CN113662939B - Application of composition of norcantharidin magnesium and sorafenib in preparation of anti-liver cancer drugs - Google Patents
Application of composition of norcantharidin magnesium and sorafenib in preparation of anti-liver cancer drugs Download PDFInfo
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Abstract
The invention discloses an application of a composition of norcantharidin magnesium and sorafenib in preparing an anti-liver cancer medicament, the combined composition can effectively treat liver cancer, the effect is obviously better than that of single medicines of the norcantharidin magnesium and sorafenib, and the combination of the two can obviously activate a transcription factor FOXO1 to realize the purpose of inhibiting invasion and metastasis of liver cancer cells, so that the two have a synergistic effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method and application of a magnesium norcantharidate and sorafenib combined composition in preparing an anti-liver cancer medicine.
Background
Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide, and has the characteristics of high metastasis rate and recurrence rate. More than 80% of liver cancer patients are diagnosed at an advanced stage, making treatment very limited and prognosis poor. Due to recurrence and metastasis of tumors, survival rate of liver cancer patients is still lower than 20% for 5 years. Although various strategies for treating liver cancer metastasis have emerged, such as tumor vaccines, immunotherapy, etc., survival has only slightly increased in the last decades.
Metastasis is a major feature of malignant behavior of tumors and is an important cause of failure of clinical treatment. Thus, finding a target for treating or preventing tumor metastasis is an important point in tumor treatment.
In addition, with the extension of the treatment period of the drug, clinical drug resistance also develops into a normal state, and single drug treatment is limited. Therefore, the combined drug for inhibiting tumor invasion and metastasis has important clinical significance. The combination can inhibit cancer more effectively, thereby treating cancer patients more effectively.
FOXO1 is an important member of FOX transcription factor family, and participates in growth and development, metabolism, tumor formation, etc. of organisms by regulating various physiological processes such as oxidative stress, proliferation, apoptosis, etc. of cells. Studies have shown that FOXO1 inhibits invasion and metastasis of hepatoma cells. Therefore, the targeted activation of FOXO1 may achieve the purpose of inhibiting liver cancer cell metastasis.
Sorafenib is the first anti-liver cancer chemotherapeutic drug approved by the FDA, can effectively prolong the survival time of patients with advanced hepatocellular carcinoma, but the curative effect is limited due to the development of drug resistance. Therefore, the medicine which can cooperate with the sorafenib to resist the liver cancer is sought, the dosage of the sorafenib can be effectively reduced, the toxic and side effects of the sorafenib are reduced, the treatment safety index is improved, and meanwhile, the defect and the defect of single medicine treatment of the sorafenib are overcome.
The subject group obtains a compound which can inhibit invasion and metastasis of liver cancer cells and activate FOXO1, namely, norcantharidin magnesium through a large number of compound activity screening experiments in the earlier stage, and discovers that the compound and sorafenib are used together to have the effect of synergistically inhibiting invasion and metastasis of liver cancer cells through combined drug screening.
At present, no report is made at home and abroad on the research of inhibiting liver cancer cell invasion and metastasis by activating FOXO1 by combining the norcantharidin magnesium and sorafenib.
Disclosure of Invention
The invention aims to overcome the defects and the shortcomings of the existing therapeutic drugs, and particularly provides a pharmaceutical composition for treating cancers, which aims at the current situation that the existing therapeutic drugs are not more than the effective drugs for liver cancer.
A first object of the present invention is to provide the use of a combination of magnesium norcantharidate and sorafenib for the preparation of a medicament for the treatment of cancer.
A second object of the present invention is to provide a medicament for treating cancer comprising norcantharidate magnesium and sorafenib.
Use of norcantharidin magnesium and sorafenib in the manufacture of a medicament for the treatment of cancer.
Preferably, the cancer is liver cancer.
The application of the combination of the norcantharidin acid magnesium and the sorafenib in preparing medicaments for inhibiting invasion and metastasis of cancer cells.
Preferably, the cancer cell is a liver cancer cell.
Preferably, the drug for inhibiting cancer cells is a drug for inhibiting invasion and metastasis of cancer cells.
More preferably, the liver cancer cells are liver cancer cell types SMMC-7721 and SK-Hep-1.
A cancer therapeutic comprising magnesium norcantharidate and sorafenib.
Preferably, the cancer is liver cancer.
Preferably, the mass ratio of the norcantharidate magnesium to the sorafenib is: 75-100 parts of: 50 parts.
Preferably, the drug is targeted by the transcription factor FOXO1.
More preferably, the drug is one that inhibits invasion and metastasis of liver cancer cells.
In order to find a medicine combination capable of generating a synergistic anticancer effect, the cantharidin derivative and a small molecular inhibitor medicine for resisting liver cancer are subjected to combined screening.
The liver cancer SMMC-7721 cell strain is used as a test cell strain, and a large number of screening experiments and analytical researches for a long time show that one pairing combination can produce synergistic effect, and the anticancer efficiency is obviously enhanced. The pair of combined medicines is as follows: the norcantharidin acid magnesium and sorafenib.
The structural formula of the norcantharidin acid magnesium is as follows:
sorafenib with CAS 284461-73-0, molecular formula C 21 H 16 ClF 3 N 4 O 3 Molecular weight 464.825, structural formula:
next, we detected the effect of the combination of norcantharidin magnesium and sorafenib on the invasion and migration of liver cancer SMMC-7721 cells through Transwell cell invasion and migration experiments, and found that the combination of low-concentration norcantharidin magnesium and sorafenib can effectively inhibit the invasion and migration of cancer cells, and the combination effect is superior to that of the single drug of norcantharidin magnesium and sorafenib.
Furthermore, we further verify the combination scheme of the norcantharidin acid magnesium and the sorafenib on the liver cancer SK-Hep-1 cell line, and the experimental result shows that the invasion and the metastasis of the liver cancer SK-Hep-1 cell line by the norcantharidin acid magnesium and the sorafenib can be effectively and synergistically inhibited, so that the anticancer efficiency is obviously enhanced.
To determine whether the synergistic inhibition of liver cancer SMMC-7721, SK-Hep-1 cell invasion and metastasis by norcantharidin magnesium and sorafenib is associated with activation of the transcription factor FOXO1. We prove through western blot experiments that the combination of the norcantharidin acid magnesium and the sorafenib can enhance the activation of the FOXO1, and the combination effect is superior to that of the single medicine of the norcantharidin acid magnesium and the sorafenib. The above results indicate that the synergistic inhibition of invasion and metastasis of hepatoma cells by norcantharidate magnesium and sorafenib is achieved by activating the transcription factor FOXO1.
Compared with the prior art, the beneficial effects of the invention include, for example:
the combined medicine can obviously improve the effect of inhibiting the invasion and metastasis of liver cancer SMMC-7721 and SK-Hep-1 cells, and the inhibition effect is obviously superior to that of single use of norcantharidin magnesium and sorafenib, and the curative effect is clear, so that the two have a synergistic effect after being matched with experiments under the specific proportion of the invention, and have good clinical application prospect.
In addition, because the norcantharidin magnesium is a derivative of the traditional Chinese medicine cantharidin, compared with cantharidin, the norcantharidin magnesium has the characteristics of low toxicity, good water solubility and the like, and can greatly reduce the use amount of sorafenib when being combined with sorafenib, thereby reducing the toxic and side effects of the sorafenib and improving the therapeutic safety index. The combination scheme shows a synergistic effect, overcomes the defects and shortcomings of single-drug treatment, and has good clinical application prospect.
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FIG. 1 shows the results of invasion and migration of liver cancer SMMC-7721 and SK-Hep-1 cells treated by different groups.
FIG. 2 shows the results of detection of phosphorylated FOXO1 protein by western blot experiments of liver cancer SMMC-7721 and SK-Hep-1 cells treated in different groups.
Detailed Description
The present invention is further illustrated in the following figures and specific examples, which are not intended to limit the invention in any way, unless otherwise specified, as reagents, apparatus and methods which are conventional in the art.
Materials and reagents used in the present invention are commercially available unless otherwise specified.
Example 1
Combination of norcantharidin magnesium and sorafenib inhibits invasion and metastasis of liver cancer SMMC-7721 cells by activating expression of transcription factor FOXO1
The present example was divided into 4 groups, a control group (no drug addition), a norcantharidin magnesium group (concentration: 7.5. Mu.M), a sorafenib group (concentration: 5. Mu.M), and a norcantharidin magnesium and sorafenib combination group (concentrations: 7.5. Mu.M, 5. Mu.M, respectively).
Cell invasion experiments. After being treated by 24 h of different groups, liver cancer SMMC-7721 cells are collected, resuspended and inoculated into the upper hole of a Transwell cell with matrigel, the inoculation density is 20000 pieces/hole, 600 mul of RPMI-1640 culture medium containing 10% fetal bovine serum is added into the lower hole, the temperature is 37 ℃ and the CO is 5% 2 After 24. 24 h culture in the environment, the culture solution was discarded, 4% paraformaldehyde was fixed, and after 1% crystal violet staining solution was used, the culture solution was observed under a stereoscopic microscope and photographed. The results are shown in the graph1A shows that the cell invasion rate of the drug-treated group is significantly lower than that of the control group; however, when the norcantharidin magnesium and sorafenib are combined, the invasion rate of the liver cancer SMMC-7721 cells is lower, and the liver cancer SMMC-7721 cells are obviously better than that of the single use of the norcantharidin magnesium and sorafenib, and the synergistic effect of inhibiting the invasion of the liver cancer SMMC-7721 cells is good.
Cell migration experiments. Inoculating the liver cancer SMMC-7721 cell suspension treated with 24 h in different groups into upper well of Transwell chamber, inoculating 20000 cells/well, adding 600 μl RPMI-1640 culture medium containing 10% foetal calf serum into lower well, 37 deg.C, 5% CO 2 After 24. 24 h of culture in the environment, the culture solution is discarded, 4% paraformaldehyde is fixed, and after 1% crystal violet staining solution is stained, the culture solution is observed and photographed under a stereoscopic microscope. As shown in the figure 1B, compared with the single drug group of norcantharidin acid magnesium and sorafenib, the combined drug group has obviously better migration inhibition capability of liver cancer SMMC-7721 cells than the single drug group, and has good synergistic effect.
In order to determine whether the combined synergy mechanism of the norcantharidin magnesium and the sorafenib is related to the activation of the transcription factor FOXO1, the western blot is adopted to detect the expression of the phosphorylated FOXO1 protein, and the result is shown in figure 2A, compared with the combination of the norcantharidin magnesium and the sorafenib single drug group, the combination drug group can obviously reduce the expression of the phosphorylated FOXO1 protein, and the existing research shows that the accumulation of the dephosphorylation of the FOXO1 in the cell nucleus is a flag of the activation of the FOXO1, so that the combined use of the norcantharidin magnesium and the sorafenib can obviously activate the expression of the FOXO1 protein, further inhibit the invasion and the metastasis of liver cancer SMMC-7721 cells, and the synergistic effect is good.
In summary, the research results of the present case find that: the combined use of the norcantharidin magnesium and the sorafenib can obviously inhibit invasion and metastasis of liver cancer SMMC-7721 cells; the inhibition effect is obviously better than that of the single use of the norcantharidin magnesium and the sorafenib, the curative effect is clear, and the two have a synergistic effect after being matched with experiments under the specific proportion of the invention, thus having good clinical application prospect.
Example 2
Combination of norcantharidin magnesium and sorafenib inhibits invasion and metastasis of liver cancer SK-Hep-1 cells by activating expression of transcription factor FOXO1
The present example was divided into 4 groups, a control group (no drug addition), a norcantharidin magnesium group (concentration: 10. Mu.M), a sorafenib group (concentration: 5. Mu.M), and a norcantharidin magnesium and sorafenib combination group (concentrations: 10. Mu.M, 5. Mu.M, respectively).
Cell invasion experiments. After 24 h of liver cancer SK-Hep-1 cells are treated in different groups, the cells are collected and resuspended, inoculated into the upper hole of a Transwell chamber with matrigel, the inoculation density is 20000 pieces/hole, 600 mul of RPMI-1640 culture medium containing 10% fetal bovine serum is added into the lower hole, the temperature is 37 ℃ and the CO is 5% 2 After 24. 24 h culture in the environment, the culture solution was discarded, 4% paraformaldehyde was fixed, and after 1% crystal violet staining solution was used, the culture solution was observed under a stereoscopic microscope and photographed. As a result, as shown in fig. 1C, the cell invasion rate of the drug-treated group was significantly lower than that of the control group; however, when the norcantharidin magnesium and sorafenib are combined, the invasion rate of liver cancer SK-Hep-1 cells is lower, the method is obviously superior to that of single use of the norcantharidin magnesium and sorafenib, and the synergistic effect of inhibiting liver cancer SK-Hep-1 cell invasion is good.
Cell migration experiments. Inoculating liver cancer SK-Hep-1 cell suspension treated with 24-h of different groups into upper well of Transwell chamber, inoculating 20000 cells/well, adding 600 μl RPMI-1640 culture medium containing 10% foetal calf serum into lower well, 37 deg.C, 5% CO 2 After 24. 24 h of culture in the environment, the culture solution is discarded, 4% paraformaldehyde is fixed, and after 1% crystal violet staining solution is stained, the culture solution is observed and photographed under a stereoscopic microscope. As shown in the figure 1D, compared with the single drug group of norcantharidate magnesium and sorafenib, the combination drug group has obviously better migration inhibition capability of liver cancer SK-Hep-1 cells than the single drug group, and has good synergistic effect.
In order to determine whether the combined synergy mechanism of the norcantharidin magnesium and the sorafenib is related to the activation of the transcription factor FOXO1, the western blot is adopted to detect the expression of the phosphorylated FOXO1 protein, and the result is shown in figure 2B, compared with the combination of the norcantharidin magnesium and the sorafenib single drug group, the combined drug group can obviously reduce the expression quantity of the phosphorylated FOXO1 protein, and the existing research shows that the accumulation of the dephosphorylation of the FOXO1 in the cell nucleus is a flag of the activation of the FOXO1, so that the combined use of the norcantharidin magnesium and the sorafenib can obviously activate the expression of the FOXO1 protein, further inhibit the invasion and the metastasis of liver cancer SK-Hep-1 cells, and has good synergistic effect.
In summary, the research results of the present case find that: the combined use of the norcantharidin acid magnesium and the sorafenib can obviously promote and inhibit invasion and metastasis of liver cancer Sk-Hep-1 cells; the inhibition effect is obviously better than that of the single use of the norcantharidin magnesium and the sorafenib, and the curative effect is clear, so that the two have a synergistic effect after being matched with experiments under the specific proportion, and have good clinical application prospect.
Claims (2)
1. The application of the composition of the norcantharidin acid magnesium and the sorafenib in preparing the anti-liver cancer medicine is characterized in that the structural formula of the norcantharidin acid magnesium is as follows:
sorafenib with CAS 284461-73-0, molecular formula C 21 H 16 ClF 3 N 4 O 3 Molecular weight 464.825, structural formula:
the mass ratio of the norcantharidin acid magnesium to the sorafenib is as follows: 75-100 parts of: 50 parts;
the anti-liver cancer drug is a drug for inhibiting invasion and metastasis of liver cancer cells, and the inhibition is to inhibit the invasion and metastasis of liver cancer cells by activating a transcription factor FOXO1.
2. The use according to claim 1, wherein the anti-liver cancer medicament comprises a pharmaceutically acceptable carrier.
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