CN114522178A - Application of gambogic acid and doxorubicin hydrochloride in preparation of anti-T cell lymphoma drugs - Google Patents
Application of gambogic acid and doxorubicin hydrochloride in preparation of anti-T cell lymphoma drugs Download PDFInfo
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- CN114522178A CN114522178A CN202210027994.0A CN202210027994A CN114522178A CN 114522178 A CN114522178 A CN 114522178A CN 202210027994 A CN202210027994 A CN 202210027994A CN 114522178 A CN114522178 A CN 114522178A
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- cell lymphoma
- gambogic acid
- doxorubicin hydrochloride
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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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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 discloses an application of gambogic acid and doxorubicin hydrochloride in preparation of a T-cell lymphoma resistant medicament, and belongs to the technical field of biological medicines. The invention discovers that the natural compound Gambogic Acid (GA) can obviously inhibit the growth of T cell lymphoma cells by combining with low-dose doxorubicin hydrochloride. Further, CCK8 experiments prove that the combination of gambogic acid and low-dose doxorubicin hydrochloride can play a synergistic effect on resisting T cell lymphoma, and the application potential of the combined administration on resisting T cell lymphoma is prompted.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of gambogic acid and doxorubicin hydrochloride in preparation of a T-cell lymphoma resistant medicine.
Background
The gambogic acid is an active monomer separated from the traditional Chinese medicine gamboge, and researches show that the gambogic acid has a potential anti-tumor effect and can inhibit various common human tumors such as lung cancer, liver cancer, breast cancer, gastric cancer, melanoma, leukemia and the like. Gambogic acid achieves the effect of resisting solid tumor growth mainly through inducing apoptosis, retarding cell cycle progression, inhibiting cancer cell metastasis, inhibiting angiogenesis and other ways. Besides, the gambogic acid is found to be directly combined with BH3 polypeptide binding sites of six proteins (Bcl-XL, Bcl-2, Bcl-W, Bcl-B, Bfl-1 and Mcl-1) of an anti-apoptotic protein Bcl-2 family, so that the apoptosis of HL-60 cells and Junkat cells of human acute myelocytic leukemia is promoted.
Doxorubicin hydrochloride is an antitumor antibiotic that achieves antitumor effects by inhibiting the synthesis of cancer cell genetic material nucleic acid. The product has wide antitumor spectrum, and can kill various tumor cells. In the invention, gambogic acid is combined with low-dose doxorubicin hydrochloride to exert a synergistic anti-tumor effect, so that a novel treatment strategy is provided for clinical combined medication.
Disclosure of Invention
The invention aims to provide application of gambogic acid and doxorubicin hydrochloride in preparation of a T cell lymphoma resistant medicament.
The invention discovers that the natural compound Gambogic Acid (GA) can obviously inhibit the growth of T cell lymphoma cells by combining with low-dose doxorubicin hydrochloride. Further, CCK8 experiments prove that the combination of gambogic acid and low-dose doxorubicin hydrochloride can play a synergistic effect on resisting T cell lymphoma, and the application potential of the combined administration on resisting T cell lymphoma is prompted.
Drawings
FIG. 1 shows the effect of gambogic acid in combination with low-dose doxorubicin on the growth of T-cell lymphoma cell line Hut-102.
FIG. 2 shows the effect of gambogic acid on the growth of T-cell lymphoma cell line Hut-102.
FIG. 3 shows the effect of adriamycin on the growth of T-cell lymphoma cell line Hut-102.
FIG. 4 shows the effect of gambogic acid in combination with daunorubicin on the growth of T-cell lymphoma cell line Hut-102.
Detailed Description
The invention is described in further detail below with reference to the figures and the specific examples, which should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.
The reagents adopted by the invention are as follows:
1. reagent
(1) Gambogic acid (C)38H44O8Molecular weight: 628.75) was provided by university of Chinese pharmacy, as yellow powder with purity greater than 97%, and the drug powder was made up to 0.01M stock solution with dimethyl sulfoxide (DMSO) before use and stored at-80 ℃.
Adriamycin hydrochloride (C)27H29NO11HCl, molecular weight 579.99) was supplied by the buohu hospital, tokyo, south, white powder, and the drug powder was prepared as a 1mM concentration stock solution with dimethyl sulfoxide (DMSO) before use and stored at-80 ℃ in the dark.
All reagents were prepared to the desired concentration just before use in RPMI-1640 medium containing 10% fetal bovine serum.
(2) Cell culture reagent
Culture solution: RPMI-1640 medium, purchased from GIBCO, USA. 10.39g of RPMI-1640 powder was dissolved in 1000mL of sterile triple distilled water, and 2.0g of NaHCO was added3Adjusting pH to 7.0 with 1M hydrochloric acid, filtering with cylindrical filter, sterilizing, packaging, and storing in refrigerator at 4 deg.C. Before use, 100U/mL penicillin and 100U/mL streptomycin are added.
② fetal bovine serum: product of GIBCO, usa. Inactivating in 56 deg.C water bath for 30min, subpackaging, and storing in-20 deg.C low temperature refrigerator.
③ PBS buffer solution: weighing 8.0g of NaCl, 0.20g of KCl and Na2HPO4·H2O 1.56g、KH2PO4.2.0g, dissolved in 1000mL of triple distilled water, autoclaved, and stored in a refrigerator at 4 ℃.
(3) Cell growth activity inhibition detection related reagent
The CCK8 kit was purchased from Vazyme.
2. Cell line
The human T-cell lymphoma cell line Hut-102 was purchased from Shanghai national academy of sciences cell. Hut-102 cells were cultured in RPMI1640 medium containing 100U/mL penicillin, 100mg/mL streptomycin, and 10% fetal bovine serum.
Example 1
Effect of Gambogic acid in combination with Doxorubicin hydrochloride (DOX) on growth of human T cell lymphoma cells
The CCK-8 cytometric kit (referred to as CCK-8 kit) is a rapid, highly sensitive, non-radioactive colorimetric assay kit that relies on WST-8(2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl)) -2H-tetrazole monosodium salt) for its widespread use in cell proliferation and cytotoxicity assays.
WST-8 can be reduced to a highly water-soluble orange yellow formazan product (formazan) by some dehydrogenases in mitochondria under the action of an electron coupled carrier-Methoxy PMS. The color depth of the generated formazan is in direct proportion to cell proliferation and in inverse proportion to cytotoxicity. The absorbance is measured at a wavelength of 450nm using a microplate reader, and can indirectly reflect the number of living cells, from which the viability of the cells can be detected.
Cells were packed as 1 x 104Culturing the cells per mL in a 96-well enzyme label plate at a cell density, wherein the volume of the cells in each well is 100 mu l, and simultaneously adding 100 mu l of gambogic acid and doxorubicin hydrochloride with specified concentration; after the cells which are given the medicine are continuously placed in an incubator to be cultured for 24 hours, 20 mu l of CCK8 reagent is added into each hole; after further incubation for 4h, the absorbance was measured using a wavelength of 450 nm.
And (3) after the detected light absorption value is finished, calculating the growth inhibition rate of the drug to the cells according to the following formula:
synergy of the two drugs was judged using the Combination Index (CI). CI ═ DA/ICX, A + DB/ICX, B (A, B represents two different drugs, ICX, A and ICX, B is the concentration of the two drugs used alone to achieve a growth inhibition of X, and DA and DB are the concentrations of the two drugs used in combination to achieve a growth inhibition of X). According to the judgment method of Soriano et al, 0.9-1.1 of CI is additive effect, 0.8-0.9 of CI is low-degree synergistic effect, 0.6-0.8 of CI is moderate synergistic effect, 0.4-0.6 of CI is high-degree synergistic effect, and 0.2-0.4 of CI is strong synergistic effect. The results were calculated and counted using the compusyn software.
The inhibitory effect of the natural compound Gambogic Acid (GA) in combination with Doxorubicin hydrochloride (DOXorubicin, DOX) on the growth of the T-cell lymphoma cell line Hut-102 was determined by the CCK8 assay at the 24h time point.
As shown in fig. 1 to fig. 3, gambogic acid in combination with doxorubicin hydrochloride significantly inhibited the growth of T-cell lymphoma cell line Hut-102 cells compared to the doxorubicin hydrochloride alone group, and this result preliminarily confirms the effect of gambogic acid in combination with chemotherapeutic drugs against T-cell lymphoma. The Combination Index (CI) of the two drugs under the action of different concentrations is shown in the table 1, and the CI is less than 0.8, which indicates that the two drugs have synergistic effect.
TABLE 1 Gambogic acid in combination with doxorubicin hydrochloride Combination Index (CI)
| GA(μM) | Doxorubicin(μM) | Cl |
| 0.5 | 0.02 | 5.66865 |
| 0.5 | 0.04 | 0.49052 |
| 0.5 | 0.08 | 0.53052 |
| 0.5 | 0.16 | 0.52913 |
| 0.5 | 0.32 | 0.66206 |
| 0.5 | 0.64 | 0.78683 |
| 0.5 | 1.28 | 1.21209 |
The results show that the natural compound Gambogic Acid (GA) can obviously inhibit the growth of T cell lymphoma cells by combining with low-dose doxorubicin hydrochloride, and a CCK8 experiment proves that the combination of gambogic acid and low-dose doxorubicin hydrochloride can play a synergistic effect on resisting T cell lymphoma, thereby prompting the application potential of the combined administration on resisting T cell lymphoma.
In addition, the results of the research on the gambogic acid combined with daunorubicin against T cell malignancies are shown in Table 2, Table 3 and FIG. 4.
TABLE 2 Gambogic acid-daunorubicin combination index (Cl)
| GA(μM) | Daunorubicin(μM) | Cl |
| 0.5 | 0.16 | 55.926 |
| 0.5 | 0.32 | 14.0929 |
| 0.5 | 0.64 | 2.44071 |
| 0.5 | 1.28 | 0.78003 |
| 0.5 | 2.56 | 0.66741 |
| 0.5 | 5.12 | 1.30780 |
| 0.5 | 10.24 | 2.51019 |
TABLE 3 Gambogic acid-daunorubicin combination index (Cl)
| GA(μM) | Daunorubicin(μM) | |
| 1 | 0.16 | 59.2347 |
| 1 | 0.32 | 15.2139 |
| 1 | 0.64 | 2.74882 |
| 1 | 1.28 | 0.89769 |
| 1 | 2.56 | 0.74486 |
| 1 | 5.12 | 1.38689 |
| 1 | 10.24 | 2.58885 |
From the above results, it is clear that 0.5. mu.M gambogic acid and 1. mu.M combined anthracycline Daunorubicin (Daunorubicin) have no synergistic antitumor effect with human T lymphoma cell line Hut-102.
Claims (3)
1. Application of gambogic acid and doxorubicin hydrochloride in preparation of anti-T cell lymphoma drugs.
2. Use according to claim 1, characterized in that: the molar ratio of gambogic acid to doxorubicin hydrochloride in the anti-T cell lymphoma drug is 0.5: 0.04-0.5: 0.64.
3. use according to claim 2, characterized in that: the molar ratio of gambogic acid to doxorubicin hydrochloride in the anti-T cell lymphoma drug is 0.5: 0.04-0.5: 0.16.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115093434A (en) * | 2022-06-21 | 2022-09-23 | 中国中医科学院中药研究所 | Gambogic acid nanometer preparation and preparation method thereof |
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2022
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115093434A (en) * | 2022-06-21 | 2022-09-23 | 中国中医科学院中药研究所 | Gambogic acid nanometer preparation and preparation method thereof |
| CN115093434B (en) * | 2022-06-21 | 2023-06-23 | 中国中医科学院中药研究所 | Gambogic acid nano preparation and preparation method thereof |
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