CN115040524A - Use of 4-cholesten-3-ones for the treatment of multiple myeloma bone disease - Google Patents
Use of 4-cholesten-3-ones for the treatment of multiple myeloma bone disease Download PDFInfo
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- CN115040524A CN115040524A CN202210893755.3A CN202210893755A CN115040524A CN 115040524 A CN115040524 A CN 115040524A CN 202210893755 A CN202210893755 A CN 202210893755A CN 115040524 A CN115040524 A CN 115040524A
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- cholesten
- multiple myeloma
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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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
Abstract
The invention provides application of 4-cholesten-3-one in treating multiple myeloma bone diseases, and relates to the field of biological medicines.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of 4-cholesten-3-one in treating multiple myeloma bone diseases.
Background
Multiple Myeloma (MM) is one of the most common types of malignant plasmacytomas, also known as myeloma, plasma cell myeloma, or Kahler's disease, the second largest disease of the hematological family. Multiple myeloma bone disease is one of the characteristic clinical manifestations of multiple myeloma, with approximately 90% of patients developing myeloma bone disease in the course of the disease, including systemic osteoporosis, osteolytic destruction, and pathological fractures. The pathogenesis of multiple myeloma bone disease is that myeloma cells release RANKL, TNF, SDF-1, IL-6 osteoclast activating factors and osteoblast inhibiting factors such as Dkk-1, IL-3, TGF-beta and Hepatocyte Growth Factor (HGF), so that osteoclast is over-activated to inhibit the growth of osteoblast, and the imbalance of bone remodeling process of bone resorption and bone formation is caused.
The current main measures for treating multiple myeloma bone diseases are to control the primary pathogenesis by chemotherapy or targeted therapy, and to control the primary pathogenesis by using zoledronic acid which is a medicament for inhibiting bone resorption. However, zoledronic acid can only inhibit osteoclast, cannot achieve the effect of increasing osteogenesis, cannot repair the generated bone destruction, and has a poor treatment effect.
Disclosure of Invention
The invention mainly aims to provide application of 4-cholesten-3-ketone in treating multiple myeloma bone diseases, and aims to provide a better medicament for treating multiple myeloma bone diseases, so that the medicament can repair bone destruction which occurs.
In order to achieve the above object, the present invention proposes the use of 4-cholesten-3-one for treating multiple myeloma bone disease.
Alternatively, the 4-cholesten-3-one comprises a pharmaceutically acceptable salt thereof.
Alternatively, the 4-cholesten-3-one is used in combination with other kinds of drugs for inhibiting bone resorption or drugs for treating multiple myeloma, or the 4-cholesten-3-one and pharmaceutically acceptable salts thereof are used alone.
The invention also provides application of the 4-cholesten-3-ketone in preparing a medicinal preparation for treating multiple myeloma bone diseases.
Alternatively, the 4-cholesten-3-one comprises a pharmaceutically acceptable salt thereof.
Optionally, the pharmaceutical preparation can be in the form of tablets, solutions, suspensions, emulsions, powders, granules, capsules, microcapsules, microspheres, injections, or liposomes, and optionally comprises pharmaceutical excipients.
The invention also provides a pharmaceutical preparation for treating multiple myeloma bone disease, and the active ingredient of the pharmaceutical preparation comprises 4-cholesten-3-ketone.
Optionally, the pharmaceutical preparation is in the form of tablet, solution, suspension, emulsion, powder, granule, capsule, microcapsule, microsphere, injection, or liposome, and optionally comprises pharmaceutical adjuvants.
According to the technical scheme, the 4-cholesten-3-one is adopted to treat multiple myeloma bone diseases, so that bone destruction can be reduced, bone mass can be increased, fracture can be reduced, and the treatment effect is more obvious than that of the existing multiple myeloma bone disease treatment medicine.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the structures shown in the drawings without creative efforts.
FIG. 1 is a schematic diagram of the chemical structure of 4-cholesten-3-one;
FIG. 2 shows the results of osteogenic differentiation of bone marrow mesenchymal stem cells by using different tortoise plastron components;
FIG. 3 is a graph showing the results of 4-cholesten-3-one in reducing the number of osteoclasts in a mouse model of multiple myeloma bone disease;
FIG. 4a is a high throughput micro CT scan 3D bone reconstruction result graph;
fig. 4b is a graph of the results of calculating bone volume fraction and bone mass from the high throughput micro CT scan 3D bone reconstruction results.
The implementation, functional features and advantages of the objects of the present invention will be further explained with reference to the accompanying drawings.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides application of 4-cholesten-3-ketone in treating multiple myeloma bone diseases.
4-cholesten-3-one is a chemical with the chemical formula C 27 H 44 O, the chemical structural formula of which is shown in figure 1. The 4-cholesten-3-one can be extracted from natural products, for example, the active ingredient of carapax et Plastrum Testudinis comprises 4-cholesten-3-one, and 4-cholesten-3-one can be extracted from carapax et Plastrum Testudinis. The 4-cholesten-3-one can also be obtained by fungus fermentation or chemical synthesis.
Alternatively, the 4-cholesten-3-one includes pharmaceutically acceptable salts thereof.
Alternatively, the 4-cholesten-3-one is used in combination with other kinds of drugs for inhibiting bone resorption or drugs for treating multiple myeloma, or the 4-cholesten-3-one and pharmaceutically acceptable salts thereof are used alone.
For example, 4-cholesten-3-one can be used in combination with zoledronic acid, which is an existing therapeutic drug for bone diseases of multiple myeloma, or in combination with chemotherapeutic drugs, targeted drugs, and the like for treating multiple myeloma.
The invention also provides application of the 4-cholesten-3-ketone in preparing a medicinal preparation for treating multiple myeloma bone diseases.
Alternatively, the 4-cholesten-3-one includes pharmaceutically acceptable salts thereof.
Optionally, the pharmaceutical preparation is in the form of tablet, solution, suspension, emulsion, powder, granule, capsule, microcapsule, microsphere, injection, or liposome, and optionally comprises pharmaceutical adjuvants.
The pharmaceutical excipients may include, for example, osmotic pressure regulator, pH regulator, solubilizer, cosolvent, antioxidant, bacteriostatic agent, emulsifier, suspending agent, humectant, absorbent, diluent, flocculant, release retardant, etc.
The invention also provides a pharmaceutical preparation for treating multiple myeloma bone disease, and the active ingredient of the pharmaceutical preparation comprises 4-cholesten-3-ketone.
Optionally, the pharmaceutical preparation can be in the form of tablets, solutions, suspensions, emulsions, powders, granules, capsules, microcapsules, microspheres, injections, or liposomes, and optionally comprises pharmaceutical excipients.
Embodiments of the present invention will be described in detail below with reference to specific examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
1. Experimental Material
1.1 Experimental animals
Healthy SPF grade BALB/c Nude Nude mice, female, 4-6 weeks, were provided by the Experimental animals center of the university of traditional Chinese medicine, Guangzhou. Animal license number: SCXK (Jing) 2019-0020.
1.2 reagents
4-cholesten-3-one standard substance, octadecanoic acid ethyl ester standard substance and tetradecanoic acid sterol standard substance (Si Ke biological siko biology, purity: not less than 98% HPLC); zoledronic acid injection (Tianqingyitai); osteogenic induction differentiation medium (seiko biotechnology limited); myeloma cell Y3-Ag1,2,3 cell line, bone marrow mesenchymal stem cell (Nanjing Kaikyi biology, Inc.); TRAP staining kit (bi yun limited), alizarin red staining kit (bi yun limited); BODIPY probe and H2DCFDA probe (seimer feishell science ltd); mitochondrial fluorescent probes (Solebao technologies, Inc.).
The 4-cholesten-3-ketone injection is prepared by taking normal saline as a solvent, taking 4-cholesten-3-ketone standard product powder as a solute and sterilizing the powder at a concentration of 8 mu g/ml; the quality of the 4-cholesten-3-one injection meets the enterprise requirement standard.
1.3 instruments
CO 2 Incubator, orinbas inverted microscope, zeiss laser confocal LSM 880, high resolution micro CT (brueck Skyscan 1172).
Example 1 osteogenic differentiation experiment of mesenchymal Stem cells
1.1 Experimental treatment
After the logarithmic growth phase of Y3-Ag1,2,3 cells and BMSC was reached, a cell suspension was prepared. A0.4-micron Transwell chamber is used to divide a six-well plate into an upper part and a lower part, Y3-Ag123 and BMSC are planted on the six-well plate in a ratio of 1:1, wherein BMSC cells are planted on the upper layer, and Y3-Ag123 cells are planted on the lower layer. The Transwell chamber can prevent the cell from passing through, but does not influence the secretion function among cells and the exchange between cytokines. After co-culturing for a suitable period of time, the medium was aspirated, washed once with PBS, digested for 5min at 37 ℃ by adding 0.25% EDTA trypsin to the upper layer, and digested by adding DMEM high-sugar complete medium. BMSC cells are completely collected into a 15ml centrifuge tube as much as possible, and the cells are collected by centrifugation at 1500rmp for 5min, so as to obtain the bone marrow mesenchymal stem cells of the model group.
The mesenchymal stem cells of the model group were treated with 4-cholesten-3-one standard, ethyl octadecanoate standard, and tetradecanoic acid sterol standard at a concentration of 30. mu.g/ml for 3 days, and BMSC not treated with Y3-Ag123 cells was used as a control group. And (3) inducing the bone mesenchymal stem cells of each group to be osteogenic by using an osteogenesis induction differentiation culture medium.
1.2 alizarin Red staining detection of osteogenic differentiation
After 21 days of induction of osteogenesis, the solution was discarded and carefully washed 3 times with PBS. Fixing with 95% ethanol for 15min, removing ethanol, and washing with distilled water for 1 time. Adding 1% alizarin red S staining solution, and dyeing at normal temperature for 5 min. Discarding the dye solution, slowly washing with distilled water, and performing microscopic examination.
1.3 results of the experiment
The experimental result is shown in fig. 2, compared with the control group, the osteogenesis quantity of the model group is greatly reduced, which indicates that the modeling is successful, and the ethyl octadecanoate, the tetradecanoic acid sterol and the 4-cholesten-3-one all have the effect of promoting the osteogenic differentiation of the mesenchymal stem cells, wherein the 4-cholesten-3-one has the optimal effect of promoting the osteogenic differentiation of the mesenchymal stem cells.
Example 2 multiple myeloma bone disease mouse model experiment
2.1 multiple myeloma bone disease mouse model preparation and treatment
15 female BALB/c-nu nude mice were randomly assigned to 5 groups of 3 mice per group at 4-6 weeks, including control, model, zoledronic acid, 4-sterone low and 4-sterone high dose groups. The group was treated with Y3-Ag123 (multiple myeloma cell line) 1X 10 by tail vein injection except for the control group 6 Only molding is carried out; the control group was injected with physiological saline. Isoflurane anesthesia machine, wiping rat tail with iodophor for disinfection, decolorizing with 75% alcohol and dilating tail vein. The syringe draws up the PBS resuspended Y3-Ag123 for injection through the tail vein.
After 3 days, 125 mu g/kg sc biw of zoledronic acid injection is injected subcutaneously in the zoledronic acid group; 4-sterone high-dose group is injected with 4-cholesten-3-one injection (dissolved in normal saline) 400 mu g/kg ip qd; 4-sterone low-dose group is injected with 4-cholesten-3-one injection (dissolved in normal saline) 40 mu g/kg ip qd. Passing CO after 21 days 2 BALB/c-nu nude mice were sacrificed by asphyxiation.
2.2 TRAP staining for osteoclast number
The left tibia of each group of mice was fixed in 4% (v/v) formalin for 7 days, decalcified and embedded in paraffin, paraffin sections were prepared, TRAP-stained, and the number of osteoclasts in the bone tissue of each group of mice was observed under a microscope, and TRAP-stained osteoclasts appeared in wine red.
2.3 Trace CT bone mass measurement
The right tibia of each group of mice is placed into 4% (v/v) formalin for fixation for 7 days, and the bone mass of each group of mice is calculated by analyzing data such as the integral number of the bone parts of each group after scanning by using a high-resolution micro CT system.
2.4 results of the experiment
2.41 TRAP staining results
The experimental results are shown in fig. 3, and compared with the control group, the model group shows over-activation of osteoclast, which indicates successful modeling. Compared with the model group, the zoledronic acid group and the 4-sterone high/low dose group have obviously reduced osteoclast activation, and the 4-sterone high dose group has the best effect and is better than the zoledronic acid group and the 4-sterone low dose group.
2.42 micro CT results
As shown in FIGS. 4a and 4b, the number of bone fragments in the model group was significantly decreased compared to the control group, and the difference was statistically significant (P < 0.05), indicating that the modeling was successful and that the bone catabolism in the model group was greater than the bone anabolism. Compared with the model group, the bone body integral number of the zoledronic acid group and the 4-sterone high-dose group is obviously increased, the 4-sterone high-dose group is superior to the zoledronic acid group, the difference has statistical significance (P is less than 0.05), and the bone anabolism of the 4-sterone high-dose group is obviously superior to bone catabolism.
Example 3 clinical trials of multiple myeloma bone disease
1. The injection is prepared by adopting a preparation method of medicinal injection, and the 4-cholesten-3-ketone is prepared into 20mg/ml injection by using water for injection. The product can be used for intraperitoneal injection (ip), and is administered once a day for adult (20 mg/day).
2. Preparing 4-cholesten-3-ketone into capsules by adopting a capsule preparation method, mixing 4-cholesten-3-ketone, calcium carbonate and starch in a ratio of 5: 1: 0.1, evenly mixing the components, preparing the mixture into granules, and filling the granules into capsules with the content of 30mg each, wherein each capsule contains 25mg of 4-cholesten-3-ketone.
The taking method comprises the following steps: it is administered orally at a dose of 1-2 granules for 2 times per day for adult. 4 weeks is a treatment course, and the dosage is reduced after two treatment courses.
3. Preparing 4-cholesten-3-ketone into tablets by adopting a preparation method of medicinal tablets, mixing the 4-cholesten-3-ketone with calcium carbonate and starch according to a ratio of 5: 1: mixing at a ratio of 0.1, sieving with 81 mesh sieve, and tabletting. Making into tablet with weight of 50mg, each tablet contains 4-cholesten-3-one 40 mg.
The taking method comprises the following steps: it is administered orally at a dose of 1-2 tablets per time, 2 times daily for adult. 4 weeks is a treatment course, and the dosage is reduced after two treatment courses.
The effect is as follows: reduce bone destruction, increase bone mass, and reduce fracture.
The above description is only an alternative embodiment of the present invention, and is not intended to limit the scope of the present invention, and all modifications and equivalents made by the contents of the present specification and the accompanying drawings, or directly/indirectly applied to other related technical fields, which are within the spirit of the present invention, are included in the scope of the present invention.
Claims (8)
- Use of 4-cholesten-3-one for the treatment of multiple myeloma bone disease.
- 2. The use according to claim 1, wherein said 4-cholesten-3-one comprises a pharmaceutically acceptable salt thereof.
- 3. Use according to claim 1 or 2, wherein said 4-cholesten-3-one is used in combination with other kinds of drugs inhibiting bone resorption or drugs treating multiple myeloma, or said 4-cholesten-3-one and pharmaceutically acceptable salts thereof are used alone.
- Use of 4-cholesten-3-one for the preparation of a pharmaceutical preparation for the treatment of multiple myeloma bone disease.
- 5. The use according to claim 4, wherein said 4-cholesten-3-one comprises a pharmaceutically acceptable salt thereof.
- 6. The use according to claim 4 or 5, wherein the pharmaceutical preparation is in the form of tablet, solution, suspension, emulsion, powder, granule, capsule, microcapsule, microsphere, injection, liposome, and optionally comprises pharmaceutical adjuvants.
- 7. A pharmaceutical preparation for treating multiple myeloma bone disease, which is characterized in that the active ingredient of the pharmaceutical preparation comprises 4-cholesten-3-one.
- 8. The pharmaceutical preparation according to claim 7, wherein the form of the pharmaceutical preparation comprises tablets, solutions, suspensions, emulsions, powders, granules, capsules, microcapsules, microspheres, injections, and liposomes, and the pharmaceutical preparation optionally comprises pharmaceutical excipients.
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