Pharmaceutical composition for reducing toxicity of chemotherapeutic drugs and application of pharmaceutical composition

Abstract

The invention is applicable to the technical field of biological medicines, and provides a pharmaceutical composition for reducing toxicity of chemotherapeutic drugs and application of the pharmaceutical composition, and application of lipoic acid or pharmaceutically acceptable derivatives thereof in preparation of drugs for reducing toxicity of chemotherapeutic drugs. A cytotoxicity test, a cell viability test, a flow cytometry and the like verify that the lipoic acid or the derivative lipoic amide thereof can inhibit the toxicity of chemotherapeutic drugs to cells and reduce pyroptosis caused by the chemotherapeutic drugs; in-vivo experiments of mice prove that the lipoic acid or the derivative lipoic amide thereof can significantly reduce the toxicity of chemotherapeutic drugs such as cis-platinum and the like to various tissues and organs in the mice, and has wide medical application.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to a pharmaceutical composition for reducing the toxicity of chemotherapy drugs and an application thereof. Background Art

[0002] Chemotherapy is a mainstay of cancer treatment, but its toxicity to normal tissues limits its clinical application. Chemotherapeutic drugs, such as cisplatin, activate caspase-3 to cleave GSDME, inducing pyroptosis and causing normal tissue damage. Current strategies to mitigate chemotherapy toxicity primarily focus on dose adjustments or adjuvant drug combinations, but these efforts are limited and may compromise chemotherapy efficacy. Therefore, there is an urgent need to develop novel drug combinations that can specifically inhibit chemotherapy-related toxicity without interfering with its anticancer activity.

[0003] Lipoic acid (α-lipoic acid) is commonly used clinically, either orally or intravenously. As an antioxidant or metabolic enhancer, it exhibits a wide range of pharmacological effects, including anti-inflammatory and antioxidant effects, regulation of glucose metabolism, and neurotrophic effects. Its derivative, lipoamide, is less commonly used as a drug and is typically used in laboratories as a coenzyme in energy metabolism studies. It is occasionally found in multivitamins or specific metabolic regulators. No toxic side effects have been reported within the effective dose range. However, current research on the use of lipoic acid and its derivatives in reducing the toxicity of chemotherapeutic drugs is lacking. Summary of the Invention

[0004] The purpose of the embodiments of the present invention is to provide a pharmaceutical composition for reducing the toxicity of chemotherapy drugs, aiming to solve the problems raised in the above background technology.

[0005] The embodiment of the present invention is achieved by providing a pharmaceutical composition for reducing the toxicity of chemotherapy drugs, wherein the active ingredient of the pharmaceutical composition is lipoic acid or a pharmaceutically acceptable derivative thereof.

[0006] Preferably, the pharmaceutically acceptable derivative of lipoic acid is lipoamide.

[0007] Preferably, the chemotherapy drug is one or more of cisplatin, oxaliplatin, and carboplatin.

[0008] Preferably, the pharmaceutical composition inhibits the cleavage of GSDME by caspase-3 by binding to the GSDME protein, thereby blocking the pyroptosis pathway and reducing cytotoxicity.

[0009] Another object of the present invention is to provide a use of lipoic acid or a pharmaceutically acceptable derivative thereof in the preparation of a chemotherapeutic drug for reducing toxicity.

[0010] Preferably, the pharmaceutically acceptable derivative of lipoic acid is lipoamide.

[0011] Preferably, the chemotherapy drug is one or more of cisplatin, oxaliplatin, and carboplatin.

[0012] The present invention demonstrates through cytotoxicity tests, cell viability tests, flow cytometry, and the like that lipoic acid or its derivative lipoamide can inhibit the toxicity of chemotherapy drugs to cells and reduce pyroptosis caused by chemotherapy drugs. Furthermore, in vivo experiments in mice demonstrate that lipoic acid or its derivative lipoamide can significantly reduce the toxicity of chemotherapy drugs such as cisplatin to various tissues and organs in mice. In summary, the embodiments of the present invention provide that lipoic acid or its derivative lipoamide can reduce the toxicity of chemotherapy drugs. It is disclosed that lipoic acid and its derivative lipoamide can bind to GSDME protein, inhibit the cleavage of GSDME by caspase-3, thereby blocking the pyroptosis pathway and reducing cytotoxicity, and have a wide range of medical uses. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 The results of the cytotoxicity test provided in Example 1 of the present invention; Figure 2 The results of the cell activity test provided in Example 2 of the present invention; Figure 3 The results of the flow cytometry test provided in Example 3 of the present invention; Figure 4 The results of the in vivo test in mice are provided in Example 4 of the present invention. DETAILED DESCRIPTION

[0014] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0015] The specific implementation of the present invention is described in detail below with reference to specific embodiments.

[0016] Example 1, cytotoxicity test: GSDME-positive cells (A375 cells, Mewo cells, or Hela cells stably expressing GSDME) were inoculated into cell culture plates and pretreated with different doses of lipoic acid and its derivative lipoamide for 48 hours. Then, the chemotherapy drug cisplatin was added for stimulation for 16 hours or the caspase 3 activators Raptial and PAC-1 were added for stimulation for 2-8 hours. The release of lactate dehydrogenase (LDH) in the supernatant of each cell culture was measured to evaluate the cytotoxicity caused by chemotherapeutic drugs and caspase 3 activators inducing cell pyroptosis. The results are as follows: Figure 1 As shown; according to Figure 1 It can be seen that after treating the cells with chemotherapy drugs or caspase 3 activators, they showed obvious cytotoxicity and released a large amount of LDH, while the amount of LDH released by cells treated with lipoic acid and its derivative lipoamide was significantly reduced, indicating that cell pyroptosis induced by chemotherapy drugs or caspase 3 activators was significantly inhibited, and lipoic acid and its derivative lipoamide played a significant protective role.

[0017] Example 2, cell activity test: GSDME-positive cells (A375 cells or Hela cells stably expressing GSDME) were seeded into cell culture plates and pre-treated with different doses of lipoic acid for 48 hours. They were then stimulated with the chemotherapy drug cisplatin for 16 hours or with the caspase 3 activators Raptial and PAC-1 for 2-8 hours. The metabolic status of each cell was measured by CCK8 to evaluate the changes in cell activity caused by chemotherapeutic drugs and caspase 3 activators-induced cell pyroptosis. The results are shown in Figure 3. Figure 2 As shown; according to Figure 2 It can be seen that after treating cells with chemotherapy drugs or caspase 3 activators, cell activity decreased significantly, while the activity of cells treated with lipoic acid was significantly enhanced, indicating that cell pyroptosis induced by chemotherapy drugs or caspase 3 activators was significantly inhibited, and lipoic acid played a significant protective role on cells treated with chemotherapy drugs.

[0018] Example 3, flow cytometry: GSDME-positive cells (A375 cells or Hela cells stably expressing GSDME) were inoculated into cell culture plates and pretreated with different doses of lipoamide for 48 hours. Then, the chemotherapy drug cisplatin was added for 16 hours or the caspase 3 activator Raptial or PAC-1 was added for stimulation for 2-8 hours. Then, the cells in each group were digested with EDTA-free trypsin and stained with PI (propidium iodide) and Fic-labeled Annexin. The cell apoptosis was analyzed by flow cytometry. The results are shown in the figure. Figure 3 As shown; according to Figure 3 It can be seen that after the cells were treated with chemotherapy drugs or caspase 3 activators, the cells showed obvious double positivity for PI and annexin V, which is a typical feature of apoptosis. The double positivity for PI and annexin V in cells treated with lipoamide decreased significantly, indicating that the cell pyroptosis induced by chemotherapy drugs or caspase 3 activators was significantly inhibited, and lipoamide played a significant protective role on cells treated with chemotherapy drugs.

[0019] Example 4, in vivo test in mice: Mice were randomly divided into blank group, cisplatin group, cisplatin-lipoic acid treatment group, and cisplatin-lipoamide treatment group. The mice in cisplatin-lipoic acid treatment group and cisplatin-lipoamide treatment group were subcutaneously injected with 12.5 mg / kg body weight of lipoic acid or lipoamide one day in advance, and the blank group and cisplatin group were given equal amounts of solvent control. On the second day, the mice in cisplatin group, cisplatin-lipoic acid treatment group, and cisplatin-lipoamide treatment group were intraperitoneally injected with 18 mg / kg body weight of cisplatin, and observed for 3 days. The mice in cisplatin-lipoic acid treatment group and cisplatin-lipoamide treatment group were subcutaneously injected with 12.5 mg / kg body weight of lipoic acid or lipoamide every 12 hours, and the blank group and cisplatin group were given equal amounts of solvent control. After 3 days, the mice were euthanized, the mouse colon was isolated, the length change was observed, and the pathological sections were prepared by HE staining to observe the pathological damage of intestinal villi. Figure 4 As shown; according to Figure 4 It can be seen that in mice that were not given lipoic acid or lipoamide, cisplatin treatment caused obvious intestinal toxicity, the colon was significantly shortened, and the intestinal wall tissue had obvious lesions, the intestinal wall became thinner, and the intestinal villi shortened or even disappeared. However, the colon of mice that were given lipoic acid or lipoamide grew significantly, and there were almost no intestinal lesions, indicating that lipoic acid and lipoamide can play a significant protective role in mice treated with chemotherapy drugs.

[0020] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for reducing the toxicity of chemotherapy drugs, characterized in that: The active ingredient of the pharmaceutical composition is lipoic acid or a pharmaceutically acceptable derivative thereof.

2. The pharmaceutical composition for reducing toxicity of chemotherapy drugs according to claim 1, characterized in that: The pharmaceutically acceptable derivative of lipoic acid is lipoamide.

3. The pharmaceutical composition for reducing toxicity of chemotherapy drugs according to claim 1, characterized in that: The chemotherapy drug is one or more of cisplatin, oxaliplatin, and carboplatin.

4. The pharmaceutical composition for reducing toxicity of chemotherapy drugs according to claim 1, characterized in that: The pharmaceutical composition inhibits the cleavage of GSDME by caspase-3 by binding to the GSDME protein, thereby blocking the pyroptosis pathway and reducing cytotoxicity.

5. Use of lipoic acid or its pharmaceutically acceptable derivatives in the preparation of chemotherapeutic drugs for reducing toxicity.

6. The use according to claim 5, characterized in that The pharmaceutically acceptable derivative of lipoic acid is lipoamide.

7. The use according to claim 5, characterized in that The chemotherapy drug is one or more of cisplatin, oxaliplatin, and carboplatin.

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