CN115154452A - Application of emodin succinyl ethyl ester in preparing medicine for treating ovarian cancer - Google Patents
Application of emodin succinyl ethyl ester in preparing medicine for treating ovarian cancer Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses an application of emodin succinyl ethyl ester in preparing a medicament for treating ovarian cancer, belonging to the technical field of medicaments. The invention specifically discloses confirmation of the anti-ovarian cancer effect of the emodin succinyl ethyl ester through a cell viability determination experiment, a scratch experiment, an invasion experiment, a flow cytometry experiment and an ovarian cancer tumor-bearing mouse model in vivo experiment. According to the invention, the emodin succinyl ethyl ester can be prepared into tablets, powders, capsules, granules and suspensions with pharmaceutically acceptable carriers, is orally taken for treating ovarian cancer, and can be used for inhibiting the progression of ovarian cancer in a single administration mode or a combined treatment mode.
Description
Technical Field
The invention relates to an application of emodin succinyl ethyl ester in preparation of an anti-ovarian cancer medicament, belonging to the technical field of medicaments.
Background
Emodin (formula I) is also called cinnabarinin A, has chemical name of 1,3, 8-trihydroxy-6-methylanthraquinone, belongs to anthraquinone compounds, and exists in rhizome and root of Rheum palmatum L., rheum officinale, rheum tanguticum Maxim. Ex Maxim. Et Maxim. Of Polygonaceae in free form and glycoside form. In recent years, researches show that emodin has an inhibiting effect on various tumors such as lung cancer, gastric cancer, pancreatic cancer, breast cancer and the like, and the mechanism of emodin is related to various ways such as inhibiting tumor cell proliferation, promoting apoptosis of tumor cells, resisting angiogenesis and the like. Meanwhile, the emodin has better synergistic effect with the clinically used antitumor drugs, chemoradiotherapy and the like. However, emodin itself has the disadvantages of high toxicity, low bioavailability, etc., so that no clinical report is available. The emodin succinyl ethyl ester subjected to chemical modification reduces toxicity and Gibbs free energy, has good drugability and has an anti-ovarian cancer effect.
Ovarian cancer is one of common malignant gynecological tumors, has higher lethality than cervical cancer and uterine cancer, accounts for the first gynecological tumors, and seriously threatens the life safety of women. The international cancer research institute issued data that predicted that by 2020, there will be 1930 new cases of cancer and 1000 deaths of cancer worldwide, with ovarian cancer occurring at 4.3% in 900 ten thousand female cancer patients and up to 4.7% in 440 ten thousand deaths female patients, both in the eighth place for each cancer (Rl Siegel, kd Miller, a jemal cancer statics, 2020.Ca cancer j. Clin., 2020.). In China, according to the latest tumor data released by the national cancer center in 2020, 5.2 ten thousand cases of new ovarian cancer in 2015, 2.5 ten thousand cases of dead patients and high death rate reside in the tenth place of various cancers (Zheng Rongshou, he Jie, etc. 2015, china's journal of malignant tumor, 2019). Because the ovary is located in the deep pelvic cavity and has small volume, the ovarian cancer is difficult to find in the early stage of the disease process, most of the ovarian cancer has spread to the organs of the pelvic abdominal cavity when the ovarian cancer is found, and therefore, more than 80 percent of patients have advanced treatment. The 5-year survival rate of the advanced ovarian cancer patients is only 20-40%, while the 5-year survival rate of the early ovarian cancer patients can reach 70-90%. Because the ovary is positioned in the deep pelvic cavity, the ovary is difficult to access or screen, the ovarian cancer is often asymptomatic at the early stage, 70 percent of the ovarian cancer spreads to the uterus, bilateral appendages, omentum and pelvic organs when being diagnosed, and the ovarian cancer has complex tissue types, so the ovarian cancer is a hot point of current research in both diagnosis and treatment.
At present, the conventional treatment modes of ovarian cancer are surgery, radiotherapy and chemotherapy, and in addition, targeted therapy, endocrine therapy, radiotherapy and the like also have certain curative effects. But surgical treatment has difficulty in completely preserving fertility in young patients; radiotherapy is not sensitive to endoblastoma of ovary, immature teratoma, embryo cancer, etc., and has greater side effects on abdomen and pelvic cavity, so chemotherapy is the only auxiliary treatment means for ovarian cancer. However, chemotherapy drugs such as doxorubicin used clinically have severe cardiotoxicity and may even cause arrhythmia and heart failure in patients, so that it is important to develop safe and effective chemotherapy drugs.
PFKFB4 as a molecular pivot may promote carbohydrate metabolism and transcriptional activation in malignancies by stimulating SRC-3. PFKFB4, also known as fructose-2-phosphate-kinase/fructose-2, 6-bisphosphatase 4, is an enzyme that synthesizes fructose-2, 6-diphosphate, and is widely present in various biological cells. PFKFB4 is caused by hypoxia, is highly expressed in cancer cells, and is essential for the survival of cancer cells under hypoxic conditions. Therefore, PFKFB4 may be an effective molecular target for developing antitumor drugs. Studies have shown that PFKFB4 is able to induce phosphorylation of SRC-3, translocate SRC-3 into the nucleus after phosphorylation, bind to ATF-4, modulate mTORC1, and affect proliferation, migration, and invasion of ovarian cancer (S Dasgupta, et al.
Disclosure of Invention
The invention aims to provide a brand-new compound for treating ovarian cancer, namely application of emodin succinyl ethyl ester in preparing anti-ovarian cancer medicaments.
In order to achieve the purpose, the invention adopts the following technical means:
the invention adopts cell activity determination experiment, scratch experiment, invasion experiment and flow typeCell experiments and ovarian cancer tumor-bearing mouse models confirm the ovarian cancer resistance of the emodin succinyl ethyl ester in vivo experiments and immunoblotting experiments. Compared with a blank control group, CCK8 experiments prove that 3, 10, 30 and 100 mu mol/L of emodin succinyl ethyl ester can reduce the cell activity of the OVHM of ovarian cancer cells, the inhibition rate of the emodin succinyl ethyl ester is increased along with the increase of concentration, and the inhibition rate reaches the maximum at 100 mu mol/L, and the IC50 is 10.27 mu mol/L; flow cytometry analysis proves that 10, 30 and 100 mu mol/l of emodin succinyl ethyl ester can induce apoptosis of ovarian cancer cells; scratch experiments prove that the emodin succinyl ethyl ester inhibits the migration of ovarian cancer cells; transwell experiments prove that the rheum emodin succinyl ethyl ester reduces the invasion capacity of ovarian cancer cells. The ovarian cancer tumor-bearing mouse model proves that 21 days after the administration, the model group, the doxorubicin group and the emodin succinyl ethyl ester are 20mg/kg d -1 、60mg/kg·d -1 、180mg/kg·d -1 Tumor volumes of groups were: 1.02 +/-0.092 cm 3 、0.66±0.088cm 3 、0.81±0.134cm 3 、0.55±0.060cm 3 、0.65±0.066cm 3 (ii) a The weights of the tumors are 0.64 +/-0.09 g, 0.38 +/-0.06 g, 0.39 +/-0.06 g, 0.34 +/-0.05 g and 0.35 +/-0.03 g respectively. Compared with a tumor model group, 60mg/kg d -1 、180mg/kg·d -1 The dose of the emodin succinyl ethyl ester dispersion can reduce the tumor volume and the weight of tumor-bearing mice. Compared with a model group, the emodin succinyl ethyl ester inhibits the expression of PFKFB4, SRC-3, p-SRC-3 and downstream ATF-4, ASNS, p-mTORC1 and Bcl-2 thereof in ovarian cancer on the protein level, increases the Bax/Bcl-2 ratio and induces the apoptosis of tumor cells.
On the basis of the research, the invention provides application of emodin succinyl ethyl ester in preparing a medicament for treating ovarian cancer, wherein the chemical name of the emodin succinyl ethyl ester is as follows: 1, 8-dihydroxy-3-succinic acid monoethyl ester group-6-methylanthraquinone, molecular formula: c 21 H 18 O 8 Molecular weight: 398.
the structure of the emodin succinyl ethyl ester is shown in the following formula II.
Preferably, the medicament can reduce the activity of tumor cells, inhibit migration and invasion of ovarian cancer cells, induce apoptosis of the ovarian cancer cells and delay the progression of ovarian cancer.
Wherein, the emodin succinyl ethyl ester and a pharmaceutically acceptable carrier are preferably prepared into tablets, powder, capsules, granules or suspensions for oral administration.
Wherein, preferably, the medicaments are for administration alone or in combination therapy.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a novel medicine for treating ovarian cancer. The in vivo experiment of a cell viability determination experiment, a scratch experiment, an invasion experiment, a flow cytometry experiment and an ovarian cancer tumor-bearing mouse model confirms that the emodin succinyl ethyl ester has a remarkable anti-ovarian cancer effect. The invention provides a new technical means for treating ovarian cancer.
Drawings
FIG. 1 shows that emodin succinyl ethyl ester affects OVHM cell activity of mouse ovarian cancer cells (P < 0.05;. P < 0.01;. P < 0.001. Compared to placebo);
FIG. 2 shows OVHM cell IC of mouse ovarian cancer cells treated with emodin succinyl ethyl ester 50 Calculating a graph;
FIG. 3 shows the effect of emodin succinyl ethyl ester on the apoptosis of OVHM cells of mouse ovarian cancer cells (P < 0.05;. P < 0.01;. P < 0.001. Compared to the blank control group);
FIG. 4 shows the cell migration patterns of OVHM cells of mouse ovarian cancer cells (P < 0.05;. P < 0.01;. P < 0.001. Compared with the blank control group);
FIG. 5 is a graph showing that emodin succinyl ethyl ester affects OVHM cell invasion of mouse ovarian cancer cells (P <0.05 compared to a blank control group; P <0.01 compared to a blank control group; P <0.001 compared to a blank control group);
FIG. 6 is a graph showing the growth of mouse ovarian cancer cells after administration of emodin succinyl ethyl ester through gastric gavage;
FIG. 7 is a representation of tumors taken 21 days after gastric gavage of emodin succinyl ethyl ester ([ P ] 0.05 compared to model group; [ P ] 0.01 compared to model group; [ P ] 0.001 compared to model group);
FIG. 8 is a statistical plot of tumor volumes taken 21 days after administration of emodin succinyl ethyl ester by gavage (.: P < 0.05;: P < 0.01;) compared to the model group;
FIG. 9 is a graph of tumor weight statistics taken 21 days after gastric gavage of emodin succinyl ethyl ester (P <0.05 in comparison to the model group; P <0.01 in comparison to the model group);
FIG. 10 is a representation of electrophoretic bands for PFKFB4/SRC-3/ATF-4/ASNS/mTOR signaling pathway in ovarian cancer tissue modulated by emodin succinylethyl ester (P < 0.05;. P < 0.01. In comparison to model group).
Detailed Description
The present invention is further illustrated by the following experiments in conjunction with examples, it being understood that these examples are for illustrative purposes only and in no way limit the scope of the present invention.
Example 1 Activity assay and IC of emodin succinyl ethyl ester on OVHM cells of mouse ovarian cancer cells 50 Computing
Cell viability was measured using the CCK8 assay. OVHM cells in logarithmic growth phase were seeded in 96-well plates. They were then exposed to 3, 10, 30, 100. Mu. Mol/L emodin succinylethyl ester and 10. Mu.g/mL doxorubicin. After 24h, CCK8 reagent was added to 96-well plates at 10. Mu.L per well and incubated at 37 ℃ for 1h. After removal, the 96-well plate was shaken on a shaker for 10min, and finally the absorbance value at 450nm was read for each well with a microplate reader.
The results are shown in FIG. 1, and it can be seen from FIG. 1 that emodin succinyl ethyl ester can inhibit the cell OVHM of mouse ovarian cancer cellsCell viability, and the inhibitory effect is dose-dependent ( * : p in comparison with blank control<0.05； ** : p in comparison with blank control<0.01， *** : p in comparison with blank control<0.001). As can be seen from FIG. 2, the amount-effect curve is plotted with the concentration of emodin succinyl ethyl ester as abscissa and the inhibition rate against ovarian cancer cells as ordinate, and the concentration of emodin succinyl ethyl ester at 50% inhibition rate is calculated as IC 50 The value is obtained. The IC of the emodin succinyl ethyl ester on ovarian cancer cells can be obtained by calculation 50 The concentration was 10.27. Mu. Mol/L.
EXAMPLE 2 determination of apoptosis of mouse ovarian cancer cells OVHM with emodin succinyl ethyl ester
The influence of emodin succinyl ethyl ester on OVHM cell apoptosis is detected by using a flow cytometry technology. OVHM cells in log growth phase were seeded in 6-well plates. Then 10, 30 and 100 mu mol/L emodin succinyl ethyl ester, 10 mu mol/L emodin and 10 mu g/mL doxorubicin are respectively added. After 24h of drug treatment, cells were digested with EDTA-free pancreatin, centrifuged at 1000r/min for 5min, washed twice with 4 ℃ pre-cooled PBS, resuspended, adjusted to a cell concentration of 2X 10 6 And (3) adding 10 mu Lannexin V and 5 mu L Propidium Iodide (PI) in sequence, incubating for 5min at room temperature in a dark place, and detecting and analyzing the apoptosis rate of each group by a flow cytometer.
The results are shown in FIGS. 3A and B, and the apoptosis rates of the blank control group, doxorubicin group, emodin succinylethyl 10, 30 and 100. Mu. Mol/L groups were 9.824. + -. 1.16%, 32.976. + -. 3.67%, 14.274. + -. 1.09%, 15.03. + -. 1.73%, 23.028. + -. 1.00% and 28.986. + -. 0.91%, respectively, as shown in FIGS. 3A and B. Therefore, 10, 30 and 100 mu mol/L emodin succinyl ethyl ester can induce the apoptosis of ovarian cancer cells.
EXAMPLE 3 experiment of determining OVHM cell migration of mouse ovarian cancer cells by using emodin succinyl ethyl ester
The influence of emodin succinyl ethyl ester on OVHM cell migration is detected by using a scratch experiment. OVHM cells in logarithmic growth phase were seeded in 6-well plates. When the cell confluence degree reaches more than 90%, an artificial wound is manufactured by a 10 mu L gun head, and then 10 mu mol/L, 30 mu mol/L, 100 mu mol/L emodin succinyl ethyl ester, 10 mu mol/L emodin and 10 mu g/mL doxorubicin are respectively added. The cell migration distance was observed by photographing under an inverted microscope at 0h, 12h and 24h, respectively, and finally data analysis was performed using Image Pro Plus software.
The results are shown in fig. 4A and B, and it can be seen from fig. 4A and B that the cell migration rates of the blank control group, doxorubicin group, emodin succinyl ethyl ester 10, 30, 100 μmol/L group after the drug treatment for 12h are 58.56 ± 4.74%, 19.97 ± 1.80%, 25.62 ± 3.29%, 17.13 ± 5.11%, 14.18 ± 2.68%, 4.61 ± 3.47%, respectively; after 24h of drug treatment, the cell migration rates are 68.98 + -1.26%, 6.09 + -1.72%, 41.91 + -1.77%, 34.64 + -5.48%, 19.93 + -5.37%, 11.89 + -5.08%, respectively. Therefore, the results show that 10, 30 and 100 mu mol/L of emodin succinyl ethyl ester can inhibit the migration of ovarian cancer cells.
EXAMPLE 4 determination of cell invasion of mouse ovarian cancer cells OVHM by emodin succinyl ethyl ester
The effect of emodin succinyl ethyl ester on OVHM cell invasion was examined using a Transwell experiment. Matrigel was diluted with pre-cooled serum-free medium at 10, 100. Mu.L per well and allowed to set in an incubator at 37 ℃ for 1h. Taking OVHM cells in logarithmic growth phase, adjusting cell density to 2.5 × 10 5 one/mL. Adding 200 μ L cell suspension into the chamber, adding 10, 30, 100 μmol/L emodin succinyl ethyl ester, respectively, adding 10 μ g/mL doxorubicin to the positive control group, 37 deg.C, 5% 2 After 24h incubation, 0.1% crystal violet was added and stained for 20min before photographing.
The results are shown in fig. 5A and B, and it can be seen from fig. 5A and B that the relative cell invasion rates of the blank control group, doxorubicin group, emodin succinyl ethyl 10, 30, and 100 μmol/L group are 100.00 ± 7.04%, 19.63 ± 1.00%, 68.10 ± 7.72%, 71.78 ± 5.61%, 58.28 ± 3.80%, and 38.04 ± 3.246%, respectively. Therefore, the above results indicate that 10, 30, 100 μmol/L emodin succinyl ethyl ester can inhibit ovarian cancer cell invasion.
EXAMPLE 5 pharmacodynamic experiment of emodin succinyl ethyl ester against ovarian cancer
Culturing ovarian cancer cell OVHM to 5-8 generations, and making into cell with density of 1 × 10 6 one/mL tumor cell suspension, 0.3mL tumor cells were injected subcutaneously into the right back of BALB/c mice. After 1 day of model preparation, BALB/c mice were randomly assigned to 5 groups. The tumor model group, doxorubicin (4 mg/kg) group, emodin succinyl ethyl ester (20 mg/kg) group, emodin succinyl ethyl ester (60 mg/kg) group and emodin succinyl ethyl ester (180 mg/kg) group are included, and each group comprises 8 individuals. After grouping, the doxorubicin group was administered intraperitoneally 2 times a week for a total of 7 times. The test drug groups were administered once a day for 21 days by gavage. Neoplasia and BALB/c mice survival were observed. One week after the administration, the tumor sizes of the respective groups were measured every 3 days, and the tumor sizes were calculated according to the formula and a tumor growth curve was drawn. The material was taken 3 weeks after dosing, the tumor was weighed, the volume measured and photographed.
The results are shown in FIGS. 6-9, and from FIGS. 6-9, it can be seen that emodin succinylethyl ester inhibits the growth of ovarian cancer, and reduces the volume and weight of tumor: ( * : p in comparison with model control group<0.05； ** : p in comparison with model control group<0.01， *** : p in comparison with model control group<0.001)。
Example 6 emodin succinyl ethyl ester regulates PFKFB4/SRC-3/ATF-4/ASNS/mTOR signaling pathway to inhibit ovarian cancer progression
An immunoblotting experiment is adopted to detect the regulation and control effect of the emodin succinyl ethyl ester on PFKFB4/SRC-3/ATF-4/ASNS/mTOR signal pathways. Tumor tissue was placed on ice and lysed with RIPA protein lysate. After sonication, the cell or tissue lysate was centrifuged twice and the supernatant collected. Total protein was separated using polyacrylamide gel electrophoresis, transferred to NC membranes and blocked with 5% skim milk for 2h, then placed in primary antibody and shaken overnight in a refrigerator at 4 ℃. After 12h, the secondary antibody was incubated for 1h. The membranes were scanned and the grey values of the protein bands were analyzed using an odsse infrared fluorescence scanning system.
The results are shown in FIG. 10, and it can be seen from FIG. 10 that compared with the model group, emodin succinyl ethyl ester inhibits the expression of PFKFB4, SRC-3, p-SRC-3 and its downstream ATF-4, ASNS, p-mTORC1, bcl-2 at protein level, increases Bax/Bcl-2 ratio, and induces tumor cell apoptosis.
The foregoing is merely a preferred embodiment of this invention, which is intended to be illustrative, not limiting; those skilled in the art will appreciate that many variations, modifications, and even equivalent variations are possible within the spirit and scope of the invention as defined in the appended claims.
Claims (4)
1. The application of the emodin succinyl ethyl ester in the preparation of the medicine for treating ovarian cancer is disclosed, wherein the chemical name of the emodin succinyl ethyl ester is as follows: 1, 8-dihydroxy-3-succinic acid monoethyl ester group-6-methylanthraquinone, molecular formula: c 21 H 18 O 8 Molecular weight: 398.
2. the use of claim 1, wherein the medicament is capable of reducing the viability of tumor cells, inhibiting migration and invasion of ovarian cancer cells, inducing apoptosis of ovarian cancer cells, and delaying progression of ovarian cancer.
3. The use according to claim 1, wherein emodin succinyl ethyl ester is formulated with a pharmaceutically acceptable carrier into tablets, powders, capsules, granules or suspensions for oral administration.
4. The use according to claim 1, wherein the medicament is for administration alone or in combination therapy.
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