CN116889566A - Application of amsacrine in the treatment of β-catenin mutant liver cancer - Google Patents
Application of amsacrine in the treatment of β-catenin mutant liver cancer Download PDFInfo
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Abstract
The invention provides application of amsacrine in treating beta-catenin mutant liver cancer, and belongs to the technical field of medicines. The invention discovers that amsacrine specifically kills the beta-catenin mutant liver cancer through drug screening, and proves that the low-dose amsacrine has a therapeutic effect on the beta-catenin mutant liver cancer in animal experiments, has small drug side effect and is not good for treating the beta-catenin wild type liver cancer. The invention widens the clinical application range of amsacrine treatment and solves the technical problem that amsacrine is poorly applied to solid tumors.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of amsacrine in treating beta-catenin mutant liver cancer.
Background
Targeted combination immunotherapy is a first-line treatment regimen for advanced hepatocellular carcinoma (Hepatocellular carcinoma, HCC, hereinafter referred to as liver cancer), but studies indicate that CTNNB1 mutant liver cancer cannot benefit from targeted immunotherapy. Beta-catenin is encoded by CTNNB1 gene and is a key effector molecule of Wnt/beta-catenin signal pathway. And the beta-catenin mutation is the most common oncogenic mutation in liver cancer. Therefore, finding a therapeutic regimen for the mutant liver cancer of β -catenin is critical for improving survival of patients with advanced liver cancer. The current antitumor drugs aimed at beta-catenin mutation are mainly Wnt/beta-catenin signaling pathway inhibitors, wherein targeting binding to beta-catenin mutation is the most direct way. The drugs currently developed include: OMP-54M28, PRI-724, WNT-974, etc., but the beta-catenin mutation lacks a specific binding site, has a complex spatial structure, and is difficult to design a high-affinity and effective inhibitor, so the direct targeting of the beta-catenin mutation has not been successful. Meanwhile, in inhibitors entering clinical research, serious adverse events related to medicines mostly occur, wherein gastrointestinal reactions, bone marrow suppression and bone toxicity are obvious, such as vomiting, diarrhea, fever, granulocytopenia, thrombocytopenia, anemia, fracture, hypercalcemia and the like.
Clinical researches show that Amsacrine (m-AMSA) has activity on acute leukemia and lymphoma, but Amsacrine has the problems of low efficiency, high dosage, insignificant effect, significant side effects and the like in the aspect of treating solid tumors, and is not suitable for clinical application. Meanwhile, in clinical experimental research of solid tumors of liver cancer, due to insufficient sample size, the beta-catenin mutant liver cancer is not subjected to subgroup analysis, so that the application of amsacrine in the solid tumors is limited.
Disclosure of Invention
The invention provides application of amsacrine in treating beta-catenin mutant liver cancer, low-dose amsacrine has remarkable treatment effect on beta-catenin mutant liver cancer, and has small side effect.
In order to solve the technical problems, the invention provides the following technical scheme:
the invention provides application of amsacrine in preparing a medicament for treating beta-catenin mutant liver cancer.
Preferably, the effective concentration of the amsacrine is 1.5-20 mu M.
Preferably, the amount of the amsacrine is 2-10 mg/kg.
The invention provides a medicine for treating beta-catenin mutant liver cancer, which comprises amsacrine.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier.
Preferably, the dosage forms of the medicine comprise tablets, capsules, granules, injections and pills.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers that the low-dose amsacrine has remarkable inhibition effect on the beta-catenin mutant liver cancer for the first time, has small side effect on the medicament, has poor inhibition effect on beta-catenin wild type liver cancer cells, widens the clinical application range of amsacrine treatment, and mainly solves the technical problem of poor application of amsacrine in solid tumors.
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FIG. 1 construction of beta-catenin wild type and mutant liver cancer cell lines (A.Western Blot detection of sg-beta-catenin MHCC97H monoclonal cells; B.Western Blot detection of MHCC97H beta-catenin) WT And beta-catenin S45P Expression of the cells; C.MHCc97H2 beta-catenin S45P Peak diagram of amplified product Sanger sequencing; MHCC 97H.beta. -catenin WT Peak pattern of the amplified product Sanger sequencing).
FIG. 2 high throughput screening of specific killer beta-catenin S45P FDA approved drugs for liver cancer cells (A. Drug screening results schematic; B-C. Treatment of different concentrations of amsacrine for 48H followed by MHCC97H and HCCLM3 cells EC) 50 Results; D. topoisomerase inhibitor and acridine analog treated 48H followed by MHCC97H and HCCLM3 cell survival results, drug concentration 10 μΜ treated 48H; western Blot detection of γH2AX levels; the experiments were independently repeated 3 more times and all data are shown as mean ± SD).
FIG. 3 amsacrine specifically inhibits proliferation of β -catenin mutant liver cancer (A. The effect of amsacrine treatment on tumor volume of subcutaneous tumor of liver cancer (n=7), average swellingTumor volume±sem; B. tumor overview of liver cancer subcutaneous tumor at day 15 after amsacrine treatment; C. survival curve of liver cancer subcutaneous tumor mice after amsacrine treatment (n=7); D. survival curve of liver orthotopic tumor mice after amsacrine treatment (n=9); E. representative images of live imaging of in-situ hepatoma on day 1 and day 10 of amsacrine treatment, tumor overview of in-situ hepatoma on day 15; F. weight effects of amsacrine treatment on liver vaccinated orthotopic tumor mice (beta-catenin WT n＝12，β-catenin S45P n=6); tumor size±sem, mean body weight±sd; * : p (P)<0.05；***：P<0.001；****：P<0.0001)。
Detailed Description
The invention provides application of amsacrine in preparing a medicament for treating beta-catenin mutant liver cancer. The effective concentration of the amsacrine is 1.5-20 mu M, preferably 2-18 mu M, and the amsacrine remarkably inhibits the proliferation of beta-catenin mutant liver cancer cells and has low side effect. The amount of amsacrine used in the invention is 2-10 mg/kg, preferably 4-8 mg/kg.
In the invention, amsacrine has poor curative effect on solid tumors through in vitro drug screening and EC 50 Experiments prove that the amsacrine can specifically kill the beta-catenin mutant liver cancer, and has no obvious effect on the wild liver cancer; the results of animal experiments also show that amsacrine can inhibit the growth of beta-catenin mutant liver cancer and prolong the survival of tumor-bearing mice, but has no therapeutic effect on the growth of beta-catenin wild type tumors and the survival of mice, and the amsacrine has certain safety in treating beta-catenin mutant liver cancer, thereby providing a preliminary basis for clinical transformation treatment of liver cancer.
The invention provides a medicine for treating beta-catenin mutant liver cancer. The medicament also comprises a pharmaceutically acceptable carrier. The carrier of the invention is medicinal auxiliary materials used in the preparation of medicaments, including but not limited to isotonic agents, buffers, flavoring agents, excipients, fillers, adhesives, disintegrants, lubricants and the like; may also be selected for adaptation to the compound, such as: emulsifying agent, solubilizer, bacteriostat, analgesic and antioxidant, etc., which can effectively improve the stability and solubility of the compound in pharmaceutical preparation or change the release rate and absorption rate of the compound, etc., thereby improving the metabolism of the compound in living body and further enhancing the administration effect of the composition.
In the invention, the dosage forms of the medicine comprise tablets, capsules, granules, injections and pills. The medicine also comprises, but is not limited to, aqueous solution powder injection, powder, patch, suppository, emulsion, cream, gel, aerosol, spray, powder fog, sustained release agent or controlled release agent and the like.
In the present invention, all raw material components are commercially available products well known to those skilled in the art unless specified otherwise.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
EXAMPLE 1 construction of beta-catenin WT And beta-catenin S45P Liver cancer cell strain
1. A MHCC97H humanized liver cancer monoclonal cell strain with CTNNB1 knocked out is constructed by using CRISPER/Cas9 and a cell monoclonal technology.
The MHCC97H cell line is utilized, and the expression of CTNNB1 gene is knocked out through lentivirus mediated sgRNA, and the vector is U6-sgRNA-EF1a-Cas9-FLAG-P2A-puromycin. After 72h of transfection, resistant cells were screened with 2. Mu.g/mL puromycin for 3 days and the cells continued to be grown in expansion. In order to obtain MHCC97H cells with stable CTNNB1 gene knockout, monoclonal screening technology is utilized to separate MHCC97H sgCTNNB1 into single cells, and after single cells are subjected to expansion culture under the screening of 2 mug/mL puromycin, the total protein of the cells is extracted to verify the expression condition of beta-catenin protein. The WesternBlot results show that the expression level of the beta-catenin protein of the cell colony 1 is obviously reduced, which indicates that the cell colony 1 completely knocks out the beta-catenin expression and can be used as a monoclonal cell strain (MHCC 97H sgCTNNB 1-1) with CTNNB1 gene knocked out (figure 1A).
2. Transfection of lentivirus over-expression wild type and mutant beta-catenin on the basis of monoclonal cell strain, construction of beta-catenin WT And beta-catenin S45P Liver cancer cell strain
Construction of MHCC97 HsgCTNNB 1-1 by stably overexpressing wild-type, S45P Point mutation beta-catenin by lentiviral transfection WT And beta-catenin S45P Liver cancer cell lines. Western Blot results show that MHCC97H beta-catenin WT And beta-catenin S45P The cell significantly up-regulated the expression level of beta-catenin and target gene GS protein relative to the empty control group, suggesting that beta-catenin is over-expressed successfully (FIG. 1B).
To determine the CTNNB1 gene sequences in β -catenin wild type and mutant hepatoma cells, further Sanger sequencing analysis was performed. MHCC97 Hbeta-catenin S45P Within the target fragment of CTNNB1 gene, sanger sequencing found that the 45 th codon of β -catenin was unimodal, and the base sequence was mutated from TCT to CCT, resulting in the change of the 45 th amino acid from serine to proline (fig. 1C). MHCC97 Hbeta-catenin WT Cell Sanger sequencing peak patterns showed that the CTNNB1 gene fragment was wild type (FIG. 1D). In combination with the above experiments, the conclusion was that: MHCC97Hβ -catenin wild type (MHCC 97Hβ -catenin) WT ) S45P-beta-catenin mutant (MHCC 97 Hbeta-catenin) S45P ) The construction of the liver cancer cell line is successful.
HCCLM3 beta-catenin mutation and wild liver cancer cell strain construction method are the same as above.
Example 2 high throughput drug screening
1. Primary screening: FDA approved marketed drug library (LY-1022) was purchased from MCE, and the drug library contained 2383 drugs, provided at a concentration of 10mM, and stored in a refrigerator at-80 ℃.
1) Experiment design: beta-catenin S45P MHCC97H cell lines were seeded in 96-well plates to adjust cell density to 5X 10 3 And/or holes. Each plate was provided with 54 experimental wells (18 drugs at 3 concentrations each), 6 control wells, 6 blank control wells. Inoculating cells in the control hole, but only adding the complete culture medium and the same volume of the dissolution liquid of the medicine; in blank wellsOnly complete medium was added without seeding the cells.
2) Drug screening experiments: after cell attachment, the drug stock was diluted to 5, 10, 20. Mu.M, 100. Mu.L/well with complete culture and added to the experimental wells for 48h. After 48h of drug treatment, the medium was removed and complete medium containing 10% CCK-8 was added per well, totaling 100. Mu.L. At 37 ℃,5% CO 2 The cells were incubated in the incubator in the dark for 2h, and then the absorbance (OD) of each well at 450nm was measured by an ELISA reader.
3) Analysis of drug screening experimental data: cell viability= (experimental well absorbance value-blank control well absorbance value)/(control well absorbance value-blank control well absorbance value) was calculated. The cell viability of less than or equal to 0.4 is used as a standard for the drug to have a remarkable inhibition effect on cells. In order to screen the drug which satisfies the significant inhibition effect on the beta-catenin mutant liver cancer as far as possible, the cell viability is lower than or equal to 0.4 after any concentration treatment, and the drug can be selected as a candidate drug. By beta-catenin S45P The cell viability of the MHCC97H cell strain after three-concentration drug treatment is integrated, and 338 drugs are screened out. Then, the candidate drug with the inhibition effect on the beta-catenin mutant liver cancer cells is obtained for secondary screening.
2. Secondary screening
1) The experimental design is the same as that of primary screening;
2) Drug screening experiments: after cell attachment, the drug stock solution of the primary screening "candidate drug" was diluted to 5, 10, 20. Mu.M, 100. Mu.L/well using complete medium and added to the experimental wells for 48h. CCK-8 experiments were performed as the primary screening step.
3) Analysis of drug screening experimental data: calculating the cell activity, taking the cell activity of less than or equal to 0.4 as a standard of the drug having a remarkable inhibition effect on cells, and taking the cell activity of more than or equal to 1.5 as a standard of the drug having a remarkable promotion effect on cells. In order to reduce adverse events caused by inhibiting physiological beta-catenin signal paths as much as possible, firstly, medicines with obvious effects on beta-catenin wild type liver cancer cells are removed, namely, MHCC97H beta-catenin is reserved after treatment for 48H at concentrations of 5, 10 and 20 mu M WT Is used for treating cancer with cell viability of 0.4-1.5And (3) an object. And simultaneously to beta-catenin S45P Drug with remarkable inhibitory effect on MHCC97H cells, namely MHCC97H beta-catenin after 48H treatment at 5, 10, 20 mu M concentration S45P A drug having a cell viability of less than 0.4. 35 drugs were obtained in total and were screened again as "positive drugs".
3. Re-screening
1) The experimental design is the same as that of primary screening;
2) Drug screening experiments: after cell attachment, the drug stock solution of the second screening "positive drug" was diluted to 5, 10, 20. Mu.M, 100. Mu.L/well with complete medium and added to the experimental wells for 48h. CCK-8 experiments were performed as the primary screening step.
3) Analysis of drug screening experimental data: in order to obtain the medicine for obviously distinguishing the wild type and the mutant type beta-catenin, the activity of the beta-catenin mutant liver cancer cell after the medicine treatment is set to be less than 0.4 in the screening again, and the survival ratio of the wild type to the mutant type cell is more than twice as high as the screening standard of the positive medicine. And (3) screening 8 medicines again from 35 medicines which have no obvious effect on the beta-catenin wild type liver cancer cells obtained in the secondary screening. The 8 medicines have obvious inhibition effect only on beta-catenin mutant liver cancer cells, and have no obvious inhibition effect on physiological beta-catenin signal channels. Among these are 5 antitumor drugs, 1 topoisomerase inhibitor and 4 nucleotide analogues. During the screening, the method is verified again according to the lowest drug concentration with the killing effect during the secondary screening, and finally the amsacrine is found to distinguish liver cancer cells of the beta-catenin wild type and mutant type and specifically kill the beta-catenin S45P Mutant liver cancer cells. The whole screening process is shown in fig. 2A.
Example 3 Effect of amsacrine on beta-catenin wild type and mutant hepatoma cells
1.EC 50 And (3) testing: human liver cancer cell MHCC97H beta-catenin in logarithmic growth phase and good growth state WT Beta-catenin S45P Hepatoma cell or HCCLM3 beta-catenin WT Beta-catenin S45P Liver cancer cells are respectively inoculated into 96-well plates, and the cell density is adjusted to be 5 multiplied by 10 3 /well. Culturing for 24hAfter the cells are attached, the amsacrine is used for respectively treating the beta-catenin mutant liver cancer cells and the beta-catenin wild liver cancer cells. The amsacrine treatment concentration is 10 -3 、10 -2 、10 -1 0.4, 0.8, 1.6, 3.2, 6.4, 12.8, 25.6, 51.2, 64, 80, 100, 200, 400, and 800 μm. After 48 hours of continuous culture, 100 mu L of complete culture medium containing 10% of CCK-8 solution is changed for 2 hours of continuous culture, OD value at 450nm is detected by using an enzyme label instrument, and cell viability is calculated, and cell inhibition rate=1-cell survival rate.
The results show that in MHCC97H beta-catenin WT Beta-catenin S45P EC of amsacrine in hepatoma cells 50 12.35. Mu.M and 2.65. Mu.M respectively; in HCCLM3 beta-catenin WT And beta-catenin S45P EC of amsacrine in hepatoma cells 50 17.18. Mu.M and 8.33. Mu.M, respectively (FIGS. 2B-C). The above results confirm that: the amsacrine has more specific killing effect on the beta-catenin mutant liver cancer in two human liver cancer cells.
2. Influence of drugs having similar molecular structures and action mechanisms to amsacrine on beta-catenin wild type and mutant liver cancer cells
Treatment of 18 topoisomerase inhibitors and 3 acridine analogues in the FDA-approved drug library with β -catenin wild-type and mutant liver cancer cells, respectively (treatment mode was the same as in step 1 of this example), and treatment at a concentration of 10 μm for 48H revealed that only amsacrine showed specific killing of β -catenin mutant liver cancer in both mhc c97H and HCCLM3 liver cancer cell lines (fig. 2D). And the amsacrine treatment had no specific effect on the expression of the DNA damage repair key protein γh2ax (fig. 2E). This suggests that the specific inhibitory effect of amsacrine on β -catenin mutant liver cancer may not depend on the mechanism of action of topoisomerase inhibitors and acridine molecular structures.
Example 4 therapeutic Effect of amsacrine on subcutaneous and hepatic in situ tumors in mice
1. Construction of liver cancer cell line stably over-expressing luciferase Gene
Ubi-MCS-firefly-Luciferase-IRES-puromycin lentivirus was constructed by Shanghai Ji Kai Gene chemical technologies Co. Will stabilizeHepa1-6 cells which are used for determining over-expression beta-catenin wild type and mutant type are respectively inoculated into a 6-hole plate, and the cell density is adjusted to be 1 multiplied by 10 5 And/or holes. After cell attachment, the complete medium was removed and the cells were gently rinsed with PBS buffer. PBS liquid was removed, and 1mL of DMEM medium without serum, 40 μ LHitransG P virus infection enhancing liquid and over-expressed lentivirus liquid (moi=10) were added. After the liquid is uniformly mixed by shaking, the cells are placed in a cell incubator for continuous culture. After 12h, the morphology of the cells was observed under an inverted microscope, and the medium was replaced with 1mL of serum-free DMEM medium. After culturing for 72 hours, the cells are replaced by a complete culture medium containing 2 mug/mL puromycin for 3 days, and the rest cells are subjected to expansion culture by using the complete culture medium, so that the beta-catenin wild type or mutant type Hepa1-6 cell strain with stable over-expressed luciferase gene can be obtained.
2. Laboratory animals and treatments
Female C57BL/6 mice (4-6 weeks old) were supplied by the university of south medical science animal center.
Construction of mouse subcutaneous tumor model: murine hepatoma cells (5×10) 6 And a) subcutaneously planted in the right back of C57BL/6 mice; tumor volume was calculated: length x width 2 /2. When the tumor reaches about 300mm 3 Treatment was performed at time, randomized, tumor volumes were measured every 2 days. For ethical reasons, when the tumor volume reaches 1500mm 3 The mice are killed by cervical fracture in the process of time, and the mice are subjected to innocent treatment. Endpoint was designated as day 15 after initiation of treatment.
Construction of a mouse carcinoma in situ model: c57BL/6 mice were anesthetized by intraperitoneal injection of 1% sodium pentobarbital solution. After disinfection of the iodophor, the liver was exposed to a median incision in the upper abdomen and 1X 10 6 Murine hepatoma cells were slowly injected under the liver capsule and then the abdominal cavity was closed. Detection of hepatic carcinoma in situ bioluminescence using a small animal in vivo imager (IVIS@Lumina II system) when the total tumor ROI reached 10 6 The treatment was performed at intervals of 5 days, and the change in fluorescence intensity of the carcinoma in situ of the liver was detected by using in vivo imaging. Mice were given tail vein injection of amsacrine (8 mg/kg or 4 mg/kg) on days 1, 8 of the initiation of treatment, and changes in body weight of the mice were recorded. After 14 days of treatment, mice were sacrificed and the liver was resectedHeavy for subsequent experiments.
3. Mouse living body imaging experiment
The D-potassium fluorescein salt is dissolved by a sterile PBS buffer solution to prepare a storage solution of 15mg/mL, and the storage solution is preserved in a refrigerator at the temperature of minus 20 ℃ in a dark place after filtering and sterilizing by a 0.22 mu m filter membrane. The body surface of the upper abdomen of each mouse is dehaired before detection, 1% pentobarbital sodium solution is injected intraperitoneally for anesthesia, 15mg/mL of potassium salt solution of fluorescein is injected intraperitoneally according to 10uL/g for 5-10min, and then the mice are developed. 5 mice were taken at a time, and the mice were adjusted to a supine position to expose the tumor. Exposure conditions: 10bin, field of view, exposure time 60s. And after photographing is finished, the tumor part is circled by using the aura software to obtain the ROI value.
4. Statistical method
Experiments for the above design test were independently repeated 3 or more times, and the comparison between groups was analyzed using One-Way ANOVA variance analysis, the comparison between groups was analyzed using Student's t test, and the comparison between mice weights was analyzed using paired Student's t test. All data except tumor volume change are shown as mean ± SD, while tumor volume change data are shown as mean ± SEM. Survival curves of the different groups of mice were analyzed using the Kaplan-Meier method. Survival data were compared using a log rank Mantel-Cox test. p <0.05 is considered statistically significant. All data were counted using GraphPad Prism 7.
The experimental results of mice and animals prove that amsacrine can effectively distinguish beta-catenin wild type liver cancer from mutant liver cancer, specifically inhibit tumor growth of beta-catenin mutant liver cancer and prolong survival time of mice (figures 3A-E). There was no obvious difference in weight change of tumor-bearing mice with in-situ tumors of liver before and after the administration of amsacrine, indicating that amsacrine has certain safety in treating liver cancer (fig. 3F).
In conclusion, amsacrine can specifically kill beta-catenin mutant liver cancer, and has low side effects of the medicine, but has no therapeutic effect on beta-catenin wild type liver cancer.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
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