

[0023] (2) Evaluation of cell viability: CCK-8 kit is a commonly used colorimetric detection kit for detecting cell viability. After drug treatment, 10 μL of CCK-8 working solution was added to each well and incubated in the cell culture incubator for 2 h. The absorbance at 450 nm was then measured and the inhibition rate was calculated. Figure 1 As shown, the inhibition rate of paclitaxel alone for 24 hours was less than 10%, while 0.02μM, 0.2μM and 2μM Licofelone could not effectively inhibit the activity of A549, but combined with paclitaxel, they could significantly enhance the effect of paclitaxel. This result shows that Licofelone can significantly enhance the anti-tumor effect of paclitaxel.

[0024] Example 2

[0025] The application of the combination of licofelone and taxanes in the treatment of solid tumors is as follows:

[0026] (1) Grouping and treatment: After digestion, the tumor samples were cultured in a special culture medium for PTCs to obtain PTCs. After a period of growth, PTCs with a diameter greater than 40 μm were evenly spotted on a Genex Health 100-well plate, with about 30-50 PTCs in each well. They were then divided into a negative control group, a paclitaxel group (0.75 μM), a licofelone (100 μM), and a paclitaxel (0.75 μM) + licofelone (100 μM) group, with three replicate wells in each group. The corresponding drugs were added on the day of spotting and treated for seven days.

[0027] (2) Evaluation of PTCs area: Before and seven days after drug treatment, the area of ​​PTCs in each group was measured using the analysis software provided by the microscope, and the ratio of the average area of ​​PTCs in each group after drug treatment was obtained, and then the normalized result was obtained by comparing it with the control group. Figure 2 As shown, paclitaxel or licofelone alone could not reduce the average area of ​​PTC, while the combination group could significantly reduce the area of ​​PTC. The results show that licofelone can significantly enhance the effect of paclitaxel in inhibiting tumor growth.

[0028] (3) Evaluation of PTCs activity: ATP is an indicator of living cell metabolism and often reflects the number of living cells. Seven days after drug treatment, the CellTiter-Glo detection kit (purchased from Promega Biotech Co., Ltd.) was used to detect the fluorescence signal value generated by ATP to reflect the activity of PTCs, and the signal value was normalized relative to the control group. The results are shown in Figure 3 As shown, paclitaxel alone can kill PTCs to a certain extent, while Licofelone combined with paclitaxel can significantly enhance the killing effect. The results show that Licofelone can significantly enhance the killing effect of paclitaxel on tumors.

[0029] It can be seen from the above examples that the combination of Licofelone and Paclitaxel in the present application can significantly enhance the inhibitory effect of Paclitaxel on tumors.

[0030] In summary, this application proposes for the first time that Licofelone combined with taxanes can be used for the treatment of pan-solid tumors. The present invention proves that Licofelone can significantly improve the tumor killing effect of low-concentration taxanes. In addition to cell lines, the present invention uses the PTCs model to simulate the tumor microenvironment, and the drug screening results are highly simulated and credible. The results show that Licofelone combined with paclitaxel can effectively inhibit the progression of various solid tumors, suggesting that the dose of paclitaxel can be appropriately reduced in the pharmaceutical composition, effectively inhibiting tumor progression while reducing adverse reactions, so the present invention has considerable application potential in the clinic.

[0031] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without making any creative work shall fall within the scope of protection of the present invention.

Claims

1. Application of a combination of licofelone and taxanes in the treatment of solid tumors.

2. The use of the combination of Licofelone and taxanes in the treatment of solid tumors according to claim 1, characterized in that: The solid tumors include lung cancer, brain cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, liver cancer, kidney cancer, stomach cancer, head and neck cancer, ovarian cancer, esophageal cancer, pancreatic cancer, and osteosarcoma.

3. The use of the combination of Licofelone and taxanes in the treatment of solid tumors according to claim 1, characterized in that: The taxane drug is paclitaxel.

4. The use of the combination of Licofelone and taxanes in the treatment of solid tumors according to claim 1, characterized in that: The concentration ratio of the taxane drug to Licofelone is 1:1-1000.

5. Use of the combination of Licofelone and taxanes in the treatment of solid tumors according to claim 1, characterized in that: The dosage form of the composition is one of capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment and suppository.

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