CN115006418B - Application of digoxin in preparation of medicines for inhibiting colorectal cancer metastasis - Google Patents
Application of digoxin in preparation of medicines for inhibiting colorectal cancer metastasis Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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Abstract
The invention discloses an application of digoxin in preparing a medicament for inhibiting colorectal cancer metastasis. The number of IFN-gamma+CD8+ T cells and the number of IFN-gamma+CD4+ T cells in the liver microenvironment of the model mouse after digoxin treatment are obviously improved, so that the anti-tumor immunity of the organism is promoted, and the colorectal cancer metastasis is influenced. In addition, the liver weight of the model mouse is obviously reduced, the number of transfer nodules is obviously reduced, but the weight is not obviously changed, which indicates that the liver transfer capacity in colorectal cancer can be obviously reduced after the model mouse is treated by digoxin; and has no obvious effect on the weight of mice. The invention expands the clinical application field of digoxin, provides a new way for inhibiting liver metastasis of colorectal cancer, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of medical application. More particularly, the use of digoxin in the manufacture of a medicament for inhibiting colorectal cancer metastasis.
Background
Colorectal cancer (colorectal cancer, CRC) is one of the main cancers threatening the life health of residents in China, and causes a serious social burden. According to the latest data published by the national cancer center, 38.76 thousands of new cases of colorectal cancer in China account for 9.87% of the incidence of all malignant tumors in 2015; the number of cases of death caused by colorectal cancer is 18.71 tens of thousands, accounting for 8.01% of all malignant tumor deaths. How to effectively reduce the colorectal cancer disease burden of China is a great public health problem to be solved urgently. The occurrence and development of colorectal cancer mostly follow the sequence of 'adenoma-cancer', and the time for the progress from precancerous lesions to cancers generally takes 5-10 years, thereby providing an important time window for early diagnosis and clinical intervention of diseases. The 5-year relative survival rate for stage i colorectal cancer is 90%, while the 5-year relative survival rate for stage iv colorectal cancer with distant metastasis is only 14%. The cause of colorectal cancer is not clear, but a great deal of research evidence indicates that the occurrence and development of colorectal cancer are the result of the combined action of various factors such as heredity, environment, life style and the like. Established risk factors are currently investigated such as: family history of colorectal cancer, inflammatory bowel disease, red and processed meat intake, diabetes, obesity, heavy drinking, and the like.
The common chemotherapeutic drugs for colorectal cancer mainly comprise fluorouracil drugs, and a large number of reports on colorectal cancer therapeutic drugs are provided. Digoxin (digoxin) is used as a representative cardiac glycoside drug and is mainly used for treating heart failure and arrhythmia clinically; there are studies showing that digoxin has some application in anticancer, for example, research on apoptosis effect of digoxin on MDA-MB-231 cells of triple negative breast cancer, lv Yuchen, 2019 discloses that digoxin inhibits activity of MDA-MB-321 cells, promotes apoptosis, induces autophagy, and may have potential effect on triple negative breast cancer. Effect of digoxin on growth and apoptosis of human gastric cancer SGC7901 cells Chen Gonglian, 2017 discloses that as the digoxin concentration increases gradually, starting from 50nmol/L, the survival rate of SGC7901 cells decreases gradually, and when the digoxin concentration reaches 500nmol/L, the survival rate of SGC7901 cells decreases to a minimum.
However, colorectal cancer is susceptible to metastasis, especially liver is the most major target organ for colorectal cancer metastasis, which is one of the major points and difficulties in colorectal cancer treatment. 15-25% of patients with colorectal cancer have liver metastases at the time of diagnosis, while another 15-25% of patients can undergo liver metastases after radical surgery of primary foci of colorectal cancer, most (80-90%) of which initially cannot get radical excision. Liver metastasis is also the leading cause of death in colorectal cancer patients, the median survival of untreated liver metastatic patients is only 3.9 months, the 5-year survival rate of unresectable patients is less than 5%, and the median survival of patients with complete resections of liver metastases (or can reach the "no disease evidence (no evidence of disease, NED)" state) is 35 months, with 5-year survival rates of 30-57%. Therefore, exploring inhibition of liver metastasis of colorectal cancer is a serious difficulty in colorectal cancer treatment.
Disclosure of Invention
Aiming at the prior art problems, the invention provides a medicament capable of inhibiting colorectal cancer liver metastasis, which can effectively inhibit colorectal cancer liver metastasis and promote organism anti-tumor immunity. The invention expands the clinical application field of digoxin, provides a new way for inhibiting liver metastasis of colorectal cancer, and has good application prospect.
A first object of the present invention is to provide the use of digoxin for the preparation of a medicament for promoting apoptosis of cancer metastasis cells of colorectal cancer.
A second object of the present invention is to provide the use of digoxin for the preparation of a medicament for preventing or inhibiting or treating colorectal cancer metastasis.
In order to achieve the above object, the present invention is realized by the following technical scheme:
the inventor groups have conducted long-term and deep researches on colorectal cancer and colorectal cancer metastasis, and the results of screening, testing and verifying a large number of medicines show that in a colorectal cancer liver metastasis model of an immunized normal mouse, the digoxin treatment group can obviously reduce the liver metastasis capacity in the colorectal cancer body, and the weight of the mouse has no obvious change. More specifically, in a liver metastasis model of colorectal cancer of an immunized normal mouse, the digoxin treatment group can obviously increase the number of IFN-gamma+CD8+ T cells and IFN-gamma+CD4+ T cells in the liver microenvironment of the model mouse, so that the anti-tumor immunity is promoted, and the liver metastasis of the colorectal cancer is influenced.
Accordingly, the present invention claims the following:
use of digoxin in the manufacture of a medicament for promoting apoptosis of cancer metastasis cells of colorectal cancer.
Further, the cancer metastasis cells of colorectal cancer are liver metastasis cells.
Further, the digoxin promotes apoptosis of liver metastasis cells of colorectal cancer by affecting the liver microenvironment.
Further, the digoxin promotes apoptosis of liver metastasis cells of colorectal cancer by increasing the number of immune cells in the liver microenvironment.
Furthermore, the use of digoxin in the preparation of a medicament for preventing or inhibiting or treating colorectal cancer metastasis shall also fall within the scope of protection of the present application.
Further, the colorectal cancer metastasis is liver metastasis of colorectal cancer.
Further, the digoxin prevents or inhibits or treats liver metastasis of colorectal cancer by affecting the liver microenvironment.
Further, the digoxin prevents or inhibits or treats liver metastasis of colorectal cancer by increasing the number of immune cells in the liver microenvironment.
Further, the immune cells are cytotoxic T lymphocytes.
Further, the cytotoxic T lymphocytes include IFN- γ+cd8+ T cells and/or IFN- γ+cd4+ T cells.
Preferably, the IFN-gamma+CD8+ T cells are Tc 1 cells.
Preferably, the IFN-gamma+CD4+ T cells are Th 1 cells.
Further, the colorectal cancer cells are selected from colorectal cancer cells of mice.
Preferably, the colorectal cancer cells are selected from mouse colorectal cancer cells MC38.
The invention has the following beneficial effects:
the research shows that the digoxin can effectively inhibit liver metastasis of colorectal cancer, and the number of immune cells in the liver microenvironment of a model mouse treated by the digoxin is obviously increased, such as IFN-gamma+CD8+ T cells and IFN-gamma+CD4+ T cells, so that the number of the immune cells is increased to promote anti-tumor immunity of an organism and influence the liver metastasis of the colorectal cancer. In addition, the research of the invention shows that the liver weight of the model mice is obviously reduced, the number of the metastasis nodules is obviously reduced, but the body weight is not obviously changed, which shows that the liver metastasis capacity in colorectal cancer can be obviously reduced after digoxin treatment; and has no obvious effect on the weight of mice. The invention further expands the clinical application field of digoxin, provides a new way for inhibiting liver metastasis of colorectal cancer, and has good application prospect.
Drawings
FIG. 1 is a schematic representation of liver sections of a mouse liver metastasis model in example 1.
FIG. 2 is a comparison of the number of metastasis nodes of the mouse liver metastasis model in example 1.
FIG. 3 is a comparison of liver weights of mouse liver metastasis models in example 1.
Fig. 4 is a weight change of the mouse liver transfer model at different times in example 1.
FIG. 5 shows the change in IFN-. Gamma. + CD8+ T cell numbers in the mouse liver metastasis model of example 2.
FIG. 6 shows the change in IFN-. Gamma. + CD4+ T cell numbers in the mouse liver metastasis model of example 2.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1 Effect of digoxin on colorectal cancer cell metastasis and mouse body weight
1. Experimental materials
Medicament: digoxin;
colorectal cancer cells: mouse colorectal cancer cell MC38;
experimental animals: commercially available healthy C57 mice of similar body weight size and the same age.
2. Purpose of experiment
The liver metastasis model of colorectal cancer of an immunized normal mouse is constructed through portal intravenous injection, and after the treatment of the mouse model, the influence of digoxin on the liver metastasis model of colorectal cancer of the mouse (liver metastasis in vivo of colorectal cancer cell MC38 of the mouse) is detected.
3. Experimental method
Healthy C57 mice were randomly divided into 2 groups, control group and digoxin-treated group, 5C 57 mice per group were subjected to parallel experiments, and after adaptive feeding, the mouse colorectal cancer liver metastasis model was constructed as follows.
Digestion of MC38 cells in logarithmic growth phase with pancreatin, taking 5×10 5 MC38 cells were resuspended in 100. Mu.l PBS and 5X 10 cells were then used 5 MC38 cells were injected into the portal vein of mice in the control group and digoxin-treated group, respectively, to construct a model of colorectal cancer liver metastasis in mice.
Injection treatment was performed on day 2, day 3, day 5, day 6, day 8, day 9, day 10, day 11, day 13, wherein the control group was injected with an equal volume of PBS and the digoxin-treated group was injected with 2.5mg/kg digoxin solution to the abdominal cavity of the mice based on the weight of the mice. Each group of mice was weighed every 3 days. After 2 weeks, mice were euthanized, livers of the mice were taken out for photographing, the number of whole liver metastases was counted, then fixed with paraformaldehyde, HE stained after slicing, and photographed under a microscope.
4. Experimental results
As shown in fig. 1-4, in the colorectal cancer liver metastasis model of the immunized normal mice, compared with the control group (injected with PBS), the liver weight of the mice in the digoxin-treated group is obviously reduced relative to the liver weight of the mice in the control group, and the number of metastasis nodules is obviously reduced; the HE staining results after slicing corresponded to the nodules, and it was evident that the effect of digoxin treatment on inhibition of colorectal cancer liver metastasis was superior to the control. In addition, there was no significant change in body weight in the digoxin-treated mice compared to the control mice. Taken together, it is shown that digoxin treated mice can significantly reduce liver transfer capacity in colorectal cancer.
Example 2 Effect of digoxin on immune cells in colorectal cancer liver metastasis liver microenvironment
1. Experimental materials
Medicament: digoxin;
colorectal cancer cells: mouse colorectal cancer cell MC38;
experimental animals: commercially available healthy C57 mice of similar body weight size and the same age.
2. Purpose of experiment
And constructing an immune normal mouse colorectal cancer liver transfer model through portal intravenous injection, and detecting the influence of digoxin on immune cells in a model mouse colorectal cancer liver transfer microenvironment after the mouse model is treated.
3. Experimental method
Healthy C57 mice were randomly divided into 2 groups, control group and digoxin-treated group, 5C 57 mice per group were subjected to parallel experiments, and after adaptive feeding, the mouse colorectal cancer liver metastasis model was constructed as follows.
Digestion of MC38 cells in logarithmic growth phase with pancreatin, taking 5×10 5 Cells were resuspended in 100 μl PBS. Will be 5X 10 5 MC38 cells were injected into portal veins of two groups of C57 mice, respectively, to construct a mouse colorectal cancer liver metastasis model.
Injection treatment was performed on day 2, day 3, day 5, day 6, day 8, day 9, day 10, day 11, day 13, wherein the control group was injected with an equal volume of PBS and the digoxin-treated group was injected with a digoxin solution of 2.5mg/kg to the abdominal cavity of the mice based on the weight of the mice. After 2 weeks, mice were euthanized, fresh mouse livers were removed, and the number of immune cells in the liver microenvironment was detected by flow after the mouse livers were lysed.
4. Experimental results
As shown in fig. 5-6, the number of IFN- γ+cd8+ T cells and the number of IFN- γ+cd4+ T cells in the liver microenvironment of mice in the digoxin treatment group were significantly increased, which indicates that digoxin treatment can significantly increase the number of IFN- γ+cd8+ T cells and the number of IFN- γ+cd4+ T cells in the liver microenvironment of mice in the colorectal cancer liver metastasis model, thereby promoting anti-tumor immunity and inhibiting liver metastasis of colorectal cancer.
Thus, in summary, the application of digoxin in examples 1-2 was verified, an immune normal mouse colorectal cancer liver metastasis model was constructed by portal intravenous injection, and after digoxin treatment, the effect of digoxin on liver metastasis in mouse colorectal cancer cell MC38 and the weight of the mouse was detected; and constructing an immune normal mouse colorectal cancer liver metastasis model by portal intravenous injection, and detecting the influence of digoxin on immune cells in a liver microenvironment of mouse colorectal cancer liver metastasis after digoxin treatment.
The results show that digoxin treatment can significantly reduce liver metastasis capacity in colorectal cancer of a C57 mouse in a colorectal cancer liver metastasis model of an immunized normal mouse; and the body weight of the C57 mouse is not changed obviously. In a colorectal cancer liver metastasis model of an immunized normal mouse, digoxin treatment can obviously improve the number of IFN-gamma+CD8+ T cells and the number of IFN-gamma+CD4+ T cells in a colorectal cancer liver metastasis microenvironment, so that anti-tumor immunity is promoted, and colorectal cancer metastasis is influenced.
EXAMPLE 3 preparation of digoxin dispersible tablets
(1) The raw materials are selected as follows: digoxin ordinary tablet, polyvinylpyrrolidone, sodium carboxymethyl starch, microcrystalline cellulose, micro-powder silica gel, talcum powder and starch; the raw materials are all purchased in the market, talcum powder and starch are of medical specification, and the rest reagents are all analytically pure.
(2) Preparation of digoxin dispersible tablets: grinding the above materials, and sieving with 100 mesh sieve respectively. Weighing digoxin 0.25g and starch and other auxiliary materials, mixing uniformly, adding a proper amount of PVP solution and ethanol water solution, adding a proper amount of disintegrating agent (60 g/L sodium carboxymethyl starch to prepare soft material), sieving with a 40-mesh sieve, and preparing wet granules. And then drying at 50-60 ℃ for 1-2 h. Taking out the dry granules, sieving with 40 mesh sieve, granulating, adding pulvis Talci and micropowder silica gel as lubricant, adding auxiliary disintegrating agent MCC, mixing uniformly by equal increment method, tabletting to obtain tablet with diameter of 8mm, tablet weight of 200mg, and hardness controlled at (3.5+ -0.5) kg/mm 2 Digoxin dispersible tablet of (c).
The foregoing examples are illustrative only and serve to explain some features of the method of the invention. The claims that follow are intended to claim the broadest possible scope as conceivable and the embodiments presented herein are demonstrated for the applicant's true test results. It is, therefore, not the intention of the applicant that the appended claims be limited by the choice of examples illustrating the features of the invention. Some numerical ranges used in the claims also include sub-ranges within which variations in these ranges should also be construed as being covered by the appended claims where possible.
Claims (8)
1. Use of digoxin in the manufacture of a medicament for promoting apoptosis of cancer metastasis cells of colorectal cancer, characterized in that the cancer metastasis cells of colorectal cancer are liver metastasis cells of colorectal cancer.
2. The use according to claim 1, wherein the medicament promotes apoptosis of liver metastases of colorectal cancer by increasing the number of immune cells in the liver microenvironment.
3. Use of digoxin in the manufacture of a medicament for preventing or inhibiting or treating colorectal cancer metastasis, characterized in that the colorectal cancer metastasis is colon cancer liver metastasis.
4. The use according to claim 3, wherein the medicament prevents or inhibits or treats liver metastasis from colorectal cancer by increasing the number of immune cells in the liver microenvironment.
5. The use according to any one of claims 1 to 4, wherein the colorectal cancer cells are selected from the group consisting of mouse colorectal cancer cells MC38.
6. The use according to claim 4, wherein the immune cells are cytotoxic T lymphocytes.
7. The use according to claim 6, wherein the cytotoxic T lymphocytes comprise IFN- γ+cd8+ T cells and/or IFN- γ+cd4+ T cells.
8. The use according to claim 7, wherein the IFN- γ+cd8+ T cells are Tc 1 cells and the IFN- γ+cd4+ T cells are Th 1 cells.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101909637A (en) * | 2007-11-13 | 2010-12-08 | 菲尼克斯生物技术公司 | Method of determining the probability of a therapeutic response in cancer chemotherapy with cardiac glycoside |
| FR3039065A1 (en) * | 2015-07-20 | 2017-01-27 | Yvon Cayre | PRODUCT FOR COMBATING PROLIFERATION OF CANCER CELLS |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101909637A (en) * | 2007-11-13 | 2010-12-08 | 菲尼克斯生物技术公司 | Method of determining the probability of a therapeutic response in cancer chemotherapy with cardiac glycoside |
| FR3039065A1 (en) * | 2015-07-20 | 2017-01-27 | Yvon Cayre | PRODUCT FOR COMBATING PROLIFERATION OF CANCER CELLS |
Non-Patent Citations (1)
| Title |
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| Multifaceted anti-colorectal tumor effect of digoxin on HCT8 and SW620 cells in vitro;Yong-Qiang Hou等;《Gastroenterology Report》;第8卷(第6期);465–475 * |
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