CN113769098B - Application of MLL-menin inhibitor composition in preparation of anti-liver cancer drugs - Google Patents

Application of MLL-menin inhibitor composition in preparation of anti-liver cancer drugs Download PDF

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CN113769098B
CN113769098B CN202111106083.9A CN202111106083A CN113769098B CN 113769098 B CN113769098 B CN 113769098B CN 202111106083 A CN202111106083 A CN 202111106083A CN 113769098 B CN113769098 B CN 113769098B
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郑小丽
曾苏
吴式琇
王绿化
汪佳琪
余露山
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Abstract

The invention provides an application of an MLL-menin inhibitor composition in preparation of anti-liver cancer drugs, wherein the composition consists of an MLL-menin inhibitor and paclitaxel. The composition disclosed by the invention has the advantages that the expression level of CYP1B1 is reduced by inhibiting MLL from catalyzing H3K4me3, the combination effect of the paclitaxel on tubulin is enhanced, the sensitivity of an in-vitro hepatocyte cancer cell line and an in-vivo hepatocellular carcinoma mouse on the paclitaxel is synergistically increased, and the chemotherapeutic curative effect is remarkably improved after the hepatocellular carcinoma which is highly resistant to the paclitaxel and is ineffective by using a single apparent genetic medicament MLL-menin inhibitor is treated by the composition. The composition of the invention provides a new chemotherapeutic drug for hepatocellular carcinoma resistant to paclitaxel treatment.

Description

Application of MLL-menin inhibitor composition in preparation of anti-liver cancer drugs
Technical Field
The invention belongs to the field of medicines, and relates to an application of an MLL-menin inhibitor composition in preparation of an anti-liver cancer medicine, wherein the MLL-menin inhibitor is used for realizing down-regulation of CYP1B1 protein expression level, and the MLL-menin inhibitor is applied to improving the sensitivity of hepatocellular carcinoma to paclitaxel.
Background
The global mortality rate of liver cancer is the third of cancer-related mortality rates, and as a high-incidence area of liver cancer, China accounts for more than half of the world in new-onset and death patients every year. The primary liver cancer mainly comprises hepatocellular carcinoma, intrahepatic bile duct cancer and other rare subtypes, wherein the hepatocellular carcinoma accounts for about 70-85% of the primary liver cancer. At present, the clinical liver cancer treatment faces the problems of poor curative effect, easy drug resistance, high recurrence rate and the like, and the five-year survival rate of a patient is only 12 percent, so the problem that the drug resistance phenomenon of the liver cancer treatment needs to be solved clinically urgently is solved.
CYP1B1 is an important component member of cytochrome P450 enzyme system (cytochrome P450, CYPs), has very low expression in normal liver of human body, but has high expression in various tumor tissues such as liver cancer, and the like, and the expression level is related to the drug resistance of therapeutic drugs such as paclitaxel and the like because CYP1B1 is also involved in the metabolism of some anti-cancer drugs.
Trimethylation of H3K4 (H3K4me3) is an important epigenetic marker, usually located in the gene promoter region as a marker for activating transcriptional activity, and is catalyzed by the COMPASS complex, where the catalytic subunit SET1/MLL has six homologous proteins (SET1A, SET1B, MLL1, MLL2, MLL3, and MLL 4). On the one hand, MLL protein plays a catalytic function of H3K4me3 through a protein complex (PMID:19075677) formed by the MLL protein and RbBP5, ASH2, WDR5, menin and the like, and on the other hand, the carcinogenesis of MLL fusion protein depends on the interaction of MLL fusion protein and the menin protein. Therefore, the MLL-Menin inhibitor becomes a new strategy for treating tumors, for example, MI-2 is a small molecule inhibitor for destroying the interaction between Menin and MLL which is reported for the first time, and shows good treatment effect on MLL leukemia cells and mouse models (PMID:22286128), while MI-3454 is a high-efficiency and orally-taken Menin-MLL1 interaction inhibitor obtained by structural optimization recently, and also has good tumor inhibition effect in PDX leukemia models (PMID: 31855575). At present, no experimental report of MLL-menin inhibitor on solid tumors such as liver cancer is found. Paclitaxel mainly inhibits cancer cell division and proliferation by influencing spindle formation of cancer cells during mitosis through combination with tubulin, and is mainly suitable for treating ovarian cancer and breast cancer clinically, but the curative effect on hepatocellular carcinoma is not ideal. Therefore, aiming at the drug resistance phenomenon of hepatocellular carcinoma to paclitaxel, the synergistic effect of the combined drugs is fully utilized, and the treatment effect can be optimized.
Disclosure of Invention
On the basis of research on the drug resistance mechanism of hepatocellular carcinoma to paclitaxel, the invention searches for an MLL-menin inhibitor based on the existing MLL-menin inhibitor on the market and provides a novel treatment strategy for treating hepatocellular carcinoma.
Accordingly, it is an object of the present invention to provide an MLL-menin inhibitor composition, said composition consisting of an MLL-menin inhibitor, which is MLL-menin inhibitor MI-2 or MLL-menin inhibitor MI-3454, and paclitaxel, wherein the preferred molar ratio of the MLL-menin inhibitor MI-2 to the paclitaxel is 300:1 to 60:1, and the preferred molar ratio of the MLL-menin inhibitor MI-3454 to the paclitaxel is 450:1 to 10: 1.
The invention also aims to provide the application of the composition in preparing a medicament for treating the anti-liver cancer. The liver cancer is hepatocellular carcinoma. The composition provided by the invention can reduce the expression level of CYP1B1, enhance the binding effect of paclitaxel on tubulin and synergistically increase the sensitivity of an in vitro hepatocellular carcinoma cell line and an in vivo hepatocellular carcinoma mouse on paclitaxel by inhibiting MLL from catalyzing H3K4me 3.
The composition has the beneficial effects that the expression quantity of CYP1B1 is reduced by inhibiting MLL from catalyzing H3K4me3, the binding effect of paclitaxel on tubulin is enhanced, the sensitivity of an in vitro hepatocyte cancer cell line and an in vivo hepatocellular carcinoma mouse to paclitaxel is synergistically increased, and the chemotherapy curative effect of hepatocellular carcinoma which has high resistance to paclitaxel and is ineffective to a single epigenetic medicament MLL-menin inhibitor is remarkably improved after the hepatocellular carcinoma is treated by the composition. The composition of the invention provides a new chemotherapeutic drug for hepatocellular carcinoma resistant to paclitaxel treatment.
Drawings
FIG. 1 shows the protein expression levels of CYP1B1 after MI-2 treatment of two hepatocellular carcinoma cell lines, Huh7 and Li-7.
FIG. 2 is a graph of the drug dose-response curves for MI-2 and paclitaxel in two hepatocellular carcinoma cell lines, Huh7 and Li-7.
FIG. 3 is a graph of the combination of MI-2 and paclitaxel at different concentration points in the two hepatocellular carcinoma cell lines Huh7 and Li-7.
FIG. 4 is a fluorescence plot of the effect of MI-2 and paclitaxel, alone or in combination, on tubulin polymerization in two hepatocellular carcinoma cell lines, Huh7 and Li-7.
FIG. 5 is a graphical representation of the effect of MI-2 and paclitaxel, alone or in combination, on tumor growth in a mouse model of hepatocellular carcinoma (Li-7).
FIG. 5-1 is a schematic representation of the relative volume increase of tumors.
Fig. 5-2 is a schematic representation of tumor weight.
FIGS. 5-3 are photographs of a mouse model of hepatocellular carcinoma after euthanasia.
FIGS. 5-4 are photographs of a mouse model of hepatocellular carcinoma and the tumor after isolation.
FIGS. 5-5 are schematic diagrams of relative body weight changes in a mouse model of hepatocellular carcinoma.
FIG. 6 is a photograph of a mouse model of hepatocellular carcinoma (Huh7, PDX) and a tumor after isolation.
FIG. 7 is a fluorescence plot of the effect of MI-2 and paclitaxel, alone or in combination, on tubulin polymerization in a mouse model of hepatocellular carcinoma (Li-7).
FIG. 8 is a graph of the drug dose-response curves for MI-3454 and paclitaxel in two hepatocellular carcinoma cell lines, Huh7 and Li-7.
FIG. 9 is a graph of the combination indices of MI-3454 and paclitaxel at different concentration points in two hepatocellular carcinoma cell lines, Huh7 and Li-7.
Detailed Description
The invention is further explained by combining the drawings and the embodiments.
Example 1
The invention finds that the MLL-menin inhibitor MI-2 composition can reduce the protein level of CYP1B1 in hepatocellular carcinoma cell lines Huh7 and Li-7.
Reagents and materials:
the hepatoma cell lines HuH-7 and Li-7 were purchased from Shanghai cell Bank, Chinese academy of sciences. HuH7 was cultured in DMEM medium (CORNING, cat # 10-013-CV) containing 10% GBICO fetal bovine serum, and Li-7 was cultured in RPMI-1640 medium (CORNING, cat # 10-013-CV with Sodium Pyruvate 0.11g/L) containing 10% fetal bovine serum; the culture conditions were 37 ℃ and 5% CO 2. MI-2 was purchased from TargetMol (cat # T2649).
The experimental method comprises the following steps:
huh7 and Li-7 cells were treated with DMSO (dimethyl sulfoxide) and MI-2 (10. mu. mol/L, 25. mu. mol/L, 50. mu. mol/L), respectively, to extract cell sample proteins, the RIPA lysate was chilled on ice, and the protease inhibitor PMSF was added to a final concentration of 1mmol/L, Leupepstatin was added to a final concentration of 0.5. mu.g/mL, Peptastatin was added to a final concentration of 0.7. mu.g/mL just before use. Adding a proper amount of lysate into each cell sample, placing the cell sample in a chromatography cabinet at 4 ℃, gently rotating the cell sample for 2 hours to fully lyse the cell sample, centrifuging the cell sample at 13,000rpm at 4 ℃ for 10 minutes, and taking supernatant to store at-80 ℃ or be used for subsequent protein quantification. And (3) performing relative quantification on the protein concentration by adopting the OD280 reading of an ultraviolet spectrophotometer, adjusting the concentration of the cell protein solution to be the same, and detecting the protein abundance by adopting a western blot.
The experimental results are as follows:
as shown in fig. 1, CYP1B1 protein levels were found to be significantly reduced and concentration dependent after MI-2 treatment of both hepatocellular carcinoma cell lines.
Example 2
The invention finds that the combination drug MI-2 and paclitaxel can synergistically enhance the toxicity of paclitaxel on hepatocellular carcinoma cell lines.
Reagents and materials:
paclitaxel was purchased from alatin (cat # P106869), and the remaining reagent materials were the same as in example 1.
The experimental method comprises the following steps:
preparing MI-2, paclitaxel stock solution and working solution:
using DMSO as solvent, MI-2 was diluted to 500X stock solution, paclitaxel was diluted to 1000X stock solution, and stored at-20 ℃.
The working solution is prepared immediately before use, and when the medicine is added, 10 mu L of the working solution/100 mu L of a culture system/well are added into each hole:
MI-2 working solution: mu.L stock solution + 98. mu.L medium → 100. mu.L working solution (10X)
Paclitaxel working solution: 1 μ L stock solution +99 μ L medium → 100 μ L working solution (10 ×)
Cell culture and dosing:
HuH7(5000cells/well) and Li-7(5000cells/well) cells were seeded at a certain density in 96-well plates and cultured overnight. After 24h, 10 μ L of paclitaxel at a predetermined concentration and 0.2% DMSO were added to the paclitaxel group; adding 10 μ L of predetermined concentration paclitaxel and 0.1% DMSO into MI-2 group; the two drugs are combined and 10. mu.L of paclitaxel and MI-2 are added at predetermined concentrations. The final concentration of DMSO in each group of culture system is 0.3%, and each concentration point is provided with 4 duplicate wells. The medium was replaced every 24h with fresh drug-containing medium. Drug treatment was terminated after 48 h. The preferred molar ratio of MI-2 to paclitaxel in Huh7 and Li-7 is 300:1 to 60:1, respectively.
TABLE 1 drug Final concentrations of MI-2 and paclitaxel in two cell lines
Figure BDA0003272428670000041
Figure BDA0003272428670000051
Cell viability assay:
after the drug treatment is finished, adding 100 mu L of fresh culture medium containing 10 mu L of CCK-8 solution into each well of a 96-well plate, incubating for 1-2 h at 37 ℃ in the dark, reading the absorbance at the wavelength of 450nm and 650nm (650nm is a reference wavelength) by using an enzyme-labeling instrument, and calculating the inhibition effect of each concentration point, wherein the formula is as follows:
inhibitory Effect 1-Experimental group (A) 450nm -A 650nm ) Control group (A) 450nm -A 650nm )×100％。
Quantitative analysis of dose-effect of MI-2 in combination with paclitaxel:
the inhibitory effect (inhibitoryy%) of each concentration point was first calculated. Using MI-2 or paclitaxel single drug concentration as abscissa, the corresponding inhibition effect of each concentration as ordinate, and using Prism 8.0 to plot to obtain dose-effect curve and each parameter thereof.
And using Compuyn software (Combosyn Inc.) to calculate the CI value (Combination index) of the Combination of MI-2 and paclitaxel, wherein CI >1.2 is antagonistic effect, CI <0.8 is synergistic effect, and CI between 0.8 and 1.2 is considered additive effect.
And (3) tubulin detection:
treating Huh7 and Li-7 cells with paclitaxel and/or MI-2, setting a solvent control group, an MI-2 group, paclitaxel and a combination of paclitaxel and MI-2, and detecting the influence of the paclitaxel alone or in combination on tubulin polymerization by adopting an immunofluorescence detection technology to evaluate whether the combination of the MI-2 and paclitaxel can promote the stability of tubulin and further inhibit mitosis-induced cytotoxicity.
The experimental results are as follows:
the dose-response curves of MI-2 and paclitaxel on Huh7 and Li-7 cells are shown in FIG. 2, and the combination of MI-2 and paclitaxel can increase the sensitivity of hepatocellular carcinoma to paclitaxel, and further analysis shows that the combination index CI in Huh7 cells is less than 0.8 (FIG. 3), while in Li-7 cells, the combination exerts additive effect at high concentration of the drugs, and when the concentration of paclitaxel is less than 250nM, the combination of the two drugs has synergistic effect on the cytotoxicity of Li-7 cells. And FIG. 4 illustrates that in Huh7 and Li-7 cells, MI-2 in the combination of MI-2 and paclitaxel enhances the polymerization of tubulin by paclitaxel and thus increases the toxicity of chemotherapeutic drugs to tumor cells, as compared to MI-2 alone or paclitaxel.
Example 3
The invention discovers that the combination drug MI-2 and the paclitaxel can promote the polymerization of microscopic protein in a mouse model and improve the toxicity of the paclitaxel in the mouse model.
Reagents and materials:
female Balb/C nude mice were purchased from Shanghai laboratory animal research center and bred in Zhejiang university laboratory animal center. The remaining reagent materials were the same as in example 1.
The experimental method comprises the following steps:
constructing a hepatocellular carcinoma mouse model, taking Balb/C nude mice of 4-6 weeks as experimental objects, and dividing the experimental objects into four groups: solvent control group, MI-2 group, paclitaxel group and the combination of paclitaxel and MI-2, group 5. Will be 1x10 7 The number of Li-7 or Huh7 cells are inoculated to the armpit of a nude mouse, the PDX model is used for inoculating the tumor tissue of a hepatocellular carcinoma patient with the size of small mung bean to the armpit of the nude mouse, and after about one month, when the average tumor volume reaches 100mm 3 At the beginning of treatment, the mouse model was treated with chemotherapy once every four days ( days 0, 4, 8, 12, 16, 20) for five times, with the concentrations of intraperitoneal MI-2 and paclitaxel being 20 mg/kg/time and 3 mg/kg/time, respectively. From day 0, the tumor volume was measured daily by balance weighing nude mice body weight and vernier caliper, and the formula was V ═ L × W 2 Wherein V represents the tumor volume, L is the longitudinal length of the tumor, W is the transverse length of the tumor, which are measured by a vernier caliper, and the relative tumor volume RTV is used as the most comparative index, and RTV is V/V 0 Wherein V is the tumor volume on the day of measurement, V 0 Tumor volume at day 0. Nude mice were sacrificed at day 22 and divided intoThe tumors were removed and preserved in 10% neutral formalin for use.
And (3) tubulin detection: and detecting the influence of the paclitaxel in different mouse model groups on the polymerization of the tubulin by using the tumor tissue in the formalin by adopting an immunofluorescence detection technology so as to evaluate whether the combination drug MI-2 and the paclitaxel can promote the polymerization capability of the tubulin in the mouse model.
The experimental results are as follows:
as shown in FIGS. 5-1-5-4, in a mouse model of hepatocellular carcinoma (Li-7), MI-2 and paclitaxel used alone have no tumor inhibition effect, while the combined drug MI-2 and paclitaxel have significant tumor inhibition effect, and the relative tumor volume and tumor of the combined drug are both lower than those of the single drug group, so that the combination of MI-2 and paclitaxel can increase the anti-tumor activity of paclitaxel in the mouse model of hepatocellular carcinoma. In addition, there was no significant difference in body weight between the single and combination groups (FIGS. 5-4), suggesting that the combination of MI-2 and paclitaxel was less toxic and better tolerated in the mouse model. Meanwhile, in order to confirm the tumor inhibition effect of the combination drug MI-2 and the paclitaxel. The same dosing regimen was used for good, Huh7 and PDX mouse models, with the combination being more effective in chemotherapy (fig. 6). The polymerization of tubulin in the mouse model was further examined (fig. 7), suggesting that the combination drug MI-2 and paclitaxel could enhance the anti-tumor effect of the chemotherapeutic drug paclitaxel by promoting tubulin polymerization, thereby interfering the mitotic process of the cell.
Example 4
The invention finds that the combination drug MI-3454 (another MLL-menin inhibitor) and paclitaxel can synergistically enhance the toxicity of paclitaxel on hepatocellular carcinoma cell lines. To confirm the efficacy of MLL-menin inhibitors with paclitaxel in the treatment of hepatocellular carcinoma, we performed cytotoxicity experiments with the combination of MI-3454 and paclitaxel.
Reagents and materials:
the hepatoma cell lines HuH-7 and Li-7 were purchased from Shanghai cell bank of Chinese academy of sciences and cultured as described in example 2. MI-3454 was purchased from MedChemexpress (cat. No. HY-136360).
The experimental method comprises the following steps:
cell culture and dosing:
HuH7(5000cells/well) and Li-7(5000cells/well) cells were seeded in 96-well plates at a density and cultured overnight. After 24h, 10 μ L of paclitaxel at a predetermined concentration and 0.1% DMSO were added to the paclitaxel group; MI-3454 group was supplemented with 10. mu.L of predetermined concentration of MI-3454 and 0.1% DMSO; the two drugs are combined and 10. mu.L of paclitaxel and MI-3454 are added at the same time. The final concentration of DMSO in each group of culture system is 0.2%, and 6 duplicate wells are arranged at each concentration point. The medium was replaced every 24h with fresh drug-containing medium. Drug treatment was terminated after 48 h. The molar ratio of MI-3454 to paclitaxel in Huh7 and Li-7 was 450:1 to 10: 1.
TABLE 2 drug final concentrations of MI-3454 and paclitaxel in two cell lines
Figure BDA0003272428670000071
Figure BDA0003272428670000081
Cell viability assay:
CCK-8 is adopted to detect the toxicity of the drug on cells, the inhibition effect of each concentration point is calculated, and the dosage-effect of the MI-3454 and the paclitaxel drug are quantitatively analyzed according to the inhibition effect, and the method is the same as the method described in the example 2.
The experimental results are as follows:
consistent with the results of MI-2 experiments, the dose-effect curves of MI-3454 and paclitaxel on Huh7 and Li-7 cells after single use or combined use are shown in FIG. 8, the MLL-menin high-efficiency inhibitor MI-3454 remarkably improves the chemotherapeutic effect of paclitaxel in hepatocellular carcinoma, and further analysis shows that most effective concentration points in two cell lines correspond to the combined use index CI which is less than 0.8 (FIG. 9), which indicates that the combined medicament MI-3454 and paclitaxel have synergistic effect on the cytotoxicity of Huh7 and Li-7 cells.

Claims (3)

  1. The application of the MLL-menin inhibitor composition in preparing an anti-liver cancer medicine is characterized in that liver cancer is hepatocellular carcinoma, the composition consists of an MLL-menin inhibitor and paclitaxel, the MLL-menin inhibitor is MLL-menin inhibitor MI-2 or MLL-menin inhibitor MI-3454, wherein the molar concentration ratio of the MLL-menin inhibitor MI-2 to the paclitaxel is 300:1 or 60:1, and the molar concentration ratio of the MLL-menin inhibitor MI-3454 to the paclitaxel is 450:1 or 10: 1.
  2. 2. The use of claim 1, wherein the medicament is prepared from the composition and a pharmaceutically acceptable excipient.
  3. 3. The use according to claim 1, wherein the medicament is in the form of a solid or liquid formulation.
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