CN114642675A - Application of L-sorbose in preparing medicine for treating tumor - Google Patents
Application of L-sorbose in preparing medicine for treating tumor Download PDFInfo
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- CN114642675A CN114642675A CN202110463305.6A CN202110463305A CN114642675A CN 114642675 A CN114642675 A CN 114642675A CN 202110463305 A CN202110463305 A CN 202110463305A CN 114642675 A CN114642675 A CN 114642675A
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- sorbose
- tumor
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- cancer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Veterinary Medicine (AREA)
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- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses application of L-sorbose in preparing a medicament for treating tumors. The application adopts L-sorbose to be used singly or combined with clinical commonly used medicaments for treating tumors, in-vitro experiment results show that the L-sorbose has the effect of inhibiting proliferation of human tumor cells by inhibiting tumor cell metabolism, retards cell cycle progression and promotes apoptosis, L-sorbose combined chemotherapeutic medicaments, such as sorafenib, lenvatinib, cisplatin, doxorubicin and paclitaxel, have obvious synergistic effect in killing malignant tumor cells, in-vivo experiments prove that the L-sorbose can inhibit tumor growth and does not cause obvious weight change of experimental animals, and the L-sorbose combined chemotherapeutic medicaments can be used for simultaneously matching treatment with other chemotherapeutic medicaments to improve the tumor treatment effect. The application relates to a new application of L-sorbose, which is beneficial to expanding the clinical application range of the L-sorbose, can be used for clinical adjuvant therapy of malignant tumors by combining with chemotherapeutic drugs, improves the tumor treatment effect and reduces toxic and side effects.
Description
Technical Field
The invention belongs to the anti-tumor medicine technology, and particularly relates to application of rare sugar L-sorbose in preparing a medicine for treating tumors.
Background
Cancer is the second leading cause of death worldwide, the mortality rate is second only to cardiovascular and cerebrovascular diseases, the burden of cancer continues to increase worldwide year by year, and enormous physical, emotional and economic burden is imposed on individuals, families, communities and health systems. Cancer belongs to a large group of diseases, cells grow uncontrollably abnormally and beyond their normal range to become malignant cells, invade nearby parts of the body and spread to other organs, and tumor metastasis is a major cause of cancer death.
Cancer results from a multi-stage transformation process of normal cells into tumor cells, which usually progresses from precancerous lesions to malignant tumors. These changes are the result of human genetic factors and the interaction of three classes of external factors, including: physical carcinogens such as ultraviolet light and ionizing radiation; chemical carcinogens such as asbestos, components of tobacco smoke, aflatoxins and arsenic, etc.; infection with biological carcinogens, such as certain viruses, bacteria or parasites. The current main treatment modes of cancer comprise surgical treatment, radiotherapy, chemotherapy, biological treatment and the like, but a plurality of treatment schemes for treating various cancers still have limitations. Because most patients lose the best time for surgery at the time of diagnosis, radiotherapy and chemotherapy are the main treatment means accepted by most tumor patients clinically. However, the resistance of tumor cells to chemotherapeutic drugs is often a significant cause of chemotherapy failure.
Cancer cells consume large amounts of glucose as an energy source, allowing the use of large amounts of amino acids and nucleotides when the cells over-proliferate to synthesize DNA. By taking advantage of this feature, the aerobic glycolytic metabolism of the tumor cells can reach a very high degree by providing an excess of glucose, expelling large amounts of lactate, resulting in an acidic microenvironment of the tumor cells. Therefore, interference with glucose metabolism of tumor cells can also be used as an anti-tumor strategy.
L-sorbose is one of the rare sugars. The international rare sugar society (ISRS) defines "rare sugars and their derivatives are monosaccharides that are scarcely found in nature", and although their natural abundance is low, rare sugars exhibit various biological functions. In the food industry, rare sugars have been recognized as supplements and non-nutritive sweeteners for low calorie foods. Has great development potential in the industries of synthesis, cosmetics, pharmacy and the like. For example, D-psicose can inhibit hepatic lipase activity, thereby reducing abdominal fat accumulation, and can inhibit the rise of blood glucose, and alleviate type 2 diabetes; d-tagatose is a food additive approved by the U.S. Food and Drug Administration (FDA); d-allose has multiple physiological functions, and can be used as anticancer agent, antiinflammatory agent and antioxidant; l-fructose is a non-nutritive sweetener, a glycosidase inhibitor, and an insecticide for flies and ants. Current research shows that L-sorbose can be used to synthesize glycosidase inhibitors (1-deoxygalactosidase) and L-ascorbate. But the application of the compound in antitumor pharmacy is not reported.
Disclosure of Invention
The purpose of the invention is as follows: in view of the above prior art, the present application provides the use of L-sorbose in the preparation of a medicament for the treatment of tumors.
The technical scheme is as follows: the application discloses an application of L-sorbose in preparing a medicine for treating tumors.
The application adopts a certain dosage of L-sorbose to act on human tumor cells, and experimental results show that the L-sorbose has an inhibition effect on tumor cell proliferation, and retards cell cycle progression and promotes cell apoptosis by inhibiting tumor cell metabolism.
The application also discloses application of the L-sorbose combined chemotherapy medicine in preparation of antitumor medicines.
The application adopts the L-sorbose and the tumor chemotherapy drug to be jointly used for human tumor cells, the result shows that the L-sorbose has the synergistic effect on the chemotherapy drug, and the in vivo experiment proves that the L-sorbose has no toxic or side effect while the L-sorbose is used for the synergistic effect.
The chemotherapy drugs include but are not limited to sorafenib, lenvatinib, cisplatin, doxorubicin, paclitaxel and other common clinical drugs. Preferably, the chemotherapeutic drug is sorafenib.
Tumors described herein include, but are not limited to, liver cancer, breast cancer, lung cancer, cervical cancer, lymphoma, bladder cancer, melanoma, and the like. In particular liver cancer.
The application also discloses an anti-tumor medicine composition which comprises the L-sorbose and a pharmaceutically acceptable carrier.
The application of the anti-tumor medicine composition in preparing anti-tumor medicines is also within the protection scope of the application.
Furthermore, L-sorbose can be administered in a linear form or in a cyclic form without affecting the therapeutic effect. Various methods of administration can be used in the treatment, including oral administration, intravenous injection, intramuscular injection, intratumoral injection, and the like.
Has the advantages that: the application discloses the application of L-sorbose in preparing anti-tumor drugs for the first time, and the L-sorbose inhibits the proliferation of tumor cells, retards the progress of the cell cycle and promotes the apoptosis of the cells by inhibiting the metabolism of the tumor cells. In addition, the combination of the L-sorbose and the chemotherapeutic drug can obviously enhance the treatment effect of the chemotherapeutic drug, reduce the dosage of the chemotherapeutic drug and reduce the toxic and side effects.
Drawings
FIG. 1 is a graph showing the results of the effect of different rare sugars on the growth of cancer cells;
FIG. 2 is a graph showing the growth inhibition of hepatoma cell lines by L-sorbose;
FIG. 3 is a graph of the effect of L-sorbose on the cell cycle of hepatoma cells;
FIG. 4 is a graph of the effect of L-sorbose on apoptosis of hepatoma cells;
FIG. 5 is a graph showing the effect of L-sorbose on the expression of HIF-1. alpha. and target genes associated with energy metabolism in cancer cells;
FIG. 6 is a graph of the effect of different rare sugars in combination with sorafenib on cancer cell growth;
FIG. 7 is a graph of L-sorbose in combination with sorafenib potentiating the effect of sorafenib in inhibiting cancer cell growth in vitro;
FIG. 8 shows that L-sorbose in combination with sorafenib potentiates in vivo tumor therapy.
Detailed Description
The technical solution of the present application will be described in detail with reference to the following examples.
All rare sugars used in the examples were purchased from Chishieia (Shanghai) chemical industry development Co., Ltd, and the cell line was derived from the cell resource center of the institute of basic medicine of Chinese academy of medical sciences.
Example 1: inhibition of cancer cell growth in vitro by L-sorbose
Different rare sugars are selected to stimulate human liver cancer cells Huh7 and HepG2, breast cancer cells MCF7 and lung cancer cells A549 respectively, and then the cell activity change is inspected. Selecting L-sorbose with different concentrations to stimulate human liver cancer cells Huh7 and HepG2 respectively, and calculating IC50。
By 5X 104Density of individual cells/mL cells were seeded in 96-well plates in a volume of 100 μ L per well, and the 96-well plates were placed in a cell incubator for overnight culture. Cells were stimulated 24h after cell attachment with the 50mM rare sugar standards D-Tagatose (D-Tagatose), L-Tagatose (L-Tagatose), D-Sorbose (D-Sorbose), L-Sorbose (L-Sorbose), D-Allose (D-Allose) and L-Fructose (L-frutose) or 24h, 48h and 72h with different doses (0, 5, 10, 25, 50 and 100mM) of L-Sorbose. After the administration incubation is finished, carrying out a CCK-8 experiment, firstly diluting a certain volume of CCK-8 reagent with a complete culture medium according to the proportion of 1:10, then absorbing the medicine-containing old culture medium in the holes, adding 100 mu L of diluted CCK-8 working solution into each hole, selecting 3 Blank holes, discarding the holes containing the old D-PBS, adding the prepared CCK-8 working solution as Blank (for deducting the hole background value), and then putting the 96-hole plate back to the incubator for incubation for 45min-1 h. After the incubation, the OD450nm value was measured at 450nm according to the formula [ (additional drug group-Blank)/(control group-Blank)]X 100% cell viability was calculated.
As shown in FIG. 1, the results show that 50mM L-sorbose has a certain growth inhibition effect on human hepatoma cells Huh7, HepG2, breast cancer cells MCF-7 and lung cancer cells A549, and the inhibition effect of L-sorbose on other cells except MCF7 cells is stronger than that of D-Allose. As shown in FIG. 2, L-sorbose acted on Huh7 cell IC5033.82mM (24h), 27.32mM (48h) and 30.88mM (72 h); l-sorbose on HepG2 cell IC5027.68mM (24h), 34.89mM (48h) and 22.60mM (72 h).
Example 2: cell cycle arrest of cancer cells by L-sorbose
Different concentrations of L-Sorbose are given to stimulate liver cancer cells Huh7 and HepG2, and the influence of L-Sorbose on the cell cycle is detected by flow cytometry.
By 2X 105Cell density per mL cells were seeded in 6-well plates at 2mL volumes per well and placed in a cell incubator overnight. After 24h of cell attachment, the cells were stimulated with different doses (0, 12.5, 25 and 50mM) of L-Sorbose for 24 h. After the administration incubation is finished, each group of cells is digested with pancreatin respectively, centrifuged at 1400rpm for 3min, added with 1mL of D-PBS to wash the cells gently, centrifuged at 1400rpm for 3min, and washed twice repeatedly. Preparation of Working Solution: 1 sample: 500 μ L Assay Buffer +25 μ L PI Solution +2.5 μ L RNase Solution. 0.5mL of Working Solution was added to the cell pellet for resuspension and incubated at 4 ℃ in the dark for 30 min. After the completion of the administration, the cells were dispersed by vortexing and incubated at 37 ℃ for 30min in the dark. The cells were then vortexed and the flow cytometer measured the cell cycle.
The results are shown in FIG. 3, and it can be seen from the graph that L-Sorbose has cell cycle-retarding effect on Huh7 and HepG2, blocks the cell cycle in S phase, and is dose-dependent.
Example 3: l-sorbose promotes apoptosis of cancer cells
Different concentrations of L-Sorbose are given to stimulate liver cancer cells Huh7 and HepG2, and the influence of L-Sorbose on apoptosis is detected by flow cytometry.
By 2X 105Density of individual cells/mL cells were seeded in 6-well plates at a volume of 2mL per well and placed in a cell incubator overnight. After 24h of cell attachment, the cells were stimulated with different doses (0, 12.5, 25 and 50mM) of L-Sorbose for 24 h. After the administration incubation was completed, each group of cells was digested with trypsin without EDTA, and then centrifuged at 1400rpm for 3min, 1mL of D-PBS was added to gently wash the cells, and then centrifuged at 1400rpm for 3min, and the washing was repeated twice. 1 × preparation of Annexin V Binding Solution: 10 × Annexin V Binding Solution was diluted with ultrapure water to 1 × Annexin V Binding Solution. Add 500. mu.L of Annexin V Binding Solution to the cell pellet. 100 μ L of the suspension was placed in a new EP tube, 5 μ L of Annexin V, FITC conjugate was added, and 5 μ L of PI Solution was added. Culturing at room temperature in dark for 15 min. 400 mu L of Annexin V Binding Solution is added into each EP tube respectively, and the detection is carried out by a 1h internal flow cytometer. Setting a control group: firstly, unstained cells; ② Annexin V, FITC staining fineCell (no PI); ③ PI staining of cells (Annexin V, FITC-free).
As shown in FIG. 4, it can be seen that L-Sorbose can promote apoptosis of liver cancer cells Huh7 and HepG 2.
Example 4: influence of L-sorbose on expression of cancer cell hypoxia inducible factor HIF-1 alpha and its metabolism-related target genes
After different doses (0, 12.5, 25 and 50mM) of L-sorbose act on the hepatoma cells for 24h respectively, protein expression changes of HIF-1 alpha and downstream metabolism-related target genes (HIF-1 alpha, HK2, PKM2 and LDHA) in the hepatoma cells are detected by a Western Blot method.
By 2X 105Density of individual cells/mL cells were seeded in 6-well plates at a volume of 2mL per well and placed in a cell incubator overnight. After 24h of cell attachment, the cells were stimulated by administering different doses (0, 12.5, 25 and 50mM) of L-Sorbose for 24 h. After administration incubation is finished, digesting each group of cells by pancreatin without EDTA, centrifuging at 1400rpm for 3min, washing the cells by D-PBS for 3 times, adding protein lysate and protease inhibitor into the human liver cancer cells after L-sorbose treatment, performing low-temperature lysis on ice for 30min, centrifuging at 4 ℃ and 15000rpm for 10min, collecting supernatant, quantifying, performing SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) electrophoretic separation on an equivalent protein sample, performing membrane transfer by a semidry method, sealing with 5% skimmed milk powder for 2h, adding an antibody, and incubating overnight at 4 ℃. And adding a secondary antibody marked by HRP (horse radish peroxidase) after PBST is washed, incubating at room temperature for 1h, adding a chemiluminescent solution after washing for color development, and taking an image for photographing.
The results are shown in FIG. 5, and it can be seen from the graph that the protein expression of HIF-1 α, HK2, PKM2, LDHA can be inhibited to different degrees and is dose-dependent after different doses of L-sorbose stimulate hepatoma cells for 24 h.
Example 5: l-sorbose and sorafenib combined in-vitro inhibition of cancer cell growth
The change of cell activity is detected after 25mM of different rare sugars and 2 mu M of sorafenib are used together to stimulate human liver cancer cells Huh7 and HepG 2. After the combination of 12.5mM and 25mM L-sorbose and 2. mu.M and 4. mu.M sorafenib is used for stimulating human hepatoma cells Huh7 and HepG2, the change of cell viability is detected.
By 5X 104Cells were seeded in 96-well plates at a density of 100. mu.L per well and placed in a cell incubator overnight. After 24h of cell attachment, human hepatoma cells Huh7 and HepG 224 h were stimulated by administering 25mM rare sugar standards D-Tagatose, L-Tagatose, D-Sorbose, L-Sorbose, D-Allose, L-Fructose and D-Allose in combination with 2. mu.M sorafenib, or 12.5mM and 25mM L-Sorbose in combination with 2. mu.M and 4. mu.M sorafenib. After the administration incubation is finished, carrying out a CCK-8 experiment, firstly diluting a certain volume of CCK-8 reagent with a complete culture medium according to the proportion of 1:10, then removing the old culture medium containing the medicine in the holes, adding 100 mu L of diluted CCK-8 working solution into each hole, selecting 3 Blank holes, adding the prepared CCK-8 working solution to serve as Blank (for deducting the background value of the holes), and then putting the 96-well plate back to the incubator to continue incubation for 45min-1 h. After the incubation of the CCK-8 working solution is finished, taking out the 96-well plate to be detected from the incubator, detecting the OD450nm value of each well under the wavelength of 450nm according to the formula [ (additional medicine group-Blank)/(control group-Blank)]X 100% cell viability was calculated.
The results are shown in FIG. 6, and it can be seen from the graph that the combination of 2. mu.M sorafenib with other rare sugars at 25mM has no synergistic effect except L-sorbose. As shown in figure 7, the combination of 12.5mM and 25mM of L-sorbose with 2 μ M and 4 μ M of sorafenib can obviously enhance the inhibition effect of sorafenib on the growth of cancer cells, and the combination of 12.5mM of L-sorbose with 2 μ M of sorafenib at a low dose already has an obvious effect of inhibiting the growth of cancer cells.
Example 6: combination of L-sorbose and sorafenib for enhancing tumor treatment effect
In-vivo pharmacodynamic study the inhibition effect of L-sorbose on liver cancer cells in vivo is investigated by inoculating Huh7 liver cancer cells subcutaneously in nude mice to construct a nude mouse liver cancer transplantation tumor mouse model.
Male SPF-grade Balb/c nu mice of four weeks old are adaptively raised for one week and kept in a free water intake feeding state. Culturing human hepatoma cell line Huh7 cells, and adjusting cell concentration to 1.0 × 10 with D-PBS7Per 100. mu.L, the cell suspension was gently mixed before inoculation, and 100. mu.L of Huh7 cell suspension was subcutaneously inoculated to the axillary side close to the back of each nude mouse. Feeding normally and observing closely every dayAnd (5) detecting the size of the tumor at the subcutaneous inoculation position of the nude mice. The inoculation is carried out for about four days, and the tumor volume reaches about 50mm3In time, nude mice were randomly divided into 4 groups and administered L-sorbose and sorafenib by gavage. The model group was gavaged with normal saline daily, the L-sorbose group was gavaged with 20% L-sorbose daily (200. mu.L/20 g), the sorafenib group was gavaged with 5mg/mL sorafenib (50mg/kg), and the combination group was gavaged with 20% L-sorbose daily (200. mu.L/20 g) and 5mg/mL sorafenib (50 mg/kg). Observing the growth state of the nude mice every day, recording the weight of the nude mice every other day, precisely measuring the size of the tumor by using a vernier caliper, and drawing a nude mice tumor change curve graph and a nude mice weight change curve graph. Animals were sacrificed after four weeks of dosing, intact tumors carefully dissected and weighed, and tumor tissues were divided into four portions, one portion was fixed in 10% formalin, and three portions were snap frozen with liquid nitrogen and transferred to a-80 ℃ freezer for storage.
The experimental results are shown in fig. 8, and it can be seen from the graph that, compared with the model group, both the L-sorbose group and the sorafenib group can inhibit the growth of tumor volume and the tumor weight to different degrees, and the combined group has the best inhibition effect, as can be seen from the tumor volume change curve and the tumor weight change of the nude mice. According to the weight change curve of the nude mouse, the weight change of the nude mouse is smooth and the state is good in the whole experiment process.
Claims (10)
- Application of L-sorbose in preparing medicine for treating tumor.
- 2. The use of claim 1, wherein L-sorbose inhibits tumor cell proliferation and promotes tumor cell apoptosis.
- The application of the L-sorbose and chemotherapy combination medicine in preparing antitumor medicines.
- 4. The use of claim 3, wherein the L-sorbose can enhance the toxic effects of chemotherapeutic drugs on tumor cells and tumor tissues, inhibit tumor cell proliferation, and promote tumor cell apoptosis.
- 5. The use of claim 3, wherein the chemotherapeutic agent comprises sorafenib, lenvatinib, cisplatin, doxorubicin, and paclitaxel.
- 6. The use of claim 1 or 3, wherein the tumor comprises liver cancer, cervical cancer, lung cancer, breast cancer, lymphoma, bladder cancer and melanoma.
- 7. The use of claim 6, wherein the tumor is liver cancer.
- 8. An anti-tumor pharmaceutical composition, which is characterized by comprising L-sorbose and a pharmaceutically acceptable carrier.
- 9. Use of the pharmaceutical composition of claim 8 for the preparation of a medicament for the treatment of a tumor.
- 10. The use of claim 9, wherein the tumor comprises liver cancer, cervical cancer, lung cancer, breast cancer, lymphoma, bladder cancer, and melanoma.
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