CN115414363A - Anti-liver cancer composition and application of phenformin in preparation of anti-liver cancer drug sensitizer - Google Patents
Anti-liver cancer composition and application of phenformin in preparation of anti-liver cancer drug sensitizer Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to an anti-liver cancer composition and application of phenformin in preparation of an anti-liver cancer drug sensitizer, wherein the anti-liver cancer composition comprises phenformin and rivastigmine; the application improves the anti-liver cancer effect of the anti-liver cancer drug.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an anti-liver cancer composition and application of phenformin in preparation of an anti-liver cancer medicine sensitizer.
Background
Hepatocellular carcinoma, the most common liver cancer type, accounts for 90% of primary liver cancers. Because early diagnosis is difficult and the disease condition progresses rapidly, more than 80 percent of liver cancer patients progress to the middle and late stages when diagnosed, and few effective treatment options exist; and the prognosis is poor, and the 5-year survival rate is only about 15-18%.
Lovatinib (Lenvatinib) is an oral multi-kinase target inhibitor, developed by Wako pure (Eisai) and can inhibit kinases such as vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, kit, RET and the like. Lovatinib was also approved by the FDA for patients with advanced thyroid and renal cancers and was approved by the FDA as a first-line drug for liver cancer in 2018, and is currently recognized as a first-line targeted drug for the treatment of unresectable liver cancer with Sorafenib. Global multicenter phase III clinical trials showed that, although objective tumor remission rates for ranuncutinib increased from 9.2% to 24.1% compared to sorafenib, nearly 80% of liver cancer patients remained ineffective in the treatment with ranuncutinib.
In order to increase the efficacy of drugs, researchers have focused their attention on drug combinations. The combination of small molecule targeted drugs and immune drugs, the combination of immune targeting and immune targeting, and the combination of small molecule targeted drugs and small molecule targeted drugs have been applied to pre-clinical and clinical trials of liver cancer. The combination shows better therapeutic effect and sensitivity than the single use. For example, in a clinical test of liver cancer, the combination of small molecule drugs apatinib and carpriclizumab has not only great breakthrough in curative effect, but also excellent safety. In addition, phase 1b clinical trials of a combination of lenvatinib and pembrolizumab (an anti-PD-1 antibody) for treating patients with unresectable liver cancer show that the combination of the two has a better anti-tumor effect. In addition, the combined drug is combined with drugs to reduce the dosage of single drug, and the drug action mechanisms are different, so that the drug combination is an effective mode for overcoming drug resistance and reducing toxic and side effects. However, the selection of the combination medication scheme is very difficult, so that the search for effective, small adverse reaction and clear effect and the combination medication strategy becomes urgent to improve the clinical treatment effect of the ranvatinib.
Disclosure of Invention
The invention aims to solve the technical problem of improving the anti-liver cancer effect of an anti-liver cancer drug and provides an anti-liver cancer composition and application of phenformin in preparation of an anti-liver cancer drug sensitizer.
The present embodiments provide anti-liver cancer compositions comprising phenformin and varenib.
As one example, the anti-hepatoma composition consists of phenformin and ranvatinib.
As one example, the molar ratio of phenformin to ranvatinib is 10-100.
As one embodiment, the anti-liver cancer composition further comprises pharmaceutical auxiliary materials, carriers, excipients or vectors, and can be prepared into oral tablets or oral capsules.
The embodiment of the application also provides an application of phenformin in preparation of a sensitizer for the anti-liver cancer drug, wherein the anti-liver cancer drug is Lunvatinib.
The invention has the beneficial effects that the phenformin and the ranvatinib are used together, so that the anti-liver cancer effect is effectively improved.
The invention adopts an MTT method and CompuSyn software to calculate the CI value, and the result shows that the CII value has a synergistic anti-tumor effect in vitro combination compared with the independent administration of the ranvatinib and the phenformin in the liver cancer HepG2 cell. Compared with other drugs used in clinic for liver cancer, such as sorafenib, phenformin combined with rivastigmine and phenformin + sorafenib and sorafenib + rivastigmine, the CI value is lower, and the better combination effect is achieved; and compared with metformin, the effect of phenformin sensitization on the ranvatinib is more obvious. The HepG2 cell clone formation is observed by adopting single-use and combined treatment for a certain time, and the further discovery that the phenformin can assist the Rankine to further inhibit the tumor cell proliferation. By establishing a nude mouse HepG2 cell subcutaneous tumorigenic model, the combined group of the animal body of the ranvatinib and the phenformin is determined to have more obvious in-vivo anti-tumor effect compared with a single medicine group. The dose of Ranvatinib used in "Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable heparin Carcinoma" published in Journal of Clinical Oncology in 2020 is: 8mg/d (the body weight is less than 60 kg), 12mg/d (the body weight is more than or equal to 60 kg), the dosage is converted into the mouse using dosage of 62.4mg/kg/d according to an equivalent dosage conversion method in pharmacological experiment methodology compiled by professor of xue-tert-yun, while the dosage used by the invention is 3.2mg/kg, and the dosing frequency is obviously less than that of the currently disclosed ranvatinib at 5 times per week. The synergistic effect of the combination of the ranvatinib and the phenformin at the dose of 3.2mg/kg is obvious and has obvious advantages. Western blot detection research shows that the combination of the ranvatinib and the phenformin can effectively activate the AMPK pathway. The combined use of the ranvatinib and the phenformin is verified in vitro and in vivo to have obvious synergistic anti-tumor effect, and importantly, the mechanism of the synergistic anti-tumor effect of the ranvatinib and the phenformin is clarified, the application of the basic theory is proved, the application of the ranvatinib and the phenformin in tumor clinical treatment is promoted, and the important significance is realized.
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FIG. 1: the phenformin and the lovatinib exert the anti-tumor activity and a combined index chart thereof, namely a CI value; CI <1 indicates synergy, CI =1 indicates additive effect, CI >1 indicates antagonism.
FIG. 2: the metformin cooperates with the ranvatinib to exert the anti-tumor activity and a combined index chart thereof, namely a CI value; CI <1 indicates synergy, CI =1 indicates additive effect, CI >1 indicates antagonism.
FIG. 3: sorafenib synergizes with ranvatinib to exert antitumor activity and a combined index chart thereof, namely a CI value; CI <1 indicates synergy, CI =1 indicates additive effect, and CI >1 indicates antagonism.
FIG. 4: the phenformin and the sorafenib cooperate to exert the anti-tumor activity and a combined index chart thereof, namely a CI value; CI <1 indicates synergy, CI =1 indicates additive effect, CI >1 indicates antagonism.
FIG. 5 is a schematic view of: the phenformin and the ranvatinib are used for inhibiting the clonogenic map of the hepatoma cells.
FIG. 6: the weight, volume and mouse weight change contrast chart of nude mouse tumor tissues after administration of phenformin, lenvatinib and combination of phenformin and lenvatinib are provided by the embodiment of the application.
FIG. 7: the combination of Lovatinib and phenformin causes a pattern of elevated p-AMPK protein expression levels in vitro and in vivo.
Detailed Description
In order to make the technical problems, technical solutions and advantages of the present invention more apparent, the following detailed description is given with reference to the accompanying drawings and specific embodiments, but the scope of the present invention is not limited to the following specific embodiments.
Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.
Unless otherwise specifically indicated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods. The phenformin is available from Aladdin reagent Shanghai, inc. Lovatinib is available from Gonghai Ruihui chemical technologies, inc. Sorafenib is available from the Shanghai MedChemex corporation. Metformin is available from the company Bihe Huarun, beijing.
Example 1: lovatinib and phenformin combined effect on in-vitro anti-tumor effect of hepatoma cells
By applying an MTT method, the combination of the ranvatinib and the phenformin is carried out on the liver cancer HepG2 cell strain, and the in-vitro anti-tumor effect of the single use and the combination is compared. Using the CompuSyn software, 2 concentrations were selected for phenformin and 5 concentrations for lunvatinib, and CI values were calculated.
The specific operation is as follows: adding 10% fetal bovine serum solution into DMEM medium, inoculating HepG2 cells into 96-well plate at a density of 8000 cells/well/180 μ L, at 37 deg.C, 5% 2 After culturing for 24 hours under the condition, diluting the medicines with different concentrations by using a fresh culture medium, adding 20 mu L of the diluted medicines into each hole of a culture plate added with cells, wherein the combination group comprises 10 mu L of ranvatinib and 10 mu L of phenformin, the ranvatinib monotherapy group comprises 10 mu L of ranvatinib and 10 mu L of the culture medium, the phenformin monotherapy group comprises 10 mu L of phenformin and 10 mu L of the culture medium, and at least three repeated holes are arranged at each concentration to reduce experimental errors. Control group (without adding drug to cells) and blank group (without adding drug to cells and only containing culture medium) were set.
37℃，5％CO 2 After 72h incubation under conditions, MTT reagent (2 mg/mL) was added in 50. Mu.L/well volume and incubation continued for 5h. Removing the culture medium, adding 150 μ L dimethyl sulfoxide, shaking and mixing for 15min, detecting OD value of each well with enzyme labeling instrument, and detecting wavelength of 490nm. Cell viability was calculated from OD readings and IC50 was calculated using Grapad Prism 6. The CI value was calculated using CompuSyn software. The results show that both lenvatinib and phenformin are in the liverThe cancer cells have stronger synergistic inhibition effect, the CI value is less than 0.5, and the strong synergistic effect is shown. See fig. 1.
Different drug combinations such as the combination of the ranvatinib and the metformin (figure 2), the combination of the ranvatinib and the sorafenib (figure 3), the combination of the phenformin and the sorafenib (figure 4) and the like are treated by the same method, and an MTT result shows that the combination index of the phenformin and the ranvatinib is minimum and the synergistic effect is best compared with the combination of the other three drugs. See in particular fig. 1-4.
Example 2: by adopting a clone formation test, the antitumor effects of the individual drug and the combined drug of the Rankine and the phenformin are compared in the hepatoma cell strain HepG2 cell.
The specific operation is as follows: 2000 cells were seeded in 24-well plates, 0.9mL of culture was mixed well, and 3 multiple wells were provided per group. After 24h, the drug was diluted with fresh medium and added to the above cell-added plates at 100. Mu.L per well after the cells were attached. The combination group comprises 50 mu L of Lunvatinib and 50 mu L of phenformin, the single drug comprises 50 mu L of drug liquid and 50 mu L of culture medium, and the control group comprises 100 mu L of culture medium. The administration time was set to 8 days. Placed at 37 ℃ and 5% CO 2 Continuously culturing under the condition. After 8 days, when the clone grows to 1-2mm in diameter, the culture is terminated. The supernatant was discarded and washed 2 times with PBS. 2mL of 10% paraformaldehyde was added to each well and fixed for 15min. The fixing solution is removed, and 0.5mL of crystal violet dye solution is used for dyeing for 15min. Washing off the staining solution with clear water, and airing at room temperature. And taking a picture, and detecting a light absorption value by using an enzyme-linked immunosorbent assay, wherein the wavelength is 550nm. The results show that the two-drug combination group further inhibited tumor cell proliferation compared to the individual administration of ranvatinib or phenformin, as shown in fig. 5.
Example 3: animal model test
Constructing a HepG2 liver cancer nude mouse model, and researching the combined anti-tumor effect of the Lunvatinib and the phenformin in the animal body.
The specific operation is as follows: hepG2 cells, which are well grown, were collected, and the medium was resuspended and counted, and placed on ice. Mixing the cells, injecting BALB/c female nude mice (purchased from Shirakida laboratory animals, inc. of Hunan province) with weight of 18g-20g into 5 × 10 6 100 μ L of HepG2 cells. When the nude mouse grows tumor 70-100mm under the skin 3 (about 10 days) of the reaction,dosing was started with a 100 μ L dose volume. The implementation groups are respectively as follows: a vehicle group; lovatinib-3.2 mg/kg group; phenformin-80 mg/kg group; lovatinib-3.2 mg/kg + phenformin-80 mg/kg. Wherein the Rvatinib is prepared into 64mg/mL mother liquor by DMSO, and the phenformin is prepared into 16mg/mL mother liquor by 0.5 percent of methylcellulose; the appropriate dosing solution was prepared by pipetting 8. Mu.L of DMSO or 64mg/mL of Ranvatinib stock solution and diluting with 100. Mu.L of 0.5% methylcellulose or 100. Mu.L of a 16mg/mL solution of phenformin, and the drug was ready for use. The frequency of administration was once a day, gavage, 5 times a week for 2 weeks. Tumor size was measured using a vernier caliper and recorded 1 time per day, and the lower left panel of fig. 6 recorded the tumor tissue size on day 14 of dosing. The length (L) and width (W) of the tumor were recorded and the tumor size could be calculated as tumor volume = (L × W) 2 )/2. And (5) drawing a tumor growth curve according to the tumor size of the nude mice. Nude mice were sacrificed and tumors were removed, and tumor weights were calculated for statistical analysis. The results showed that the group combining ranvatinib with phenformin significantly inhibited tumor growth in nude mice, as shown in fig. 6.
Example 4: western blot was used to detect the phosphorylation level of AMPK. The expression levels of p-AMPK by both lenvatinib and phenformin were examined in HepG2 cells and animal tumor tissues.
The test comprises the following specific steps: four groups were set (treatment groups with lenvatinib, phenformin, lenvatinib + phenformin, while the no drug treatment group was set as the control group), the cell level lenvatinib concentration was 4 μ M and the phenformin concentration was 100 μ M. After the appropriate time of drug treatment (12 h of cell treatment, 2 weeks of animal administration), the cells or animal tissues were collected to extract the protein, and the p-AMPK protein expression level was measured using western blot. FIG. 7A is animal tumor tissue and FIG. 7B is protein expression level of p-AMPK in HepG2 cells. The results show that both lenvatinib and phenformin up-regulate p-AMPK protein expression to some extent, and that the combination further up-regulates p-AMPK, indicating that phenformin can increase the ability of lenvatinib to activate AMPK.
Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to imply that the scope of the application is limited to these examples; within the context of the present application, features from the above embodiments or from different embodiments may also be combined, steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments in the present application as described above, which are not provided in detail for the sake of brevity.
It is intended that the one or more embodiments of the present application cover all such alternatives, modifications, and variations as fall within the broad scope of the present application. Therefore, any omissions, modifications, substitutions, improvements, and the like that may be made without departing from the spirit and principles of one or more embodiments of the present application are intended to be included within the scope of the present application.
Claims (6)
1. An anti-liver cancer composition, which is characterized by comprising phenformin and pravastatin.
2. The anti-hepatoma composition according to claim 1, consisting of phenformin and lenvatinib.
3. The anti-hepatoma composition according to claim 1 or 2, characterized in that the molar ratio of phenformin to lenvatinib is: 10-100:1.
4. The anti-hepatoma composition according to claim 1 or 2, further comprising a pharmaceutical adjuvant, carrier, excipient or vehicle.
5. Application of phenformin in preparing sensitizer for anti-liver cancer medicine.
6. The use according to claim 5, wherein said anti-liver cancer agent is rivastigmine.
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