CN111494361B - Application of pharmaceutical composition of fingolimod hydrochloride and curcumenol in preparation of anti-multiple myeloma drugs - Google Patents
Application of pharmaceutical composition of fingolimod hydrochloride and curcumenol in preparation of anti-multiple myeloma drugs Download PDFInfo
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Abstract
The invention discloses application of a pharmaceutical composition of fingolimod hydrochloride and curcumenol in preparation of a drug for resisting multiple myeloma. The invention utilizes the synergistic effect of Fingolimod (FTY720) HCl and Curcumol to generate better effect of inhibiting cell proliferation than the single use of the two drugs, obviously induces cell necrosis, generates stronger biological function and greatly improves the efficiency of killing multiple myeloma cells MM 1S. The pharmaceutical composition has obvious effect in a laboratory, is suitable for treating multiple myeloma patients clinically, and has great development prospect and potential application value.
Description
Technical Field
The invention relates to a new application of a pharmaceutical composition, and in particular relates to an application of a pharmaceutical composition of fingolimod hydrochloride and curcumenol in preparation of a multiple myeloma resistant drug. Belongs to the technical field of anti-cancer drugs.
Background
Multiple Myeloma (MM) is a malignant proliferative disease of plasma cells, also known as myeloma, plasma cell myeloma or Kahler's disease. Its tumor cells originate from plasma cells in the bone marrow, which are the cells that develop to the final functional stage of B lymphocytes. Multiple myeloma can therefore be classified in the range of B-lymphocyte lymphomas. B cells are abnormal in the process of differentiating into plasma cells, so that a large amount of monoclonal immunoglobulin chains or light chains (M proteins) are produced, normal polyclonal plasma cell proliferation and polyclonal immunoglobulin secretion are inhibited, and finally clinical manifestations such as bone destruction, infection, anemia, hypercalcemia, renal insufficiency and the like are complicated. Multiple myeloma accounts for approximately 1% of all malignancies and approximately 15% of hematopoietic malignancies. The prevalence rate of the cancer is the second place of the malignant tumor of the blood system, the cancer is frequently seen in old patients, and no cure method exists clinically at present. The actual incidence of the multiple myeloma in China still needs to be counted in detail, but the overall incidence is in an increasing trend. The incidence rate is high, the prognosis difference among individuals is large, and the treatment difficulty is large. The MM1S cells used in this patent were classified as multiple myeloma.
Cordyceps Sinensis (Ophiocerociceps Sinensis), also known as Cordyceps Sinensis, is a complex of Cordyceps Sinensis and Hepialidae larvae. Cordyceps sinensis of the genus Cordyceps sinensis belonging to the order Hypocreales, family Serpentiaceae, and genus Cordyceps sinensis parasitizes in Hepialus larva in mountain meadow soil to make the body of the larva rigid, and under appropriate conditions, long rod-like stroma is extracted from the tip of the stiff worm in summer, i.e., a complex of fruiting body of Cordyceps sinensis and stiff worm sclerotium (larva corpse). The cordyceps sinensis is mainly produced in alpine regions and snowy mountain grasslands in Qinghai, Tibet, Sichuan, Yunnan and Gansu provinces in China. The whole world is distributed in four countries of China, India, Nepal and Plumbum Preparatium.
Fingolimod (FTY720) HCl, generic name Fingolimod hydrochloride, molecular weight 343.9, formula C19H33NO2HCl, a novel immunosuppressive agent with anti-tumor effect, is prepared by modifying ISP-1, an antibiotic component extracted from Cordyceps (Ascomycotina akashii) culture solution, with chemical modification (introducing benzene ring and hydroxyalkyl group into ISP-1 hydroxyl chain). Is easily soluble in water and ethanol. Currently, Fingolimod (FTY720) HCl is mainly used for treating autoimmune diseases and reducing immune rejection in organ transplantation. Micromolar Fingolimod (FTY720) HCl can be used for treating multiple tumors (such as ovarian cancer, lung cancer, colon cancer, breast cancer, prostatic cancer, multiple myeloma, lymphoma and liver cancer)Has therapeutic effect.
Rhizoma Curcumae (with scientific name: Curcuma zedoaria (Christm.) Rosc) is called rhizoma Curcumae, rhizoma Curcumae Longae, rhizoma Zingiberis recens, and rhizoma Curcumae Longae, and is a perennial root herb. The rootstock has an oval block shape, and has cylindrical lateral branches on the side surfaces, long and thin root system, and expanded long oval block-shaped terminal. The leaf is long round ellipse or narrow oval, 13-24 cm long and 7-11 cm wide, and has purple halo in the middle of the vein; the petiole is about 1/3 of the leaf, and the petiole is sheathed and has small lug shape. A cylindrical spike-shaped inflorescence with the length of about 14 cm, total stalks and dense flowers; the bract is oval, the bract at the top is expanded, the color is bright red, and no flower exists in the axilla; calyx is white with 3 blunt teeth; the upper part of the flower crown lobe 3 is 1 bigger, the top end is slightly pocket-shaped, the labial lobe is round and is faint yellow, the tip 3 is shallow and round, and the tip of the middle lobe is slightly deficient. The capsule has an egg-shaped triangular shape and is smooth. The seeds are oblong. Has a fake seed coat. The flowering period is 3-5 months.
Curcumenol (Curcumol), synonym of curcumenol and curcumenol, and molecular formula C15H24O2The extract has a relative molecular mass of 236.34, is extracted from volatile oil of rhizome of Curcumae rhizoma of Zingiberaceae, and is a broad-spectrum antitumor drug. Curcumol is a hydrogenated austenite compound with a hemiketal, and is formed by combining a five-membered ring and a six-membered ring, wherein the seven-membered ring forms a five-membered ring and a six-membered ring through an oxygen bridge of the hemiketal, so that the tension of the three rings is reduced, and a stable compound with a rigid structure is formed and is easily dissolved in DMSO (dimethyl sulfoxide) and ethanol. Curcumol has been reported to have therapeutic effects on various tumors (human colon cancer, triple negative breast cancer, bladder cancer, human lung adenocarcinoma, cholangiocarcinoma, multiple myeloma, non-small cell lung cancer, etc.). The Curcumol has broad-spectrum anti-tumor effect and has great development and utilization values in anti-tumor research.
No report on the combined application of Fingolimod (FTY720) HCl and Curcumol in multiple myeloma research is found at present.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides application of a pharmaceutical composition of fingolimod hydrochloride and curcumenol in preparation of a multiple myeloma resistant drug.
In order to achieve the purpose, the invention adopts the following technical scheme:
1. application of a pharmaceutical composition of Fingolimod hydrochloride (FTY720) HCl and curcumenol (Curcumol) in preparation of anti-multiple myeloma drugs.
Preferably, the mass ratio of the fingolimod hydrochloride to the curcumenol is 0.69-1.38: 25 to 100.
Further preferably, the mass ratio of the fingolimod hydrochloride to the curcumenol is 1.03: 50.
preferably, the pharmaceutical preparation is in the form of any one selected from tablets, capsules, granules or injections.
2. An anti-multiple myeloma drug comprises the effective components of Fingolimod hydrochloride (FTY720) HCl) and Curcumol (Curcumol).
Preferably, the mass ratio of the fingolimod hydrochloride to the curcumenol is 0.69-1.38: 25 to 100.
Further preferably, the mass ratio of the fingolimod hydrochloride to the curcumenol is 1.03: 50.
preferably, the pharmaceutical preparation is in the form of any one selected from tablets, capsules, granules or injections.
The invention has the beneficial effects that:
the invention utilizes the synergistic effect of Fingolimod (FTY720) HCl and Curcumol to generate better effect of inhibiting cell proliferation than the single use of the two drugs, obviously induces cell necrosis, generates stronger biological function and greatly improves the efficiency of killing multiple myeloma cells MM 1S. The pharmaceutical composition has obvious effect in a laboratory, is suitable for treating multiple myeloma patients clinically, and has great development prospect and potential application value.
The Fingolimod (FTY720) HCl and Curcumol pharmaceutical composition has the concentration range of 2 mu M-4 mu M of Fingolimod (FTY720) HCl and the concentration range of 25 mu g/mL-100 mu g/mL of curcumenol. The optimal concentration combination of the combined medicines is as follows: fingolimod (FTY720) HCl (3. mu.M) + Curcumol (50. mu.g/mL); the concentration combination of the drug combination with synergistic effect is as follows: 2. mu.M + 50. mu.g/mL, 2. mu.M + 100. mu.g/mL, 3. mu.M + 25. mu.g/mL, 3. mu.M + 50. mu.g/mL, 3. mu.M + 100. mu.g/mL, 4. mu.M + 25. mu.g/mL, 4. mu.M + 50. mu.g/mL, 4. mu.M + 100. mu.g/mL.
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FIG. 1 is a CCK-8 assay of the effect of Fingolimod (FTY720) HCl and Curcumol on MM1S cell viability alone and after the use of combination preparations in example 1; wherein MM1S is a human multiple myeloma cell line, P <0.05, P <0.01, P <0.001, P < 0.0001;
FIG. 2 is a diagram showing the synergistic effect of the combined preparation of Fingolimod (FTY720) HCl and Curcumol at different component concentrations on MM1S cells measured by the CCK-8 method in example 2; wherein Fa: the inhibition rate; CI: a synergy index;
FIG. 3 is a graph showing the induction of apoptosis by Fingolimod (FTY720) HCl and Curcumol on MM1S cells alone and in combination using a flow assay in example 3 using Annexin V647/PI double staining; wherein the DMSO group was a control;
FIG. 4 is a graph showing the cycle retarding effect of Fingolimod (FTY720) HCl and Curcumol on MM1S cells alone and in combination using a combination preparation in example 4 by using PI single staining method; the DMSO group was the control.
Detailed Description
The present invention will be further described with reference to the accompanying drawings and examples, which are provided for the purpose of illustration only and are not intended to limit the scope of the invention.
Fingolimod (FTY720) HCl and Curcumol, both of which are related to the present invention, were purchased from Selleck.
Example 1:
the effect of Fingolimod (FTY720) HCl and Curcumol on MM1S cells alone and in combination on MM1S cell viability was examined using the CCK-8 method.
The experimental steps are as follows:
(1) MM1S cells (purchased from ATCC cell bank, USA) in logarithmic growth phase were collected, cell suspension concentration was adjusted, 100. mu.L of 96-well plate was added per well, and the cell density to be measured was made to be 1X 104Per mL;
(2) setting a zero-adjusting group without cells and only culture medium and a DMSO control group with the volume concentration of 0.1% without drugs, wherein each concentration is provided with 3 parallel holes;
(3) add 3. mu.M Fingolimod (FTY720) HCl, 50. mu.g/mL Curcumol, and 3. mu.M Fingolimod (FTY720) HCl and 50. mu.g/mL Curcumol, respectively, in a volume percent of 5% CO2Incubating in a cell incubator at 37 ℃ for 48 hours;
(4) and adding 10 mu L of CCK-8 solution into each well, incubating for 2 hours at 37 ℃ in the dark, measuring the OD value of each well at the wavelength of 450nm by using a microplate reader, performing statistical analysis, and calculating the relative survival rate of the cells.
The results of the experiment are shown in FIG. 1. The results show that the combined preparation of Fingolimod (FTY720) HCl and Curcumol has stronger proliferation inhibiting effect on MM1S cells than the combined preparation of Fingolimod (FTY720) HCl and Curcumol, and the statistical analysis shows that the combined preparation has extremely significant difference.
Example 2:
the CCK-8 method was used to examine the synergistic effect of the combination of Fingolimod (FTY720) HCl and Curcumol drugs at different concentrations on MM1S cells.
The experimental steps are as follows:
(1) collecting MM1S cells in logarithmic growth phase, adjusting cell suspension concentration, adding 100 μ L of 96-well plate per well, and plating to make cell density to be measured be 1 × 104M L per seed;
(2) setting a zero-adjusting group without cells and only culture medium and a DMSO control group with the volume concentration of 0.1% without drugs, wherein each concentration is provided with 3 parallel holes;
(3) separately adding Fingolimod (FTY720) HCl and Curcumol preparations in different concentration combinations, wherein the concentrations of the combined preparations are respectively 2 mu M +25 mu g/mL, 2 mu M +50 mu g/mL, 2 mu M +100 mu g/mL, 3 mu M +25 mu g/mL, 3 mu M +50 mu g/mL, 3 mu M +100 mu g/mL, 4 mu M +25 mu g/mL, 4 mu M +50 mu g/mL and 4 mu M +100 mu g/mL, placing the mixture in a cell culture box with volume percentage of 5% CO2 and incubating the mixture for 48 hours at 37 ℃;
(4) and adding 10 mu L of CCK-8 solution into each well, incubating for 2 hours at 37 ℃ in the dark, measuring the OD value of each well at the wavelength of 450nm by using a microplate reader, performing statistical analysis, and calculating the relative survival rate of the cells.
The results of the experiment are shown in fig. 2 and table 1. The results show that the combined preparation of high concentration Fingolimod (FTY720) HCl and Curcumol has strong synergistic effect (CI value of 0.38664), and in MM1S cells, the synergistic effect of Curcumol and Fingolimod (FTY720) HCl is not strong at low concentration, even antagonistic effect (CI value of 1.00490); the Curcumol and Fingolimod (FTY720) HCl showed a good synergy when the Curcumol concentration reached 50 ug/mL.
TABLE 1 Effect of different component concentrations Fingolimod (FTY720) HCl and Curcumol combination on MM1S cells
| Curcumol concentration (μ g/mL) | FTY720 concentration (. mu.M) | Fa (inhibition rate) | CI (drug index) |
| 25.0 | 2.0 | 0.733 | 1.00490 |
| 25.0 | 3.0 | 0.367 | 0.82077 |
| 25.0 | 4.0 | 0.098 | 0.59710 |
| 50.0 | 2.0 | 0.548 | 0.89437 |
| 50.0 | 3.0 | 0.047 | 0.38664 |
| 50.0 | 4.0 | 0.031 | 0.42293 |
| 100.0 | 2.0 | 0.397 | 0.93357 |
| 100.0 | 3.0 | 0.068 | 0.52853 |
| 100.0 | 4.0 | 0.053 | 0.58942 |
Example 3:
the effect of Fingolimod (FTY720) HCl and Curcumol on the induction of apoptosis of MM1S cells alone and in combination was examined using the Annexin V647/PI method.
The experimental steps are as follows:
(1) MM1S cells were collected in the logarithmic growth phase, and the cell suspension concentration was adjusted to 2.5X 105Per mL in a 6-well plate with a total volume of 2mL, then adding 3 μ M Fingolimod (FTY720) HCl, 50ug/mL Curcumol, and a combination of 3 μ M Fingolimod (FTY720) HCl and 50ug/mL Curcumol, respectively, and a DMSO-treated group without drug at a concentration of 0.1% by volume as a control, placing in a cell incubator for incubation for 27 hours;
(2) collecting cells, centrifuging at 2500rpm at 4 deg.C for 5min, washing the cells with pre-cooled DPBS twice, centrifuging at 2500rpm and 4 deg.C for 5min, and collecting 2-3 × 105(ii) individual cells;
(3) add 100. mu.L of 1 XBinding Buffer (Vazyme, Nanjing, China) to resuspend the cells;
(4) adding 5 μ L Annexin V647 (Vazyme, Nanjing, China), mixing, keeping out of the sun, reacting at room temperature for 5 min;
(5) adding 5 μ L of PI staining solution (Vazyme, Nanjing, China), and mixing gently;
(6) add 200. mu.L DPBS, mix gently, transfer it to flow tube, and detect apoptosis with flow cytometer.
The results of the experiment are shown in FIG. 3. The results show that the combined preparation of Fingolimod (FTY720) HCl and Curcumol can remarkably induce the MM1S cells to generate necrosis, and compared with the single use of Fingolimod (FTY720) HCl and Curcumol, the necrosis induction rate of the combined preparation of two medicines is up-regulated by more than 20%.
Example 4:
the cycle arrest of Fingolimod (FTY720) HCl and Curcumol on MM1S cells alone and in combination was detected by PI flow.
The experimental steps are as follows:
(1) MM1S cells were collected in the logarithmic growth phase, and the cell suspension concentration was adjusted to 2.5X 105In 6-well plates, the total volume is 2mL, then 3 μ M Fingolimod (FTY720) HCl, 50 μ g/mL Curcumol, and 3 μ M Fingolimod (FTY720) HCl and 50 μ g/mL Curcumol combined preparation are added respectively, and DMSO-treated group without drug with the volume concentration of 0.1% is used as a control, and the mixture is placed in a cell culture box for incubation for 27 hours;
(2) collecting cells, centrifuging at 2500rpm at 4 deg.C for 5min to collect cells, washing the cells twice with pre-cooled DPBS at 2500rpm each timeCentrifuging at 4 deg.C for 5min, collecting 3-5 × 105(ii) individual cells;
(3) after 300. mu.L of DPBS resuspended cells were added, 300. mu.L of DPBS cell suspension was added dropwise to 700. mu.L of glacial ethanol and fixed at-20 ℃ for 24 hours;
(4) centrifuging at 4 deg.C for 5min at 2500rpm, removing supernatant, adding 500 μ L DPBS for resuspension, centrifuging at 4 deg.C for 5min at 2500rpm, removing supernatant, and adding 200 μ L PI dye solution;
(5) reacting for 30min at room temperature in the dark;
(6) it was transferred to a flow tube and the cycle change was detected by flow cytometry.
The results of the experiment are shown in FIG. 4. The results show that the combined preparation of Fingolimod (FTY720) HCl and Curcumol can remarkably induce the MM1S cells to generate cycle arrest, and compared with the single use of Fingolimod (FTY720) HCl and Curcumol, the cycle arrest effect of the combined preparation is more obvious.
Although the embodiments of the present invention have been described with reference to the accompanying drawings, the scope of the present invention is not limited thereto, and various modifications and variations which do not require inventive efforts and which are made by those skilled in the art are within the scope of the present invention.
Claims (1)
1. The application of the pharmaceutical composition of fingolimod hydrochloride and curcumenol in the preparation of the anti-multiple myeloma medicine; wherein the concentration combination of the fingolimod hydrochloride and the curcumenol is respectively 2 mu M +50 mu g/mL, 2 mu M +100 mu g/mL, 3 mu M +25 mu g/mL, 3 mu M +50 mu g/mL, 3 mu M +100 mu g/mL, 4 mu M +25 mu g/mL, 4 mu M +50 mu g/mL and 4 mu M +100 mu g/mL.
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| CN109394754A (en) * | 2018-12-31 | 2019-03-01 | 中南大学 | A kind of FTY720 and rcumenol combination formulations and its application |
| CN111329849A (en) * | 2020-03-07 | 2020-06-26 | 中南大学 | Pharmaceutical composition of fingolimod hydrochloride and curcumenol and application of pharmaceutical composition in preparation of anti-oral cancer drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109394754A (en) * | 2018-12-31 | 2019-03-01 | 中南大学 | A kind of FTY720 and rcumenol combination formulations and its application |
| CN111329849A (en) * | 2020-03-07 | 2020-06-26 | 中南大学 | Pharmaceutical composition of fingolimod hydrochloride and curcumenol and application of pharmaceutical composition in preparation of anti-oral cancer drugs |
Non-Patent Citations (2)
| Title |
|---|
| FTY720诱导多发性骨髓瘤细胞株U266凋亡的机制研究;廖爱军 等;《中国实验血液学杂志》;20151231;第23卷(第6期);第1623-1627页 * |
| 莪术醇对体外多发性骨髓瘤细胞生物学行为的影响;孙红 等;《中国中西医结合杂志》;20161031;第36卷(第10期);第1229-1234页 * |
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