Application of chidamide in preparation of anti-hepatoma drug synergist

Abstract

The invention discloses application of chidamide in preparation of an anti-hepatoma drug synergist, and belongs to the technical field of medicines. According to the preparation for effectively improving the treatment effect of the anti-hepatoma medicine, chidamide serves as a sensitizer of the anti-tumor medicine, uptake of the anti-hepatoma medicine by hepatoma cells is promoted by up-regulating OATP1B3 protein expression in hepatoma tissue, accumulation of the medicine in the hepatoma tissue is increased, and therefore the anti-tumor effect of the medicine is improved. Combination of chidamide and the anti-liver cancer drug can synergistically enhance the toxicity of the drug to liver cancer, and the drug combination has biological safety and has great clinical application prospects.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to the application of chidamide in the preparation of an anti-hepatocellular carcinoma drug synergist. Background Art

[0002] Hepatocellular carcinoma is one of the tumors with extremely high malignancy. Hepatocellular carcinoma (HCC) is the main histological subtype of hepatocellular carcinoma, accounting for 90% of primary hepatocellular carcinoma. Since the early symptoms are not obvious, most patients are already in the middle and late stages at the time of diagnosis, and the treatment options are limited. The main treatments are transarterial interventional therapy and systemic anti-tumor drug therapy. The problems faced during the treatment of hepatocellular carcinoma, such as low objective response rate and primary or acquired drug resistance, make most patients unable to benefit from the treatment.

[0003] For example, Oxaliplatin (Oxa) is a third-generation platinum-based anti-tumor drug that exerts anti-tumor effects by binding to genomic DNA and is used in transarterial hepatic perfusion chemotherapy (HAIC) and systemic treatment in HCC treatment. Although chemotherapy based on oxaliplatin is effective in the treatment of HCC, primary or acquired resistance to oxaliplatin remains a major clinical challenge. Therefore, it is particularly important to study the overcoming of drug resistance in the treatment of hepatocellular carcinoma.

[0004] Organic anion transporting polypeptides (OATPs) are a class of uptake transporters, among which OATP1B3 is a liver-specific uptake transporter expressed on the basolateral membrane of human hepatocytes and is responsible for the transport of a variety of endogenous substrates and exogenous drugs including sorafenib, oxaliplatin, etc. (Lancaster C S, and al. Modulation of OATP1B-type transporter function alters cellular uptake and disposition of platinum chemotherapeutics. Molecular Cancer Therapeutics , 2013, 12(8): 1537-1544.). The OATP1B3 transporter protein is highly expressed in normal human liver, but is silenced in hepatocellular carcinoma tissues (Chen S, and al. Low expression of organic anion-transporting polypeptide 1B3 predicts a poor prognosis in hepatocellular carcinoma. World Journal of Surgical Oncology, 2020, 18:127.), which may be closely related to the therapeutic effect of its substrate drug oxaliplatin.

[0005] Chidamide (Tucidinostat, Tuc) is an orally administered novel benzamide histone deacetylase (HDAC) inhibitor that can selectively block class I and class IIb HDACs. There is currently no study reporting that chidamide is involved in regulating the expression of OATP1B3, nor any report on the combined application of chidamide and oxaliplatin in the treatment of liver cancer. Summary of the Invention

[0006] The purpose of the present invention is to provide a drug that enhances the transport of exogenous drugs by liver cancer cells, overcomes drug resistance in the treatment of liver cancer by increasing the accumulation of anti-liver cancer drugs in liver cancer cells, and improves the therapeutic effect on liver cancer.

[0007] To achieve the above purpose, the present invention adopts the following technical solutions: The present invention provides the use of chidamide in the preparation of an anti-liver cancer drug synergist. The CAS number of chidamide is 1616493-44-7, and the molecular formula is C 22 H 19 FN4O2. The mechanism of action of the synergist includes: chidamide promotes the uptake of anti-liver cancer drugs by liver cancer cells and enhances drug sensitivity by upregulating the protein expression level of OATP1B3 in liver cancer cells.

[0008] Specifically, in vitro and in vivo experiments show that chidamide administration can significantly upregulate the mRNA and protein expression levels of OATP1B3 in liver cancer cells. When chidamide is combined with anti-liver cancer chemotherapy drugs, chidamide can promote the uptake of anti-tumor drugs by liver cancer cells and significantly increase the sensitivity of liver cancer to anti-tumor drugs. Therefore, chidamide can be used as an anti-liver cancer drug synergist.

[0009] Furthermore, the anti-liver cancer drug can be, but is not limited to, oxaliplatin. In vitro and in vivo experimental results show that compared with the group treated with oxaliplatin alone, the combination of chidamide and oxaliplatin can significantly inhibit liver cancer growth, indicating that the combined use can significantly enhance the anti-liver cancer sensitivity of oxaliplatin. Mechanism studies show that chidamide enhances the protein expression of OATP1B3 in liver cancer tissues and promotes the accumulation of oxaliplatin in liver cancer cells. The results of safety assessment experiments show that compared with the group treated with oxaliplatin alone, the combined use has no significant difference in the body weight of the animal model, and the concentration of the peripheral nerve toxicity marker neurofilament light chain (NFL) in the serum also has no significant change, indicating that the combined use has low toxicity and side effects and does not cause peripheral nerve toxicity.

[0010] Further, the liver cancer is hepatocellular carcinoma, specifically but not limited to epitheloid well-differentiated hepatocellular carcinoma and highly metastatic hepatocellular carcinoma.

[0011] The present invention also provides a combined anti-liver cancer drug composition, comprising a first preparation formed by chidamide and a pharmaceutically acceptable carrier, and a second preparation formed by an anti-liver cancer drug and a pharmaceutically acceptable carrier. The present invention uses the first preparation to sensitize the anti-tumor activity of the second preparation.

[0012] Further, the anti-liver cancer drug is oxaliplatin. Research of the present invention shows that chidamide can enhance the accumulation of oxaliplatin in liver cancer cells and the drug chemotherapy sensitivity by up-regulating the expression of OATP1B3 protein in liver cancer cells.

[0013] Further, the molar ratio of chidamide to oxaliplatin in the drug composition is 2-5:1. Research shows that under this ratio condition, the combined use of chidamide and oxaliplatin can synergistically enhance the toxicity to liver cancer cells.

[0014] Furthermore, the molar ratio of chidamide to oxaliplatin in the drug composition is 3.33:1.

[0015] Further, the pharmaceutically acceptable carrier includes a filler, a wetting agent, a binder, a disintegrant or a lubricant.

[0016] Further, the drug dosage form is a solid dosage form or a liquid dosage form, and at least one of tablets, capsules, granules, solutions, suspensions, injections or lyophilized powder injections is selected.

[0017] The drug composition can be used for treating malignant tumors such as liver cancer. Specifically, the present invention also provides the application of the drug composition in the preparation of a drug for treating hepatocellular carcinoma. The hepatocellular carcinoma can be but not limited to epitheloid well-differentiated hepatocellular carcinoma and metastatic hepatocellular carcinoma.

[0018] The beneficial effects of the present invention are as follows: The research of the present invention finds that the administration of chidamide can up-regulate the expression of OATP1B3 protein in liver cancer tissues. Based on this, the present invention provides a preparation that can effectively improve the treatment effect of anti-liver cancer drugs. Using chidamide as a sensitizer for anti-tumor drugs, by up-regulating the expression of OATP1B3 protein in liver cancer tissues, it promotes the uptake of anti-liver cancer drugs by liver cancer cells, increases the accumulation of drugs in liver cancer tissues, and thus improves the anti-tumor effect of the drugs. The present invention uses the combined use of chidamide and anti-liver cancer drugs to synergistically enhance the toxicity of the drugs to liver cancer, and the combined medication has biological safety and great clinical application prospects. Description of the Drawings

[0019] Figure 1The mRNA expression levels of OATP1B3 in vitro after treating two hepatocellular carcinoma cell lines, LM3 and HuH-7, with 5 μM and 10 μM of chidamide for 72 h in Example 1.

[0020] Figure 2 The protein expression levels of OATP1B3 in vitro after treating two hepatocellular carcinoma cell lines, LM3 and HuH-7, with 5 μM and 10 μM of chidamide for 72 h in Example 1.

[0021] Figure 3 For the data processed by Image J software Figure 2 The obtained statistical analysis chart.

[0022] Figure 4 For detecting the protein expression of OATP1B3 by immunofluorescence assay after treating LM3 and HuH-7 cells with 5 μM and 10 μM of chidamide for 72 h in Example 1.

[0023] Figure 5 The drug dose-effect curves of the combination of chidamide and oxaliplatin in two hepatocellular carcinoma cell lines, LM3 and HuH-7, in Example 2.

[0024] Figure 6 The combination index CI of the combination of chidamide and oxaliplatin in two hepatocellular carcinoma cell lines, LM3 and HuH-7, in Example 2.

[0025] Figure 7 The drug combination index DRI of the combination of chidamide and oxaliplatin in two hepatocellular carcinoma cell lines, LM3 and HuH-7, in Example 2.

[0026] Figure 8 The intracellular platinum ion concentration in vitro after treating hepatocellular carcinoma cell lines LM3 and HuH-7 with 5 μM of chidamide for 72 h and further treating with oxaliplatin for 2 h in Example 3.

[0027] Figure 9 The effects of single or combined use of chidamide and oxaliplatin on the relative tumor volume growth of hepatocellular carcinoma (HCC-LM3) model mice in Example 4.

[0028] Figure 10 The tumor photos isolated after 21 days of administration of single or combined use of chidamide and oxaliplatin in the hepatocellular carcinoma model in Example 4.

[0029] Figure 11 The relative body weight changes during the administration of single or combined use of chidamide and oxaliplatin to hepatocellular carcinoma model mice in Example 4.

[0030] Figure 12For the ELISA detection of the concentration of neurofilament light chain (NFL) in the serum of mice in Example 4.

[0031] Figure 13 For the content of OATP1B3 protein in the tumor tissues of liver cancer model mice after single or combined use of chidamide and oxaliplatin in Example 5.

[0032] Figure 14 For the change in the concentration of platinum ions in the tumor after single or combined use of chidamide and oxaliplatin in Example 5. Detailed implementation manners

[0033] The technical solutions of the present invention will be further specifically described below through specific examples. It should be understood that the implementation of the present invention is not limited to the following examples, and any formal modification and / or change made to the present invention will fall within the protection scope of the present invention.

[0034] In the following examples, unless otherwise specified, all parts and percentages are in weight units, and the equipment and raw materials used can be purchased from the market or are commonly used in the art. The methods in the following examples are conventional methods in the art unless otherwise specified.

[0035] Example 1 1. Reagents and materials The liver cancer cell lines LM3 and HuH-7 were both purchased from Shanghai Saibakang Biotechnology Co., Ltd. Both LM3 and HuH-7 cells were cultured in DMEM high-glucose medium (product number: SH30243.01) and contained 10% GIBICO fetal bovine serum (product number: 10099-141C), and 1% penicillin-streptomycin (product number: CR-15140-5ea) was added on this basis; the culture conditions were both 37°C and 5% CO2. Chidamide was purchased from GlpBio (product number: GC37845). The BCA kit was purchased from Shanghai Beyotime Biotechnology Co., Ltd. (product number: P0010). The RNA extraction kit was purchased from Shanghai Yishan Biotechnology Co., Ltd. (product number: RN001). The rapid reverse transcription kit was purchased from Shanghai Yishan Biotechnology Co., Ltd. (product number: RT001). The TB Green reagent was purchased from TaKaRa (product number: RR091). The β-actin antibody was purchased from Wuhan Sanying Biotechnology Co., Ltd. (product number: 66009-1-Ig). The OATP1B3 antibody was purchased from Shanghai Abbexa Biotechnology Co., Ltd. (product number: abs103728).

[0036] 2. Experimental methods Cell administration: Inoculate LM3 and HuH7 cells in a six-well plate at a certain density and culture overnight. Treat LM3 and HuH7 cells with 0.1% DMSO, chidamide (5 μM and 10 μM) respectively. Replace the drug-containing medium every 24 h. After 72 h of treatment, extract cell samples (protein or RNA) or collect samples for immunofluorescence experiments.

[0037] Extract cell RNA and perform RT-PCR experiments: Follow the instructions of the RNA extraction kit to measure the concentration of the extracted RNA, and reverse transcribe it into cDNA for standby. Prepare the qRT-PCR system according to the instructions of the SYBR® Premix Ex Taq TM kit to detect the transcriptional level of the gene encoding OATP1B3 protein SLCO1B3 (Gene ID: 28234). All primers used were purchased from Beijing Tsingke Biotechnology Co., Ltd., and the primer sequences are shown in Table 1.

[0038] Table 1. Primer sequences Extract cell protein: Extract protein with RIPA cell lysate, centrifuge at 15000 rpm for 10 min at 4°C, take the supernatant and use the BCA method for protein quantification, and then use Western blot to detect the protein content.

[0039] Immunofluorescence experiment: Fix cells with ice-cold methanol, block with 5% BSA, incubate with primary and secondary antibodies, etc. After adding the mounting medium, observe and take pictures under a high-resolution laser confocal microscope.

[0040] 3. Experimental results As Figure 1 shown, the research results were based on LM3 and Huh7 cells. After treatment with different concentrations of 5 μM and 10 μM chidamide, PCR experiments were performed, and the transcriptional levels of OATP1B3 were upregulated to varying degrees.

[0041] As Figure 2 and Figure 3 shown, after treatment with different concentrations of 5 μM and 10 μM chidamide, the protein content of OATP1B3 was significantly upregulated and showed a concentration-dependent manner.

[0042] As Figure 4 shown, after treating LM3 and Huh7 cells with different concentrations of 5 μM and 10 μM chidamide, immunofluorescence experiments were performed. The fluorescence intensity of OATP1B3 after drug treatment was significantly upregulated, indicating an upregulation of the protein expression level of OATP1B3.

[0043] The above results indicate that chidamide can upregulate the expression of OATP1B3 in the hepatoma cell lines LM3 and HuH-7.

[0044] Example 2 1. Reagents and materials Oxaliplatin was purchased from GlpBio (product number: GC17716), and the CCK-8 solvent was purchased from GlpBio (product number: GK10001). The remaining reagent materials were the same as those in Example 1.

[0045] 2. Experimental method Cell administration: Using pure water as the solvent, oxaliplatin was prepared into a 1000× stock solution; using DMSO as the solvent, chidamide was diluted into a 1000× stock solution and stored at -20°C.

[0046] The working solution was freshly prepared before use. When adding the drug, 10 μL of the working solution was added to each well in a 200 μL medium system per well; Chidamide working solution: 2 μL of the stock solution + 98 μL of the medium were prepared into 100 μL of the working solution (20×); Oxaliplatin working solution: 2 μL of the stock solution + 98 μL of the medium were prepared into 100 μL of the working solution (20×).

[0047] LM3 (3000 cells / well) and HuH-7 (4000 cells / well) cells were inoculated into 96-well plates at a certain density and cultured overnight. 10 μL of chidamide at a predetermined concentration was added to the chidamide group and the combination group. The oxaliplatin group, i.e., the control group, was treated with 0.1% DMSO. The fresh medium containing the drug was replaced every 24 h. After 48 h of chidamide treatment, the drug concentration in the chidamide group remained unchanged. 10 μL of oxaliplatin at a predetermined concentration was added to the oxaliplatin group, and 10 μL of chidamide at a predetermined concentration and 10 μL of oxaliplatin at a predetermined concentration were added to the combination group simultaneously. Six replicate wells were set for each concentration point. After 24 h of treatment, the medium in the chidamide group was replaced with a drug-free medium, and 10 μL of oxaliplatin at a predetermined concentration was added to the oxaliplatin group and the drug combination group, and the cells were cultured for another 24 h. Finally, the cell viability was detected by the CCK-8 method. The final drug concentrations of chidamide and oxaliplatin in the two cell lines are shown in Table 2.

[0048] Table 2. Final drug concentrations in the LM3 and Huh7 cell media Tuc / μM Oxa / μM 0.002 0.0007 0.009 0.002 0.039 0.012 0.156 0.047 0.625 0.19 2.5 0.75 10 3 40 12 Quantitative analysis of the dose-effect of the combination of chidamide and oxaliplatin: First, calculate the cell viability at each concentration point. Using the concentrations of chidamide and oxaliplatin as the abscissa and the corresponding cell viability at each concentration as the ordinate, plot a graph with Gradpad Prism 9.5 to obtain the CCK8 curve graph. Use 1 - cell viability (%) as the inhibitory effect at each concentration point, and use Compusyn software to calculate the combination index (CI value) and dose reduction index (DRI value) of the two drugs by the Chou - Talalay method. CI > 1.2 indicates an antagonistic effect, CI < 0.8 indicates a synergistic effect, and CI between 0.8 - 1.2 is regarded as an additive effect. DRI is defined as the multiple of the drug dose reduction that the drug combination can achieve compared to single - drug use when reaching the same inhibitory effect level. DRI > 1 has positive significance for clinical drug use.

[0049] 3. Experimental results The dose - effect curves of chidamide and oxaliplatin used alone or in combination on LM3 and HuH - 7 cells are as Figure 5 shown, and the combined drug chidamide and oxaliplatin can increase the sensitivity of the hepatocellular carcinoma cell line to oxaliplatin.

[0050] The combination index CI of chidamide and oxaliplatin after combination on LM3 and HuH - 7 cells is as Figure 6 shown. It can be seen that chidamide can increase the sensitivity of hepatocellular carcinoma to oxaliplatin, and the CI values are all less than 0.8.

[0051] As Figure 7 shown, the dose - reduction index DRI of the dose - effect fitting curve for the combined use of drugs is all greater than 1, and the obtained data further illustrate that chidamide can increase the sensitivity of hepatocellular carcinoma to oxaliplatin.

[0052] The above results indicate that the combination of chidamide and oxaliplatin can synergistically enhance the toxicity of oxaliplatin to the hepatocellular carcinoma cell line.

[0053] Example 3 1. Reagents and materials 65% nitric acid was purchased from Shanghai Lingfeng Chemical Reagent Co., Ltd. (product number: 7697 - 37 - 2), inductively coupled plasma mass spectrometer (instrument model: Agilent 7800), and the rest of the reagent materials are the same as in Example 1 and Example 2.

[0054] 2. Experimental method Oxaliplatin accumulation determination: Drawing the standard curve: Prepare Pt standard solutions with concentrations of 0, 0.3125, 0.625, 6.25, 12.5, 25, 50, and 100 ng / mL. Add 4 μL of 1000 μg / ml Pt standard to 4 mL of 5% nitric acid solution to prepare a 100 ng / mL Pt mother solution, and dilute it step by step. All standard solutions are filtered through a 0.22 μm filter membrane and detected using an inductively coupled plasma mass spectrometer in the Scientific Experiment Center of Hangzhou Institute of Medicine, Chinese Academy of Sciences to draw the standard curve.

[0055] Sample determination: LM3 and Huh-7 cells are seeded in six-well plates and allowed to adhere overnight. After administering 5 μM Tuc for 72 h, 10 μM OXA is administered for 2 h respectively. Then, 500 μL of 65% nitric acid is added for digestion at 70 °C for 2 h. Take out 250 μL and add 3.15 mL of pure water to dilute the nitric acid concentration in the sample to 5%. The sample is filtered through a 0.22 μm filter membrane and detected using an inductively coupled plasma mass spectrometer in the Scientific Experiment Center of Hangzhou Institute of Medicine, Chinese Academy of Sciences, and then the platinum ion concentration is calculated by substituting it into the standard curve.

[0056] 3. Experimental results As Figure 8 shown, in the hepatocellular carcinoma cell lines LM3 and HuH-7 cells, chidamide significantly increased the intracellular platinum ion concentration, indicating that the combination of drugs can promote the accumulation of oxaliplatin in hepatocellular carcinoma cells.

[0057] The above results indicate that chidamide promotes the uptake of oxaliplatin by hepatocellular carcinoma cell lines.

[0058] Example 4 1. Reagents and materials Male Balb / c nude mice are purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. and raised in the Experimental Animal Center of Zhejiang Cancer Hospital. Chidamide is purchased from GlpBio (product number: GC37845), and oxaliplatin is purchased from Jiangsu Hengrui Medicine Co., Ltd. (product batch number: 240612AM). The remaining materials are the same as in Example 1.

[0059] 2. Experimental methods Using 4 - 6 week old Balb / c nude mice as experimental subjects, a subcutaneous inoculation mouse model of the liver cancer cell line LM3 was constructed. The nude mice were divided into 4 groups, with 6 mice in each group. Chidamide was suspended in a 0.5% CMC - Na solution, and oxaliplatin was dissolved in a glucose solution. On the 1st and 2nd days, the chidamide group and the combination drug group were gavaged with chidamide at a dose of 12.5 mg / kg each time, and the remaining groups were given vehicle control; on the 3rd day, the chidamide group and the combination drug group were gavaged with chidamide at a dose of 12.5 mg / kg each time, the oxaliplatin group and the combination drug group were intraperitoneally injected with 10 mg / kg each time, and the remaining groups were given vehicle control; on the 6th day, the oxaliplatin group and the combination drug group were intraperitoneally injected with 10 mg / kg each time, and the remaining groups were given vehicle control; the above was one round of drug administration, and a total of three rounds of drug administration were given. During this period, the tumor volume and body weight of the nude mice were recorded. Tumor volume calculation formula: L×W 2 / 2, where L is the medium fluidity and W is the tumor width. The relative tumor volume was calculated as the ratio of the tumor volume per day to the tumor volume on the 1st day of drug administration. The relative body weight was calculated as the ratio of the body weight of the mice per day to the body weight of the mice on the 1st day of drug administration.

[0060] On the 21st day, all the model nude mice were sacrificed, the tumors were separated, and the serum was collected.

[0061] 3. Experimental results: As Figure 9 - Figure 10 shown, in the mouse model of the liver cancer cell line LM3, the single use of chidamide did not have an obvious effect on inhibiting tumor growth, the single use of oxaliplatin slightly inhibited tumor growth, while the combination of chidamide and oxaliplatin significantly inhibited tumor growth. The relative tumor volume and tumor weight of the combination group were lower than those of the groups using chidamide and oxaliplatin alone, suggesting that the combination of chidamide and oxaliplatin can enhance the anti - liver cancer sensitivity of oxaliplatin in the liver cancer mouse model.

[0062] As Figure 11 shown, there was no significant difference in the body weight of the mice in the single - use and combination - drug groups, suggesting that the combination of chidamide and oxaliplatin has low toxicity and good tolerance in the mouse model.

[0063] As Figure 12 shown, the concentration of the peripheral nerve toxicity marker neurofilament light chain (NFL) in the serum of the mice did not change significantly in the single - use and combination - use groups, suggesting that the drug administration regimen did not cause peripheral nerve toxicity in the mice.

[0064] The above results indicate that the combination of chidamide and oxaliplatin enhances the sensitivity of liver cancer model mice to oxaliplatin.

[0065] Example 5 1. Reagents and materials The reagents and materials are the same as those in Example 3 and Example 4.

[0066] 2. Experimental Methods Under low-temperature conditions, the tumor tissues obtained in Example 4 were cut into mung bean-sized pieces (10 - 20 mg) and dispensed into new EP tubes. The tissue proteins were extracted and the protein content was detected by Western blot using the same method as in Example 1.

[0067] Under low-temperature conditions, the tumor tissues obtained in Example 4 were cut into mung bean-sized pieces (10 - 20 mg) and dispensed into new EP tubes. 65% nitric acid was directly added and digested at 70 °C for 3 h. Then, 250 μL was taken out and added to 3.15 mL of pure water to dilute the nitric acid concentration in the sample to 5%. The concentration of platinum ions taken up in the tumor tissues was measured using the same method as in Example 3.

[0068] 3. Experimental Results As Figure 13 shown, the expression of OATP1B3 protein was significantly upregulated in the tumor tissues of mice in the single-use group of chidamide and the combined-drug group.

[0069] As Figure 14 shown, compared with the single-use group of oxaliplatin, the concentration of platinum ions in the combined-drug group increased by 2.5 times.

[0070] The above results suggest that chidamide promotes the accumulation of oxaliplatin in the tumors of a mouse model of liver cancer by upregulating the expression of OATP1B3 in tumor tissues.

Claims

1. The use of chidamide in the preparation of a synergist for anti-hepatocellular carcinoma drugs, characterized in that, Chidamide promotes the uptake of anti-hepatocellular carcinoma drugs by hepatocellular carcinoma cells and enhances drug sensitivity by upregulating the protein expression level of OATP1B3 in hepatocellular carcinoma cells.

2. The application according to claim 1, characterized in that, The anti-hepatocellular carcinoma drug is oxaliplatin.

3. A drug combination for anti - liver cancer, characterized in that, It includes a first preparation formed by chidamide and a pharmaceutically acceptable carrier, and a second preparation formed by an anti-hepatocellular carcinoma drug and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, wherein, The anti-hepatocellular carcinoma drug is oxaliplatin.

5. The pharmaceutical composition according to claim 4, characterized in that, In the pharmaceutical composition, the molar ratio of chidamide to oxaliplatin is 2 - 5:

1.

6. The pharmaceutical composition according to claim 5, characterized in that, In the pharmaceutical composition, the molar ratio of chidamide to oxaliplatin is 3.33:

1.

7. The pharmaceutical composition according to claim 3, wherein The pharmaceutically acceptable carrier includes a filler, a wetting agent, a binder, a disintegrant or a lubricant.

8. The pharmaceutical composition according to claim 3, wherein, The dosage form of the pharmaceutical composition is at least one of tablets, capsules, granules, solutions, suspensions, injections, freeze-dried powder injections.

9. Use of the pharmaceutical composition according to any one of claims 3 - 8 in the preparation of a drug for treating hepatocellular carcinoma.

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