CN115414363B - 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 lenvatinib; 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 drug sensitizer.
Background
Hepatocellular carcinoma, the most common type of liver cancer, accounts for 90% of primary liver cancer. Because of the difficulty in early diagnosis, the disease progress is rapid, more than 80% of liver cancer patients have progressed to middle and late stages when diagnosis is confirmed, and almost no effective treatment option exists; and the prognosis is poor, and the survival rate of 5 years is only about 15-18%.
Lenvatinib (Lenvatinib) is an oral multi-kinase target inhibitor, and is developed by Japanese Wei Cai (Eisai) company, and can inhibit vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, kit, RET and other kinases. Lenvatinib was also FDA approved for use in patients with advanced thyroid cancer and advanced renal cancer and FDA approved as a first-line drug for liver cancer in 2018, and is currently a recognized first-line targeted drug for the treatment of unresectable liver cancer as sorafenib. Global multicenter phase III clinical trials showed that nearly 80% of liver cancer patients were ineffective in the treatment of lenvatinib, despite the improvement in objective tumor remission rate of lenvatinib compared to sorafenib from 9.2% to 24.1%.
To increase the efficacy of drugs, researchers have focused their eyes on combination means. The combination of small molecule targeting drugs and immune drugs, the combination of immune targeting and immune targeting, and the combination of small molecules and small molecule targeting drugs have been applied to preclinical and clinical trials of liver cancer. The combination shows better efficacy and sensitivity than single use. For example, in a clinical test of liver cancer, the combined use of the small molecular medicine apatinib and the carlizumab not only has a great breakthrough in curative effect, but also has excellent performance in the aspect of safety. The other clinical test of the combination of the lenvatinib and the pembrolizumab (an anti-PD-1 antibody) for treating the unresectable liver cancer patient in stage 1b shows that the combination of the two has better anti-tumor effect. In addition, the combination drug is used for reducing the dosage of single drug through drug combination, and is an effective way for overcoming drug resistance and reducing toxic and side effects due to different drug action mechanisms. However, the selection of the scheme of the combined drug is very difficult, so that the finding of effective, small adverse reaction, definite action and the combined drug treatment strategy for improving the clinical treatment effect of the lenvatinib become urgent.
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 preparing an anti-liver cancer drug sensitizer.
The embodiment of the application relates to an anti-liver cancer composition, which comprises phenformin (phenformin) and lenvatinib.
As one example, the anti-liver cancer composition consists of phenformin and lenvatinib.
As one example, the molar ratio of phenformin to lenvatinib is 10-100:1.
As one example, the anti-liver cancer composition further comprises pharmaceutical auxiliary materials, carriers, excipients or vehicles, and the anti-liver cancer composition can be prepared into oral tablets or oral capsules.
The embodiment of the application also provides application of the phenformin in preparing the sensitizer of the anti-liver cancer drug, wherein the anti-liver cancer drug is lenvatinib.
The invention has the beneficial effects that the invention combines the phenformin and the lenvatinib, thereby effectively improving the anti-liver cancer effect.
The CI value is calculated by adopting an MTT method and CompuSyn software, and the result shows that compared with the independent administration of the lenvatinib and the phenformin, the in vitro combination of the lenvatinib and the phenformin has a synergistic anti-tumor effect in liver cancer HepG2 cells. Compared with other clinically used medicines for liver cancer, such as sorafenib, the combined benzoguanamine and the combined lenvatinib have lower CI values than the benzoguanamine, the sorafenib and the combined sorafenib, and have better combined effect; and compared with metformin, the phenformin sensitized lenvatinib has more remarkable effect. 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 lenvatinib to further inhibit the proliferation of tumor cells. By establishing a subcutaneous tumor formation model of the HepG2 cell of the nude mouse, the combined group of the lenvatinib and the phenformin in the animal body has more remarkable in-vivo anti-tumor effect compared with a single-drug group. The dosage of lenvatinib used in paper "Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma" published in Journal of Clinical Oncology in 2020 was: 8mg/d (body weight less than 60 kg), 12mg/d (body weight greater than or equal to 60 kg), which is converted into a mouse dose of 62.4mg/kg/d according to the equivalent dose conversion method in the pharmacokinetics experiment methodology of the professor Xu Shuyun, whereas the dose of lenvatinib used in the present invention is 3.2mg/kg, with a frequency of 5 administrations per week, which is significantly less than the presently disclosed dose of lenvatinib. The invention has obvious advantages through the synergistic effect of the combination of the lenvatinib and the phenformin at the dosage of 3.2 mg/kg. Western blot detection researches show that the combination of the lenvatinib and the phenformin can effectively activate the AMPK pathway. Not only is the combined use of the lenvatinib and the phenformin verified from inside and outside the body to have obvious synergic anti-tumor effect, but also the mechanism of the synergic anti-tumor effect of the two is clarified, the application of the basic theory is solid, and the application of the lenvatinib and the phenformin in clinical treatment of tumors is promoted, so that the method has important significance.
Drawings
Fig. 1: the phenformin cooperates with the lenvatinib to play an anti-tumor activity and a combination index chart, namely CI value; CI <1 represents synergy, ci=1 represents additive, CI >1 represents antagonism.
Fig. 2: metformin cooperates with lenvatinib to exert anti-tumor activity and a combination index chart, namely CI value; CI <1 represents synergy, ci=1 represents additive, CI >1 represents antagonism.
Fig. 3: sorafenib cooperates with lenvatinib to exert anti-tumor activity and a combination index chart, namely CI value; CI <1 represents synergy, ci=1 represents additive, CI >1 represents antagonism.
Fig. 4: the phenformin cooperates with sorafenib to play an anti-tumor activity and a combination index chart, namely CI value; CI <1 represents synergy, ci=1 represents additive, CI >1 represents antagonism.
Fig. 5: the phenformin cooperates with the lenvatinib to inhibit the cloning of liver cancer cells.
Fig. 6: the weight and volume of tumor tissues of nude mice and the weight change comparison chart of the mice after the tumor mice are administrated with the phenformin and the lenvatinib and the combination of the phenformin and the lenvatinib are provided by the embodiment of the application.
Fig. 7: the combination of lenvatinib and phenformin resulted in a map 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 to be solved by the present invention more apparent, the following detailed description will be 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 defined otherwise, all technical and scientific terms 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 be limiting of the scope of the present invention.
Unless otherwise specifically indicated, the various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or may be prepared by existing methods. The phenformin was purchased from ala Ding Shiji Shanghai limited. And the lenvatinib is purchased from Shanghai Ruihui chemical technology Co. Sorafenib was purchased from medchemxpress, shanghai. Metformin is purchased from the company beijing huaman.
Example 1: combined effect of lenvatinib and phenformin on in-vitro anti-tumor of liver cancer cells
And (3) combining the lenvatinib and the phenformin on a liver cancer HepG2 cell line by using an MTT method, and comparing the in-vitro anti-tumor effect of the combination with that of the single use. Using CompuSyn software, 2 concentrations of phenformin and 5 concentrations of lenvatinib were selected and CI values calculated.
The specific operation is as follows: adding 10% fetal bovine serum solution into DMEM medium, inoculating HepG2 cells into 96-well plate at 8000 pieces/well/180 μl, and heating at 37deg.C with 5% CO 2 After 24h incubation, the drugs at different concentrations were diluted with fresh medium and added to the plates of the added cells at 20 μl per well, combined with 10 μl of lenvatinib+10 μl of phenformin, single-drug-group of lenvatinib 10 μl of lenvatinib+10 μl of medium, single-drug-group of phenformin 10 μl of phenformin+10 μl of medium, and at least three duplicate wells were made per concentration to reduce experimental errors. A control group (no cells added) and a blank group (no cells added and no drugs added, only medium) were additionally provided.
37℃，5％CO 2 After 72h incubation at 50. Mu.L/well volume MTT reagent (2 mg/mL) was added and incubation continued for 5h. The culture medium is removed, 150 mu L of dimethyl sulfoxide is added, the mixture is stirred and mixed uniformly for 15min, the OD value of each hole is detected by an enzyme-labeled instrument, and the detection wavelength is 490nm. From the OD value readings, cell viability was calculated and IC50 was calculated using Grapad Prism 6. The CI value is calculated using CompuSyn software. The result shows that the lenvatinib and the phenformin have strong synergistic inhibition effect in liver cancer cells, and the CI value is less than 0.5, which indicates that the lenvatinib and the phenformin have strong synergistic effect. See fig. 1.
The different drug combinations of the lenvatinib and the metformin (figure 2), the lenvatinib and the sorafenib (figure 3), the phenformin and the sorafenib (figure 4) are treated in the same method, and MTT results show that compared with the other three drug combinations, the combination index of the phenformin and the lenvatinib is the smallest, and the synergy is the best. See in particular figures 1-4.
Example 2: the anti-tumor effect of the separate administration and the combined administration of the lenvatinib and the phenformin is compared in liver cancer cell lines HepG2 cells by adopting a clone formation test.
The specific operation is as follows: 2000 cells were seeded in 24-well plates, 0.9mL of culture medium was mixed well, and 3 duplicate wells were set per group. After 24h cell attachment, 100 μl per well was added to the above-described cell-loaded plates after drug dilution with fresh medium. The combination group is 50 mu L of lenvatinib+50 mu L of phenformin, the single drug is 50 mu L of liquid medicine+50 mu L of culture medium, and the control group is 100 mu L of culture medium. The administration time was set to 8 days. Placing at 37deg.C, 5% CO 2 Continuous culture under the condition. After 8 days, the clones were grown to a diameter of 1-2mm and the culture was terminated. The supernatant was discarded and washed 2 times with PBS. 2mL of 10% paraformaldehyde was added to each well, and the mixture was fixed for 15min. The fixative was removed and 0.5mL crystal violet dye was used for 15min. Washing off the dyeing liquid with clear water, and airing at room temperature. Photographing and detecting the light absorption value by adopting an enzyme-labeled instrument, wherein the wavelength is 550nm. The results show that the two-drug combination group further inhibited tumor cell proliferation compared to either lenvatinib or phenformin alone, as shown in fig. 5.
Example 3: animal model test
And constructing a HepG2 liver cancer nude mouse model, and researching the combined anti-tumor effect of the lenvatinib and the phenformin in animals.
The specific operation is as follows: hepG2 cells with good growth status were collected, the medium resuspended and counted, and placed on ice. The cells were mixed and injected into the armpit of a BALB/c female nude mouse (available from Hunan Laikovia laboratory animal Co., ltd.) weighing 18g-20g at 5X 10 6 100. Mu.L of HepG2 cells. When the nude mice grow tumor 70-100mm subcutaneously 3 (about 10 days) administration was started, and the administration volume was 100. Mu.L. The implementation groups are respectively as follows: a vehicle group; group 3.2mg/kg of lenvatinib; phenformin-80 mg/kg group; lenvatinib-3.2 mg/kg + phenformin-80 mg/kg group. Wherein, the lenvatinib is prepared into a mother solution of 64mg/mL by DMSO, and the phenformin is prepared into a mother solution of 16mg/mL by 0.5% methylcellulose; 8 mu L of DMSO or 64mg/mL of lenvatinib mother liquor is absorbed, 100 mu L of 0.5% methyl cellulose or 100 mu L of 16mg/mL of phenformin solution is diluted to prepare corresponding administration solution, and the medicine is prepared at present. The administration frequency is once a day, and the administration is performed by stomach irrigation, 5 times a week, for 2 weeks. Tumor size was measured using vernier calipers and recorded 1 time per day, and the lower left panel of fig. 6 records tumor tissue size on day 14 of dosing. The length (L) and width (W) of the tumor were recorded, and the tumor size was calculated as tumor volume= (l×w) 2 )/2. And 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 show that the combination group of lenvatinib and phenformin significantly inhibited tumor growth in nude mice, as shown in fig. 6.
Example 4: western blot detects the phosphorylation level of AMPK. The expression levels of p-AMPK by lenvatinib and phenformin were examined in HepG2 cells and animal tumor tissues.
The test comprises the following specific steps: four groups (treatment group of lenvatinib, phenformin, and lenvatinib+phenformin, and control group of no drug treatment) were set, and the concentration of cellular-level lenvatinib was 4 μm and the concentration of phenformin was 100 μm. After a proper time of drug treatment (12 hours of cell treatment, 2 weeks of animal administration), the cells or animal tissues were collected to extract proteins, and the western blot was used to detect the p-AMPK protein expression level. FIG. 7A is a tumor tissue of an animal, and FIG. 7B is a protein expression level of p-AMPK in HepG2 cells. The results show that the p-AMPK protein expression can be regulated to a certain extent by the lenvatinib and the phenformin, which is combined with the further up regulation of the p-AMPK, demonstrate that the phenformin can increase the capacity of the lenvatinib to activate the AMPK.
Those of ordinary skill in the art will appreciate that: the discussion of any of the embodiments above is merely exemplary and is not intended to imply that the scope of the present application is limited to such examples; combinations of features of the above embodiments or in different embodiments are also possible within the spirit of the application, steps may be implemented in any order, and there are many other variations of the different aspects of one or more embodiments described above which are not provided in detail for the sake of brevity.
One or more embodiments herein are intended to embrace all such alternatives, modifications and variations that fall within the broad scope of the present application. Any omissions, modifications, equivalents, improvements, and the like, which are within the spirit and principles of the one or more embodiments in the present application, are therefore intended to be included within the scope of the present application.
Claims (6)
1. An anti-liver cancer composition is characterized by comprising phenformin and lenvatinib.
2. The anti-liver cancer composition according to claim 1, which comprises phenformin and lenvatinib.
3. The anti-liver cancer composition according to claim 1 or 2, wherein the molar ratio of phenformin to lenvatinib is: 10-100:1.
4. The anti-liver cancer composition according to claim 1 or 2, further comprising a pharmaceutically acceptable adjuvant.
5. The anti-liver cancer composition of claim 4, wherein the adjuvant is a carrier or excipient.
6. Use of an anti-liver cancer composition according to any one of claims 1-5 in the preparation of an anti-liver cancer medicament.
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