CN111671909B - Application of statins combined with ROR agonist in aspect of treating colorectal cancer - Google Patents
Application of statins combined with ROR agonist in aspect of treating colorectal cancer Download PDFInfo
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Abstract
The invention discloses application of statins and ROR agonists in preparation of medicaments for treating colorectal cancer. The invention further relates to pharmaceutical combinations comprising a statin and a ROR agonist. The research of the invention shows that the combination of the statins and the ROR agonist has obvious synergistic effect on killing colorectal cancer cells and can obviously inhibit the growth of colorectal cancer tumors in animal models, so that the drug combination can be used for treating colorectal cancer and has promising application value.
Description
Technical Field
The invention belongs to the technical field of medicines. More particularly, it relates to combination therapies for colorectal cancer and compounds for use in such combination therapies. The compounds used in combination therapy are statins and ROR agonists.
Background
Colorectal cancer is the third most common malignancy worldwide, with the second-place mortality. In China, the incidence of colorectal cancer is increased year by year, the national health and social development are seriously influenced, and the improvement of the treatment effect is very important. The treatment of colorectal cancer comprises operations, radiotherapy, chemotherapy, targeted drugs, immune checkpoint inhibitors and other drug treatments. At present, the drugs for treating colorectal cancer are very limited, and the drug resistance often occurs, so that the discovery of a new treatment target is particularly important.
Statins are a 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitor, HMG-CoA is the key rate-limiting enzyme in cholesterol synthesis, and statins are capable of significantly reducing total cholesterol levels and low density lipoprotein levels in the body. The statin medicine can be widely used in clinic, and can be used for preventing coronary heart disease and myocardial infarction and delaying atherosclerosis. Research shows that the application of statins influences the curative effect and prognosis of colorectal cancer, and the research on the application mechanism of statins in colorectal cancer treatment progresses, modern tumor medicine, 2017. However, the statin drugs have not been applied to the treatment of colorectal cancer, and the side effect reaction is obvious. In addition, a phase III prospective clinical trial published in 2015 compared the treatment of xelairi/FOLFIRI with or without simvastatin in metastatic colorectal cancer, with results showing that simvastatin failed to improve progression free survival in patients. The use of statins in the treatment of colorectal cancer is very limited and still remains to be studied further.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the existing drugs for treating colorectal cancer and the application limit of statins, and provides a novel drug combination for treating colorectal cancer, namely the combination therapy of statins and ROR agonists, which can cause the reduction of tumor growth and even the tumor shrinkage, and has good application value.
The above purpose of the invention is realized by the following technical scheme:
the research of the invention shows that the statins and the ROR agonist have obvious synergistic effect on killing colorectal cancer cells, have better Combination Index (Combination Index) and Dose Reduction Index (Dose Reduction Index), can kill the colorectal cancer together, and inhibit the growth of colorectal cancer tumors in animal models together.
Therefore, the invention provides the application of the statin and the ROR agonist in the preparation of medicaments for treating colorectal cancer, and the application of the ROR agonist in the preparation of medicaments for treating colorectal cancer.
Simultaneously provides the application of the statins and the ROR excitant in the aspect of preparing the medicine for enhancing the curative effect of the colorectal cancer and the application of the ROR excitant in the aspect of preparing the medicine for enhancing the curative effect of the colorectal cancer.
In addition, a therapeutic drug for colorectal cancer comprising a statin and a ROR agonist is provided.
Further, the medicine also comprises pharmaceutically acceptable salts or carriers, excipients and/or vehicles.
Preferably, the statin is selected from: pravastatin, lovastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, pitavastatin, or a salt or derivative thereof.
Preferably, the ROR agonist is selected from SR1078 or a salt or derivative thereof, or other compound capable of agonizing ROR transcriptional activity.
Based on the above, the present invention also provides a method of treating colorectal cancer, comprising administering to the patient a combination of two compounds:
a) a therapeutically effective amount of compound a, compound a being a statin; and
b) a therapeutically effective amount of compound B, which is a ROR agonist.
Specifically, in the above method, the statin inhibits HMG-CoA reductase, and the ROR agonist activates the transcriptional activity of ROR.
In which method compound A is administered simultaneously, concurrently, sequentially, alternately or separately with compound B.
The invention has the following beneficial effects:
the invention provides a drug combination of statins and ROR agonists, which is applied to the treatment of colorectal cancer, and the combined use of the two drugs can reduce the growth of tumors and even reduce the tumor size.
The invention provides a novel therapeutic drug combination for the treatment of colorectal cancer.
Description of the figures
FIG. 1 is a graph of the killing effect on colorectal cancer cells by statins and ROR agonists, respectively, and in combination.
Figure 2 is a combination index of drug combinations of statins and ROR agonists.
FIG. 3 is a graph of the effect of drug combinations of statins and ROR agonists on the subcutaneous tumorigenic growth of nude mice with colorectal cancer cells.
Figure 4 is a graph of the effect of drug combinations of statins and ROR agonists on the weight of subcutaneous neoplasia in nude mice with colorectal cancer cells.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated. Unless otherwise indicated, reagents and materials used in the examples were all commercially available.
The drug combination analysis adopted in the method is based on the Chou-Talalay drug combination theory, which is established by Chou and Talalay in 1983, and the drug combination effect is quantitatively analyzed. In 2005, the CompuSyn software was developed based on this theory. Chou in 2010 further perfected the method. Nowadays, the method is widely applied to drug combination analysis.
The term "Combination Index" as used herein was proposed by Chou and Talalay in 1983 to reflect the combined effect of two compounds. The CI of the two compounds is calculated by a certain algorithm, wherein the CI is less than 1 and equal to 1, and the CI greater than 1 respectively represents synergistic action, additive action and antagonistic action. When CI is less than 1, the smaller CI, the stronger the synergy.
The term "Dose Reduction Index" as used herein, also proposed by Chou and Talalay in 1983, has as an important objective the combined use of a Dose Reduction of the individual compounds, so as to maintain the original effect while reducing toxicity. DRI is a measure of the index of how much a synergistic effect is reduced by a factor of two compared to the dose of each compound used alone, at the same level of effect. At a CI less than 1, a greater DRI means a greater dose reduction for the same therapeutic effect.
The software used in the examples herein is "CompuSyn (version 1.1.1)".
Example 1 killing of colorectal cancer cells by statins and ROR agonists, respectively and in combination
1. Experimental materials
(1) Medicine preparation: atorvastatin calcium (MCE, HY-B0589), SR1078(MCE, HY-14422).
(2) Colorectal cancer cell: human colon cancer cell HCT15 and human colon adenocarcinoma cell HCT116(ATCC company).
(3) A commercially available cell activity assay kit (Promega Co., Ltd., G7570).
2. Experiment grouping
(1) Control group: blank control, i.e. cancer cells were not treated with any drug.
(2) A single drug group: cancer cells were treated with atorvastatin calcium or SR1078 gradient.
(3) Combined treatment group: cancer cells were treated with a gradient of different drug concentration combinations of atorvastatin calcium and SR 1078.
3. Cell killing experiment for detecting inhibition effect of pharmaceutical composition of atorvastatin calcium and SR1078 on colorectal cancer
(1) Method of operation
HCT15 and HCT116 cell lines were seeded in 96-well plates at 3000 cells per well and left overnight for adherence. The next day, atorvastatin calcium and SR1078 were added at the concentrations shown in FIG. 1, and after 2 days, cell activity was measured according to the procedure of the cell activity measurement kit.
(2) Results of the experiment
The results are shown in fig. 1, the killing effect of atorvastatin calcium alone and SR1078 alone are concentration-dependent, and the cell activity is obviously inhibited after the two compounds are combined, which indicates that the two compounds have synergistic effect.
Example 2 statin and ROR agonist pharmacodynamic assays
1. Experimental materials: CompuSyn (Version1.1.1) software
2. Analysis of the Effect of combination of statins and ROR agonists Using CompuSyn (Version1.1.1) software
(1) The operation method comprises the following steps: the drug inhibition data from example 1 was imported into CompuSyn (version1.1.1) software and plotted computationally for CI and DRI of atorvastatin calcium and SR 1078.
(2) Results of the experiment
The results of the CI calculations are shown in figure 2 with different concentrations of SR1078 on the abscissa and CI values on the ordinate, with the CI values for the two drugs being between about 0.2 and 0.6 under the conditions in the figure. The results show that both compounds have a better combined effect regardless of the concentration of SR1078 and the concentration of atorvastatin calcium. The DRI calculation results are shown in table 1, and both compounds were increased several to ten-fold by the single dose compared to the combined dose with the same killing effect. The CI and DRI analyses well demonstrated the combined effect of the two compounds.
TABLE 1 dose reduction index for drug combinations of statins and ROR agonists
Example 3 Effect of statins and ROR agonists on the growth of subcutaneous neoplasia in nude mice with colorectal cancer cells
1. Experimental Material
(1) Medicine preparation: the same as in example 1.
(2) Colorectal cell: the same as in example 1.
(3) Commercially available nude mice.
2. Effect of Emoke's treatment on in vivo transfer of HCT15 and HCT116 cells in nude mice model for transfer by tail vein injection
(1) Experimental methods
HCT15 and HCT116 cells were collected, resuspended in PBS buffer and injected subcutaneously into nude mice, and after the tumors had grown to reach, 20mg/kg i.p. of atorvastatin calcium and a combination of 20mg/kg i.p. of atorvastatin calcium and 20mg/kg i.p. of atorvastatin calcium were administered 1 time per day for 14 days, respectively. The long and short diameters of the tumor were measured every 4 days with an electronic vernier caliper, and the tumor volume was calculated by the following formula:
tumor volume is tumor major diameter (mm) x tumor minor diameter (mm)/2
When the tumor grows to 2000mm3When the point reaches the ethical end point. Nude mice were euthanized, tumor tissues were removed, weighed and photographed, and differences of each group were counted.
(2) Results of the experiment
The results are shown in fig. 3 and fig. 4, atorvastatin calcium alone has no significant inhibition effect on tumor growth, SR1078 alone has a certain inhibition effect on tumor growth, and the two compounds in combination have a significant inhibition effect on tumor growth and better effect than that of SR1078 alone.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. Use of a statin and a ROR agonist in the manufacture of a medicament for the treatment of colorectal cancer, wherein the statin is selected from the group consisting of: one of pravastatin, lovastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin or pitavastatin; the ROR agonist is SR 1078.
Use of a ROR agonist in the manufacture of a medicament for the treatment of colorectal cancer, wherein the ROR agonist is SR 1078.
3. Use of a statin and a ROR agonist in the manufacture of a medicament for enhancing the therapeutic efficacy of colorectal cancer, wherein the statin is selected from the group consisting of: one of pravastatin, lovastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin or pitavastatin; the ROR agonist is SR 1078.
The application of ROR agonist in the preparation of drug synergist, characterized in that the ROR agonist is SR1078, and the drug synergist is a synergist for treating colorectal cancer by statins.
5. A drug for treating colorectal cancer, comprising a statin and a ROR agonist, wherein the statin is selected from the group consisting of: one of pravastatin, lovastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin or pitavastatin; the ROR agonist is SR 1078.
6. A drug for enhancing the therapeutic effect of colorectal cancer, comprising a statin and a ROR agonist, wherein the statin is selected from the group consisting of: one of pravastatin, lovastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin or pitavastatin; the ROR agonist is SR 1078.
7. The medicament according to claim 5 or 6, further comprising a pharmaceutically acceptable salt or carrier, an excipient and/or a vehicle.
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| CN108785675A (en) * | 2017-04-26 | 2018-11-13 | 北京大学第三医院 | Statin compound improves the purposes of oncotherapy sensibility |
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