Application of the combination of epidurocin and sorafenib in the preparation of drugs for treating liver cancer

Abstract

This invention discloses the application of epinodoxine in combination with sorafenib in the preparation of drugs for treating liver cancer. Experimental results show that epinodoxine significantly inhibits the proliferation of liver cancer cells and exhibits a good synergistic effect when used in combination with sorafenib, thus reducing toxicity and enhancing sensitization.

Description

Technical Field

[0001] This invention relates to the technical field of anticancer drugs, specifically to the application of epinodocin and sorafenib in the preparation of drugs for treating liver cancer. Background Technology

[0002] Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide. According to WHO estimates, there were approximately 905,677 new cases of liver cancer globally in 2020. In my country, liver cancer has the second highest mortality rate, seriously threatening people's lives and health. Liver cancer includes several different pathological types, such as hepatocellular carcinoma (HCC), cholangiocarcinoma, and mixed hepatocellular-cholangiocarcinoma, with hepatocellular carcinoma accounting for 75%-85% of all cases. The main treatments for liver cancer include liver resection, liver transplantation, local ablation, transarterial chemoembolization, and systemic therapy. Due to its high invasiveness and recurrence rate, the five-year overall survival rate is less than 10%. Liver cancer has an insidious onset, with few early symptoms. By the time of diagnosis, most patients have already reached locally advanced stages or have metastasized to distant sites, losing the opportunity for surgery or interventional treatment. Therefore, systemic drug therapy plays a crucial role in the treatment of liver cancer. Commonly used systemic drugs in clinical practice include sorafenib, atezolizumab, and bevacizumab. Although some progress has been made in the treatment of liver cancer, the treatment effect is still not ideal, so there is an urgent need to explore new treatment drugs and treatment plans.

[0003] Sorafenib is an oral multi-kinase inhibitor and the first molecularly targeted drug approved by the US FDA for the treatment of intermediate and advanced HCC. It exhibits anti-proliferative and anti-angiogenic effects. Sorafenib inhibits the proliferation of tumor cells by inhibiting the activity of Raf-1, β-Raf and kinases in the Ras / Raf / MEK / ERK signaling pathway. In addition, sorafenib can target proteins such as platelet-derived growth factor receptor (PDGFR-β), vascular endothelial growth factor receptor (VEGFR), and hepatocyte cytokine receptor (c-KIT) to inhibit tumor angiogenesis [6]. Although sorafenib can prolong the survival of HCC patients, it has limitations such as low objective response rate, many adverse reactions and drug resistance, which affect its therapeutic effect. Therefore, screening for sorafenib effect enhancers or synergists in clinical treatment has become an objective need. Traditional Chinese herbal medicines and their extracted active ingredients have good anti-tumor effects and advantages such as safety, low toxicity, few side effects and abundant medicinal resources, and are increasingly attracting attention in clinical treatment. Traditional Chinese medicine (TCM) treatment for liver cancer offers advantages such as reducing the toxicity of radiotherapy and chemotherapy, improving tumor-related symptoms, controlling disease progression, enhancing the patient's immunity, reducing recurrence, and prolonging survival. It shows good clinical efficacy whether used alone or as an adjuvant to conventional anticancer drugs. The rational combination of TCM active ingredients with other drugs can achieve synergistic effects, effectively reduce drug resistance, decrease toxic side effects, and enhance antitumor activity. Many studies have found that the treatment strategy of combining TCM and its effective components with sorafenib has demonstrated good results and played a significant role in the treatment of liver cancer. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention aims to provide the application of the combination of epinodoxine and sorafenib in the preparation of drugs for treating liver cancer.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] Application of the combination of epidurocin and sorafenib in the preparation of drugs for the treatment of liver cancer.

[0007] It should be noted that the molar ratio of the drug concentrations of the said epidotin and the said sorafenib when used in combination is 22:6.

[0008] The present invention also provides a drug for treating liver cancer, the drug comprising the combined use of epinodoxine and sorafenib.

[0009] It should be noted that the drug also includes pharmaceutically acceptable carriers or excipients, wherein the carriers or excipients are selected from at least one of hydrating agents, thickeners, emulsifiers, preservatives, stabilizers, ion exchangers, flow aids, binders, colorants, flavorings, sweeteners, precipitation inhibitors, lubricants, dispersants, diluents, flavoring agents, antioxidants, isotonic agents, suspending agents, emulsification accelerators, buffers, disintegrants, surfactants, absorbents, release agents, and coating agents.

[0010] The beneficial effects of this invention are that the experimental results show that epidotin has a significant inhibitory effect on the proliferation of liver cancer cells, and has a good synergistic effect when used in combination with sorafenib, thus playing a role in reducing toxicity and enhancing sensitization. Attached Figure Description

[0011] Figure 1 This is a schematic diagram illustrating the inhibition of liver cancer cell proliferation by epiduroxin in Embodiment 1 of the present invention;

[0012] Figure 2 This is a schematic diagram illustrating the inhibition of liver cancer cell proliferation by sorafenib in Example 2 of the present invention;

[0013] Figure 3 This is a schematic diagram illustrating the combined use of baicaldoxine and sorafenib in Embodiment 3 of the present invention.

[0014] Figure 4 In Example 4 of this invention, the Combination Index (CI) was calculated using CalcuSyn software to evaluate the combined effect of bainodoxine and sorafenib on HepG2 and Huh7 cells.

[0015] Figure 5 This is a schematic diagram showing the data comparison in the animal in vivo experiment of Example 5 of the present invention;

[0016] Figure 6 This is a schematic diagram showing the data comparison of the animal in vivo experiment in Example 5 of the present invention. Detailed Implementation

[0017] The present invention will be further described below. It should be noted that the following embodiments are based on the present technical solution and provide detailed implementation methods and specific operation processes, but the protection scope of the present invention is not limited to these embodiments.

[0018] It should be noted that the pentacyclic diterpenoid compound extracted from the plant *Ceropegia pubescens* of the genus *Ceropegia* has the molecular formula C0.05. 20 H 26 O6 has a molecular weight of 362 Da.

[0019] This invention provides an application of epinodoxine combined with sorafenib in the preparation of a drug for treating liver cancer.

[0020] Furthermore, the molar ratio of the drug concentrations of the present invention when the epiduroxin and the sorafenib are used in combination is 22:6.

[0021] The present invention also provides a drug for treating liver cancer, the drug comprising the combined use of epinodoxine and sorafenib.

[0022] Furthermore, the drug also includes a pharmaceutically acceptable carrier or excipient selected from at least one of hydrating agents, thickeners, emulsifiers, preservatives, stabilizers, ion exchangers, flow aids, binders, colorants, flavorings, sweeteners, precipitation inhibitors, lubricants, dispersants, diluents, flavoring agents, antioxidants, isotonic agents, suspending agents, emulsification accelerators, buffers, disintegrants, surfactants, absorbents, release agents, and coating agents.

[0023] Example 1

[0024] like Figure 1 As shown, the present invention has a significant inhibitory effect on the proliferation of liver cancer cells.

[0025] Example 2

[0026] like Figure 2 As shown, the existing anti-liver cancer drug sorafenib inhibits the proliferation of liver cancer cells.

[0027] Example 3

[0028] like Figure 3 As shown, the combination of epinodoxine and sorafenib in this invention exerts a synergistic anti-cancer effect in liver cancer cells, significantly enhancing the sensitivity of liver cancer cells to sorafenib, while reducing the concentrations of epinodoxine and sorafenib, thus reducing drug toxicity and demonstrating good clinical application value.

[0029] Example 4

[0030] Based on the intermediate-efficacy principle and the Chou-Talalay equation, the combination index (CI) was calculated using CalcuSyn software to evaluate the combined effect of epinodoxine and sorafenib in HepG2 and Huh7 cells. CI < 1, CI = 1, and CI > 1 represent synergistic, additive, and antagonistic effects, respectively. The combination of epinodoxine and sorafenib in this invention resulted in a CI < 1 in hepatocellular carcinoma cells, indicating a synergistic effect between the two drugs. Furthermore, the concentrations of both drugs decreased sharply, thus reducing toxicity. The optimal synergistic effect was found at a molar ratio of 22:6 for epinodoxine and sorafenib.

[0031] Example 5

[0032] Animal in vivo experiments: SPF-grade BALB / C nude mice were selected, inoculated with Huh7 cells, and divided into blank control group, positive control group (sorafenib), epinodos in group (low, medium and high doses), and combination drug group (epinodos in combined with sorafenib). EP and sorafenib were administered by gavage, and the body weight and tumor volume of each group were measured.

[0033] The results of the in vivo animal experiments showed that, compared with the Ctrl group, the mice did not experience significant changes in body weight during the entire administration process, and their diet and all behavioral activities remained normal. However, the tumor volume in the mice changed significantly, becoming noticeably smaller (Note: the tumor volume decreased significantly when the combined drug concentration was significantly reduced).

[0034] In summary, epinodoxine can be used in combination with sorafenib, thereby significantly enhancing the anticancer effect of sorafenib on HCC. Epinodoxine and sorafenib in combination have a good inhibitory effect on HCC cells, with a combination index of 0.9 (a combination index less than 1 indicates a synergistic effect between the two drugs). Epinodoxine alone significantly inhibits the proliferation rate of HCC cells Huh7 and HepG2 in a time- and dose-dependent manner. Sorafenib's IC50 values ​​against Huh7 cells at 24, 48, and 72 h were 16.18, 11.83, and 9.81 μM, respectively, and against HepG2 cells were 23.15, 20.27, and 18.60 μM, respectively. Sorafenib alone also significantly inhibits the proliferation rate of HCC cells Huh7 and HepG2 in a time- and dose-dependent manner. The IC50 values ​​of sorafenib against Huh7 cells at 24, 48, and 72 h were 14.97, 8.41, and 6.04 μM, respectively, and against HepG2 cells were 12.57, 6.44, and 5.61 μM, respectively. However, the combination of the two drugs resulted in an unexpected outcome: a sharp decrease in the combined drug concentration. The IC50 values ​​of the two drugs against Huh7 cells at 24, 48, and 72 h were 5.98, 4.42, and 1.66 μM, respectively, and against HepG2 cells were 4.43, 3.31, and 2.85 μM, respectively. These results were also well reflected in preliminary in vivo experiments in mice, suggesting that the combination of the two drugs exerts a synergistic anti-cancer effect in HCC, significantly enhancing the sensitivity of liver cancer cells to sorafenib, while reducing the concentrations of epinodoxine and sorafenib, thus reducing drug toxicity and demonstrating good clinical application value.

[0035] For those skilled in the art, various corresponding changes and modifications can be made based on the above technical solutions and concepts, and all such changes and modifications should be included within the protection scope of the claims of this invention.

Claims

1. Application of the combination of epidurocin and sorafenib in the preparation of drugs for the treatment of liver cancer.

2. Use according to claim 1, characterized in that, The molar ratio of the drug concentrations of the aforementioned epiduroxin and the aforementioned sorafenib is 22:

6.

3. A medicament for treating liver cancer, characterized by comprising the compound according to claim 1 or 2. This includes the combined use of epinodocin and sorafenib in the drug, wherein the molar ratio of epinodocin to sorafenib in the drug is 22:

6.

4. The medicament for treating liver cancer according to claim 3, wherein The drug also includes a pharmaceutically acceptable carrier selected from at least one of the following: hydrating agents, thickeners, emulsifiers, preservatives, stabilizers, ion exchangers, flow aids, binders, colorants, flavorings, sweeteners, precipitation inhibitors, lubricants, dispersants, diluents, flavoring agents, antioxidants, isotonic agents, suspending agents, emulsification accelerators, buffers, disintegrants, surfactants, absorbents, release agents, and coating agents.

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