CN115813991A - Application of citrus fruit extract in preparation of medicine for treating breast cancer endocrine - Google Patents
Application of citrus fruit extract in preparation of medicine for treating breast cancer endocrine Download PDFInfo
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- CN115813991A CN115813991A CN202211509268.9A CN202211509268A CN115813991A CN 115813991 A CN115813991 A CN 115813991A CN 202211509268 A CN202211509268 A CN 202211509268A CN 115813991 A CN115813991 A CN 115813991A
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Abstract
The invention relates to the technical field of medicines, in particular to application of a citrus fruit extract in preparation of a medicine for treating breast cancer endocrine. The invention provides an application of citrus fruit extract in preparing a medicine for treating breast cancer endocrine. The research of the invention finds that the citrus fruit extract is used together with tamoxifen which is an endocrine treatment drug related to anti-estrogen receptor positive breast cancer tumors, so that the sensitivity of tamoxifen can be increased, the treatment dosage of tamoxifen can be reduced, the treatment time can be prolonged, and the problem and side effects of clinical tamoxifen drug resistance can be relieved to a certain extent.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of citrus fruit extract in preparing a medicine for treating breast cancer endocrine.
Background
Estrogen receptor positive breast cancer is a common type of breast cancer, and the disease state is affected by estrogen, and endocrine therapy is generally an effective treatment. Because the ER signal transduction cannot be completely inhibited, the cancer cell proliferation is difficult to effectively inhibit, and the drug resistance problem and the clinical medication are limited, a new small molecule drug for treating the ER positive breast cancer is urgently needed.
Related drugs for endocrine therapy of estrogen receptor positive breast cancer include three major classes, hormone drugs, selective estrogen receptor modulators, aromatase inhibitors. Wherein, the selective estrogen receptor regulator is divided into two subclasses, one is a competitive combined estrogen receptor regulator, and the representative drug is Tamoxifen (Tamoxifen); another class is selective estrogen receptor degraders, the representative drug is Fulvestrant (Fulvestrant). Tamoxifen is the first line drug for endocrine therapy, but with clinical application, the drug resistance problem of tamoxifen is gradually revealed. Although fulvestrant has higher efficacy and lower side effects than tamoxifen, it is effective in prolonging the survival of estrogen receptor positive breast cancer patients treated therewith. But the price is high, and the problems of intramuscular injection, poor solubility, lack of oral availability and the like are added, so that the wide application of the compound is limited. In order to solve the above problems, researchers have searched natural resources for natural compounds or extracts and tamoxifen to carry out drug combination tests, such as digoxin (Chinese pharmacological report, 2021,37, 1256-1263), paclitaxel (modern immunology, 2021,41, 105-110), sinomenine (Chinese modern applied medicine, 2020,37, 2972-2978), resveratrol (Chinese journal of Experimental surgery, 2020,37, 1646-1649), and panaxan (canceration, distortion, mutation, 2013,25, 280-284).
Citrus is the largest class of fruit used as both medicine and food in the world, is an important branch of Rutaceae plants, and is rich in variety resources. The citrus fruits are various in chemical component types, mainly comprise flavonoids, terpenes, coumarins, alkaloids and the like, and mainly comprise flavone components; the biological activity is wide, and various researches on antitumor, anti-inflammatory, antioxidant, antiviral, cardiovascular disease prevention and the like on citrus compounds have been carried out at present.
Therefore, aiming at the scientific problems, the active substance components of citrus fruits are further excavated and developed to be used as a new breast cancer treatment scheme, the development of deep processing of citrus to a large health industry is promoted, and the method has important basic and application basic research values.
Disclosure of Invention
The invention aims to overcome the drug resistance problem of tamoxifen and treat breast cancer by combining tamoxifen. A method for increasing sensitivity of citrus fruit extract to endocrine drug treatment of breast cancer is provided. In particular to a citrus fruit extract, a preparation method thereof and application of the extract in increasing the treatment sensitivity of breast cancer endocrine medicaments.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an application of a citrus fruit extract in preparing a medicine for treating breast cancer endocrine, wherein the main component of the extract is polymethoxyflavone.
Preferably, the polymethoxylated flavones include one or more of 5,7,8,4',5' -pentamethoxylated flavone, 5,6,7,4',5' -pentamethoxylated flavone, 5,6,7,8,3',4' -hexamethoxylated flavone, 3,5,6,7,8,3',4' -heptamethoxylated flavone, and 5,6,7,8,4' -pentamethoxylated flavone.
Preferably, the breast cancer is estrogen receptor positive breast cancer.
Preferably, the drug is tamoxifen.
Preferably, the mass concentration ratio of the extract to the medicine is 25-35: 1.
preferably, the preparation method of the extract comprises the following steps:
(1) Mixing citrus fruit with water, pulverizing, centrifuging for the first time to remove residue to obtain material 1, mixing material 1 with hydrochloric acid, standing, cooling to room temperature, centrifuging for the second time, and collecting precipitate to obtain material 2;
(2) Washing the material 2 obtained in the step (1) with water, centrifuging for three times to obtain a precipitate, adding absolute ethyl alcohol to leach for 2-4 times, combining leaching liquor, concentrating under reduced pressure, and drying to obtain the citrus fruit extract.
Preferably, the citrus fruit in the step (1) is mixed with water at a ratio of 8-12 g:1mL; the rotation speed of the primary centrifugation and the rotation speed of the secondary centrifugation are 8000-12000 rpm independently, and the time is 8-12 min independently; the volume ratio of the material 1 to the hydrochloric acid is 1:1.5 to 2.5; the standing time is 12-16 h.
Preferably, the mass-to-volume ratio of the material 2 to the water in the step (2) is 1g: 8-12 mL, washing for 3 times; the rotating speed of the third centrifugation is 8000-12000 rpm, and the time is 8-12 min; for each leaching, the mass-to-volume ratio of the precipitate to absolute ethyl alcohol is 1g: 1.5-2.5 mL, the leaching temperature is 22-28 ℃, and the leaching time is 12-18 min.
Preferably, the citrus fruit comprises mandarin orange, orange or mandarin orange.
Preferably, the citrus fruit comprises whole fruit, peel or pulp.
Compared with the prior art, the invention has the following beneficial effects:
(1) The research of the invention finds that the citrus fruit extract is used together with tamoxifen which is an endocrine treatment drug related to anti-estrogen receptor positive breast cancer tumors, so that the sensitivity of tamoxifen can be increased, the treatment dosage of tamoxifen can be reduced, the treatment time can be prolonged, and the problem and side effects of clinical tamoxifen drug resistance can be relieved to a certain extent.
(2) The citrus fruit extract provided by the invention is derived from natural components of rue family citrus plants, can be used as an additive component for preparing food, health-care products and medicines, and provides a brand-new solution for deep processing of citrus.
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 embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 shows the results of crystal violet cell staining after co-incubation of the extract of example 1 with MCF7 cells of human breast cancer;
FIG. 2 shows the result of the cell microscopic examination of the extract of example 1 after co-incubation with MCF7 cells of human breast cancer;
FIG. 3 is a plot of the inhibition of cell growth of the extract of example 1 on human breast cancer MCF 7;
FIG. 4 shows the results of crystal violet cell staining of the extract of example 1 in combination with 4-hydroxy tamoxifen (4 OHT) after co-incubation with human breast cancer MCF7 cells;
FIG. 5 is the combination index (CI: combinationIndex; CI <1 synergy; CI >1 antagonism) results of the extract of example 1 in combination with 4-hydroxy tamoxifen after co-incubation with human breast cancer MCF7 cells;
FIG. 6 is the results of tumor tap of SSM2-129 mouse xenograft tumor model treated with the extract of example 1 in combination with tamoxifen;
FIG. 7 is a statistical result of tumor volume of SSM2-129 mouse allograft tumor model treated with the extract of example 1 and tamoxifen;
FIG. 8 is a statistical representation of tumor weights for the SSM2-129 mouse allograft tumor model treated with the extract of example 1 in combination with tamoxifen;
FIG. 9 is a high performance liquid chromatogram and the main chemical components of extract 3-1 of example 1.
The analysis conditions of the high performance liquid chromatography are as follows: the analysis conditions of the high performance liquid chromatography are as follows: the mobile phase is methanol-water, and is eluted from 10% methanol for 5min to 60% methanol, from 60% methanol for 20min to 80% methanol, from 80% methanol for 2min to 100% methanol, and from 100% methanol for 3min; the detection wavelength is 254nm; the flow rate is 1mL/min; the sample injection amount is 10uL; the chromatographic column is InertSustanin AQ-C18,5 μm,4.6 × 250mm (UP); the chromatograph is Shimadzu LC-2030C3DPlus.
Detailed Description
The invention provides an application of a citrus fruit extract in preparing a medicine for treating breast cancer endocrine, wherein the main component of the extract is polymethoxylated flavone; citrus fruit extracts increase the sensitivity of endocrine drug treatment of breast cancer.
In the present invention, the polymethoxyflavone includes one or more of 5,7,8,4',5' -pentamethoxyflavone, 5,6,7,4',5' -pentamethoxyflavone, 5,6,7,8,3',4' -hexamethoxyflavone, 3,5,6,7,8,3',4' -heptamethoxyflavone, and 5,6,7,8,4' -pentamethoxyflavone; preferred are 5,7,8,4',5' -pentamethoxyflavone, 5,6,7,4',5' -pentamethoxyflavone, 5,6,7,8,3',4' -hexamethoxyflavone, 3,5,6,7,8,3',4' -heptamethoxyflavone and 5,6,7,8,4' -pentamethoxyflavone.
In the present invention, the breast cancer is an estrogen receptor positive breast cancer.
In the present invention, the drug is tamoxifen.
In the invention, the mass concentration ratio of the extract to the medicine is 25-35: 1; preferably 27 to 33:1; more preferably 29 to 31:1; more preferably 30.
In the present invention, the preparation method of the extract comprises the following steps:
(1) Mixing citrus fruit with water, pulverizing, centrifuging for the first time to remove residue to obtain material 1, mixing material 1 with hydrochloric acid, standing, cooling to room temperature, centrifuging for the second time, and collecting precipitate to obtain material 2;
(2) Washing the material 2 obtained in the step (1) with water, centrifuging for three times to obtain a precipitate, adding absolute ethyl alcohol to extract for 2-4 times, combining the extract, concentrating under reduced pressure, and drying to obtain an extract of citrus fruits; preferably 3 times.
In the invention, the mixing ratio of the citrus fruit in the step (1) and water is 8-12 g:1mL; preferably 9 to 11g:1mL; more preferably 10g:1mL.
In the invention, the rotation speed of the primary centrifugation and the secondary centrifugation in the step (1) is 8000-12000 rpm independently, and the time is 8-12 min independently; preferably, the rotation speed is 9000-11000 rpm independently, and the time is 9-11 min independently; further preferably, the rotation speed is 10000rpm independently and the time is 10min independently.
In the invention, the volume ratio of the material 1 to the hydrochloric acid in the step (1) is 1:1.5 to 2.5; preferably 1:2.
in the invention, the standing time in the step (1) is 12-16 h; preferably 13 to 15 hours; further preferably 14h.
In the invention, the mass-to-volume ratio of the material 2 to water in the step (2) is 1g: 8-12 mL, washing for 3 times; preferably 1g: 9-11 mL; more preferably 1g:10mL.
The rotating speed of the third centrifugation is 8000-12000 rpm, and the time is 8-12 min; preferably, the rotating speed is 9000-11000 rpm, and the time is 9-11 min; more preferably, the rotation speed is 10000rpm and the time is 10min.
In the invention, in each leaching in the step (2), the mass-to-volume ratio of the precipitate to the absolute ethyl alcohol is 1g: 1.5-2.5 mL; preferably 1g:2mL.
In the invention, the leaching temperature in the step (2) is 22-28 ℃; preferably 23 to 27 ℃; further preferably 24 to 26 ℃; more preferably 25 deg.c.
In the invention, the leaching time in the step (2) is 12-18 min; preferably 13-17 min; more preferably 14 to 16min; more preferably 15min.
In the present invention, the citrus fruit includes mandarin orange, orange or mandarin orange; preferably orange.
In the present invention, the citrus fruit includes whole fruit, peel or pulp; preferably whole fruits.
In the present invention, MCF7, SSM2, T47D-related estrogen receptor positive breast cancer cell lines were used as model cells.
In the present invention, a 129 mouse strain, the fourth breast pad on the right side, was homograft with SSM2 cell line as a model animal.
In the invention, the detection indexes selected in the model are the survival rate and the tumor inhibition rate of the estrogen receptor positive breast cancer cells after the treatment of the drug.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
This example provides a method for preparing an extract from citrus fruit, comprising the steps of:
taking fresh ripe summer oranges, cleaning, airing and weighing 178.8g, adding 18mL of tap water for crushing, centrifuging at 10000rpm for 10min for removing slag to obtain 100mL of liquid, adding 200mL of hydrochloric acid solution with the concentration of 1mol/L, carrying out acidolysis for 14h at 80 ℃, standing, cooling to room temperature, centrifuging at 10000rpm for 10min, collecting precipitate, washing the precipitate with water for 3 times, centrifuging, and mixing according to 1g: adding 5mL of absolute ethanol into the precipitate at a ratio of 2mL, leaching for 3 times, each time for 15min, mixing leaching solutions, concentrating under reduced pressure, drying, and weighing to obtain 189.6mg of citrus fruit extract, which is named as 3-1. The extract mainly comprises the following components: 5,7,8,4',5' -pentamethoxyflavone, 5,6,7,4',5' -pentamethoxyflavone, 5,6,7,8,3',4' -hexamethoxyflavone, 3,5,6,7,8,3',4' -heptamethoxyflavone and 5,6,7,8,4' -pentamethoxyflavone.
Example 2
In the embodiment, the extract in the embodiment 1 and the human estrogen receptor positive breast cancer cells are incubated to obtain MCF7, SSM2 and T47D, which can obviously inhibit the growth of tumor cells. The inhibitory activity of typical human breast cancer MCF7 cells is now described as follows.
The extract of example 1 was incubated with MCF7 cells, human estrogen receptor positive breast cancer cells, for 72 hours, as follows: the estrogen receptor positive breast cancer cells MCF7 cells were seeded in DMEM medium supplemented with 10% fetal bovine serum along with 100units/mL penicillin and 100. Mu.g/mL streptomycin at 37 ℃ and 5% CO 2 Culturing in an incubator. Inoculating the cells into a 96-well plate at a density of 5000 cells per well overnight for complete adherence of the cells, and then adding an estrogen receptor degradation agent to perform co-incubation with the completely adherent cells for 72h. Non-drug added as blank control group, and endocrine treatment drug added 4-hydroxy tamoxifen (4 OHT) as positive control groupThe cells incubated in each group were stained with a crystal violet solution, and the staining results are shown in fig. 1 and the cell microscopic examination results are shown in fig. 2. As can be seen from FIGS. 1 and 2, the estrogen receptor degrader and the human estrogen receptor positive breast cancer cell MCF7 can significantly inhibit the growth of the tumor cells when being incubated together.
The results of the staining of the live crystal violet cells after co-incubation of the extract of example 1 with MCF7 cells, human estrogen receptor positive breast cancer cells, were quantified and dissolved by shaking at room temperature for one hour using a trisodium citrate solution and measuring the absorbance at an absorption wavelength of 570 nm. The measurement results are shown in FIG. 3. As can be seen from FIG. 3, the half inhibitory concentration IC of the estrogen receptor degrading agent and the human estrogen receptor positive breast cancer MCF7 cells 50 The value was 0.06mg/mL.
Example 3
The embodiment uses the extract in example 1 in combination with estrogen receptor positive breast cancer endocrine therapeutic drug 4-hydroxytamoxifen (4 OHT), evaluates the combined effect of the two drugs on the growth inhibition of estrogen receptor positive breast cancer cell lines MCF7, SSM2 and T47D through the combination of the two drugs, and significantly inhibits the growth of tumor cells by the co-incubation of the extract with human estrogen receptor positive breast cancer cells MCF7, SSM2 and T47D which can be used in combination with estrogen receptor positive breast cancer endocrine therapeutic drug 4-hydroxytamoxifen (4 OHT), and calculates the combined index of the extract and estrogen receptor positive breast cancer endocrine therapeutic drug 4-hydroxytamoxifen (4 OHT) to be 0.4-0.8. The following is a description of a typical human breast cancer MCF7 cell-associated effect assay.
The extract of example 1 was incubated with MCF7 cells, human estrogen receptor positive breast cancer cells, for 72 hours, as follows: the estrogen receptor-positive breast cancer cells MCF7 cells were seeded in 96-well plates containing DMEM medium (10% fetal bovine serum, 100units/mL penicillin, 100. Mu.g/mL streptomycin) and placed at 37 ℃ at 5% CO 2 Culturing in an incubator. Inoculating the cells into a 96-well plate culture plate at a density of 5000 cells per well overnight for complete adherence of the cells, and then respectively carrying out half inhibition on the corresponding cells and the corresponding drugs obtained in the embodiment 2System of concentration IC 50 The extract of example 1,4 hydroxy tamoxifen (4 OHT), was added and incubated with fully adherent cells for 72h. The non-drug-added drugs are respectively used as blank control groups, the extract and the endocrine treatment drug 4-hydroxy tamoxifen (4 OHT) are respectively used as single-drug treatment control groups, and the extract and the endocrine treatment drug 4-hydroxy tamoxifen (4 OHT) are respectively used as combined-drug treatment experimental groups. And adding the cells incubated in each group for 72 hours into a crystal violet solution, standing for 40 minutes at room temperature, washing by using a fine slow water flow after dyeing is finished until no dyeing solution remains in each hole of a 96-hole plate, inverting the culture plate, completely absorbing water on a water absorption paper, and observing the dyeing result of the crystal violet solution after natural drying. The staining results are shown in FIG. 4. As can be seen from fig. 4, the extract of example 1, when used in combination with endocrine therapy drug 4-hydroxy tamoxifen (4 OHT), can significantly inhibit the growth of human estrogen receptor positive breast cancer cells MCF 7.
And adding saturated trisodium citrate solution into the 96-well culture plate dyed by the crystal violet living cells, placing the culture plate in a shaking table at room temperature, eluting and dissolving for one hour, and measuring the absorbance value at the absorption wavelength of 570 nm. And calculating the cell proliferation inhibition rate of each group of medicaments by using the measurement result in the same calculation mode as in case 2, and calculating the CI value of the combined inhibition index of the two medicaments by using the cell proliferation inhibition rate corresponding to each concentration of each medicament through CompuSyn software, wherein the CI value is less than 1 to indicate that the two medicaments have remarkable synergistic action, and the CI value is more than 1 to indicate that the two medicaments have remarkable antagonistic action. The results are shown in FIG. 5. As can be seen from FIG. 5, the extract of example 1 had a combination index CI of 0.48 for human estrogen receptor positive breast cancer cells MCF 7.
Example 4
In the present embodiment, the tumor inhibition rate of the fresh citrus orange extract containing polymethoxyflavone as the main component on estrogen receptor positive breast cancer and the combined anti-tumor treatment effect of the fresh citrus orange extract and the endocrine treatment drug tamoxifen are evaluated by an SSM2-129 breast cancer tumor-bearing mouse model. The results are shown in fig. 6-8, and the combination of the fresh orange extract and the endocrine therapy medicament tamoxifen has obvious synergistic effect and has no obvious damage to important organs.
Tumor mouse model establishment: SSM2 cells of human estrogen receptor positive breast cancer cells are divided into 1 × 10 cells 6 The density of each mouse was inoculated in the fourth breast pad on the right side of the 129 mice of the same species (18-20 g). The specific method comprises the following steps: SSM2 cells in the logarithmic growth phase were digested with 0.125% trypsin and centrifuged after cell counting, and the cells were diluted to the desired density with PBS. Subcutaneous tumor nodules of about 0.5cm in diameter were observed at 2 weeks, indicating successful establishment of the tumor mouse model. Grouping and administration treatment: mice were divided into 4 groups of 5 mice according to treatment pattern and dosing trials were started 2 weeks after tumor inoculation. The solvent was used as a control group, the extract and tamoxifen in example 1 were used as a monotherapy group, and the extract and tamoxifen in example 1 were used as a combination therapy experimental group. After the start of dosing, mouse body weights were recorded at 0,1,3,5,7,9, 11d and tumor volumes were recorded using caliper measurements. Weighing the tumor weight after the sacrifice, and calculating the tumor inhibition rate; taking tumors and important organs (heart, liver, spleen, lung and kidney) of each group of mice, fixing the tumors and the important organs with tissue fixing solution, then carrying out paraffin section, and then carrying out H&E staining and observing the effect of the drug on each important organ of the mice. As shown in fig. 6 to 8, the extract of example 1 has an obvious antitumor synergistic effect when used in combination with tamoxifen, an endocrine therapy drug, and has no obvious damage to important organs.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. An application of a citrus fruit extract in preparing a medicine for treating breast cancer endocrine is characterized in that the extract mainly contains polymethoxyflavone.
2. The use of claim 1, wherein the polymethoxylated flavones comprise one or more of 5,7,8,4',5' -pentamethoxylated flavones, 5,6,7,4',5' -pentamethoxylated flavones, 5,6,7,8,3',4' -hexamethoxylated flavones, 3,5,6,7,8,3',4' -heptamethoxylated flavones, and 5,6,7,8,4' -pentamethoxylated flavones.
3. The use of claim 1, wherein the breast cancer is estrogen receptor positive breast cancer.
4. The use of claim 2, wherein the drug is tamoxifen.
5. The use of claim 4, wherein the mass concentration ratio of the extract to the medicament is 25-35: 1.
6. the use according to claim 1, wherein the extract is prepared by a process comprising the steps of:
(1) Mixing citrus fruit with water, pulverizing, centrifuging for the first time to remove residue to obtain material 1, mixing material 1 with hydrochloric acid, standing, cooling to room temperature, centrifuging for the second time, and collecting precipitate to obtain material 2;
(2) Washing the material 2 obtained in the step (1) with water, centrifuging for three times to obtain a precipitate, adding absolute ethyl alcohol to leach for 2-4 times, combining leaching liquor, concentrating under reduced pressure, and drying to obtain the citrus fruit extract.
7. Use according to claim 6, wherein the citrus fruit of step (1) is mixed with water in a ratio of 8 to 12g:1mL; the rotation speed of the primary centrifugation and the rotation speed of the secondary centrifugation are 8000-12000 rpm independently, and the time is 8-12 min independently; the volume ratio of the material 1 to the hydrochloric acid is 1:1.5 to 2.5; the standing time is 12-16 h.
8. The use of claim 6, wherein the mass-to-volume ratio of the material 2 to the water in step (2) is 1g: 8-12 mL, washing for 3 times; the rotating speed of the third centrifugation is 8000-12000 rpm, and the time is 8-12 min; for each leaching, the mass-to-volume ratio of the precipitate to the absolute ethyl alcohol is 1g: 1.5-2.5 mL, the leaching temperature is 22-28 ℃, and the leaching time is 12-18 min.
9. Use according to claim 6, wherein the citrus fruit comprises mandarin, orange or mandarin orange.
10. Use according to claim 6, wherein the citrus fruit comprises whole fruit, peel or pulp.
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