CN115006414A - New application of ginsenoside Rg3 - Google Patents
New application of ginsenoside Rg3 Download PDFInfo
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- CN115006414A CN115006414A CN202210666535.7A CN202210666535A CN115006414A CN 115006414 A CN115006414 A CN 115006414A CN 202210666535 A CN202210666535 A CN 202210666535A CN 115006414 A CN115006414 A CN 115006414A
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- A—HUMAN NECESSITIES
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Abstract
The invention provides a new application of ginsenoside Rg3, and particularly relates to an application of the compound or derivatives thereof in preparing a medicine for preventing and/or treating drug-resistant BRAF (V600E) mutant tumors. The inventor finds that the ginsenoside Rg3 can effectively inhibit the proliferation of tumor cells which are resistant to BRAF (V600E) targeted drugs, including inherently and adaptively resistant tumor cells, and inhibit the growth of tumors. The result shows that the ginsenoside Rg3 has potential to be developed into a safe and effective drug-resistant BRAF (V600E) mutant tumor treatment drug.
Description
The application is a divisional application with the application number of 2020106191489, the application date of 2020, 07-01.s, and the invention name of 'new application of parthenolide, luteolin, chrysoeriol and ginsenoside Rg 3'.
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a natural product ginsenoside Rg3 in preparation of a medicine for preventing and/or treating drug-resistant BRAF (V600E) mutant tumors.
Background
Mitogen-activated protein kinases (MAPKs) are key signaling pathways in many cancers. BRAF is an important signaling molecule in the MAPK pathway. The mutation in BRAF was originally described in 2002, with V600E (valine at position 600 replaced by glutamic acid) being its most common mutation. It has been reported that BRAF (V600E) mutations occur in tumors such as papillary thyroid cancer (60.83%), hairy cell leukemia (58.33%), melanoma (48%), anaplastic thyroid cancer (35.96%), serous ovarian cancer (35%), breast cancer (13%), large intestine cancer (8.04%), glioma (6.5%), non-small cell lung cancer (3%), and the like. The mutation can lead to the continuous activation of BRAF, thereby activating RAF-MEK-ERK signaling cascade, promoting cell proliferation and survival, inhibiting apoptosis and finally promoting the progression of cancer.
Currently, BRAF (V600E) targeted inhibitors of Vemurafenib (Vemurafenib), Dabrafenib (Dabrafenib) and the MEK downstream of BRAF inhibitors of Trametinib (Trametinib), cobitinib (Cobimetinib) are approved for the treatment of melanoma and Erdheim-Chester leukemia. Although the clinical efficacy of these inhibitors is significant, patients often develop resistance within 6-8 months. The combined use of a BRAF (V600E) inhibitor and a MEK inhibitor is effective in improving the clinical efficacy of drug resistant patients, but patients also develop resistance to this drug combination after several months of treatment. In addition, patients with BRAF (V600E) mutant colorectal cancer are inherently resistant to BRAF (V600E) inhibitors and are not susceptible to targeted therapy. There is no ideal drug that can reverse the drug resistance of BRAF (V600E) mutant tumor. The drug resistance problem is a difficult problem to solve urgently in the process of treating BRAF (V600E) mutant malignant tumor.
Parthenolide (Parthenolide) belongs to the sesquiterpene compound, and the molecular formula is C 15 H 20 O 3 Molecular weight is 248.32, and structural formula is as follows:
the feverfew extract with parthenolide as the main active ingredient is a common health product for relieving symptoms of migraine, skin or other organ infection, and the parthenolide is better in safety. However, the effect of parthenolide on drug-resistant BRAF (V600E) mutant tumors has not been reported to date.
Luteolin (Luteolin) belongs to flavonoid, and its molecular formula is C 15 H 10 O 6 Molecular weight is 286.24, and structural formula is as follows:
luteolin is contained in flos Lonicerae, flos Chrysanthemi, Perillae herba, etc., and vegetables such as herba Apii Graveolentis, herba Coriandri, etc. The luteolin composite tablet and the luteolin composite capsule which take the luteolin as the main component are health care products for enhancing the immunity of human bodies, and the luteolin is prompted to have better safety. However, no report is available on the effect of luteolin in reversing BRAF (V600E) mutant tumor resistance.
Haloeriol (chrysoeriol) belongs to flavonoid compounds, and its molecular formula is C 16 H 12 O 6 Molecular weight is 300.3, structural formula is as follows:
the chrysoeriol mainly exists in some heat-clearing and detoxifying traditional Chinese medicines such as sweet wormwood herb, chrysanthemum, honeysuckle flower and the like. In the human body, chrysoeriol can be formed by the metabolic conversion of luteolin by catechol-O-methyltransferase. Chrysoeriol has been reported to have anti-tumor effects in breast, lung and multiple myeloma models. However, whether the BRAF (V600E) mutant tumor resistance has the effect of reversing the BRAF mutant tumor resistance is not reported at home and abroad.
Ginsenoside Rg3(Ginsenoside Rg3) belongs to triterpenes, and its molecular formula is C 42 H 72 O 13 The molecular weight is 785.01, and the structural formula is shown as formula (IV).
The ginsenoside Rg3 can be extracted from Ginseng radix. The ginseng-I capsule taking the ginsenoside Rg3 as the main component is approved by the national food and drug administration to be used for the adjuvant treatment of tumor patients. However, it is not clear whether ginsenoside Rg3 can reverse the drug resistance of BRAF (V600E) mutant tumor cells.
At present, no report is provided at home and abroad about whether natural products of parthenolide, luteolin, chrysoeriol and ginsenoside Rg3 can reverse drug resistance of tumor cells to BRAF (V600E) inhibitors.
Disclosure of Invention
Based on the above, the invention aims to provide application of parthenolide, luteolin, chrysoeriol, ginsenoside Rg3 or derivatives thereof in preparation of medicines for preventing and/or treating drug-resistant BRAF (V600E) mutant tumors.
The application of the compound in preparing a medicament for preventing and/or treating drug-resistant BRAF (V600E) mutant tumors; the compound is at least one of parthenolide or a derivative thereof, luteolin or a derivative thereof, eriodictyol or a derivative thereof and ginsenoside Rg3 or a derivative thereof.
In some of these embodiments, the resistant BRAF (V600E) mutant tumor is an acquired resistant BRAF (V600E) mutant tumor.
In some of these embodiments, the resistant BRAF (V600E) mutant tumor is an inherently resistant BRAF (V600E) mutant tumor.
In some of these embodiments, the drug-resistant BRAF (V600E) mutant tumor-resistant BRAF (V600E) targeted drugs.
In some of these embodiments, the drug-resistant BRAF (V600E) mutant tumor is resistant to a MEK targeting drug downstream of BRAF.
In some of these embodiments, the tumor is papillary thyroid carcinoma, leukemia, melanoma, anaplastic thyroid carcinoma, serous ovarian carcinoma, breast carcinoma, large bowel carcinoma, glioma, or non-small cell lung carcinoma.
In some of these embodiments, the medicament comprises the compound and a pharmaceutically acceptable excipient.
In some of these embodiments, the medicament comprises 0.1-99% by weight of the compound.
In some embodiments, the pharmaceutical composition is in the form of tablets, capsules, granules, suspensions, oral liquids, injections or ointments.
In some embodiments, the drug is administered by injection, orally, or topically.
The invention has the beneficial effects that:
the inventor finds that parthenolide, luteolin, chrysoeriol and ginsenoside Rg3 can effectively inhibit the proliferation of tumor cells which are tolerant to BRAF (V600E) targeted drugs, including inherently and adaptively tolerant tumor cells, and inhibit the growth of tumors. The results show that parthenolide, luteolin, chrysoeriol and ginsenoside Rg3 have potential to be developed into safe and effective drugs for treating drug-resistant BRAF (V600E) mutant tumors.
Drawings
FIG. 1 is a graph of the effect of varying concentrations of parthenolide on proliferation of drug resistant BRAF (V600E) mutant melanoma cells;
FIG. 2 is a graph of the effect of various concentrations of luteolin on proliferation of drug-resistant BRAF (V600E) mutant melanoma cells;
fig. 3 is a graph of the effect of varying concentrations of chrysoeriol on proliferation of drug-resistant BRAF (V600E) mutant melanoma cells;
FIG. 4 shows the effect of ginsenoside Rg3 at different concentrations on proliferation of drug-resistant BRAF (V600E) mutant melanoma cells;
FIG. 5 is a graph of the effect of parthenolide on the growth of drug resistant BRAF (V600E) mutant melanoma in nude mice;
fig. 6 is a graph of the effect of chrysoeriol on the growth of drug-resistant BRAF (V600E) mutant melanoma in nude mice.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The embodiment of the invention relates to application of a compound in preparing a medicine for preventing and/or treating drug-resistant BRAF (V600E) mutant tumors; the compound is at least one of parthenolide or a derivative thereof, luteolin or a derivative thereof, eriodictyol or a derivative thereof and ginsenoside Rg3 or a derivative thereof. For example, parthenolide or a derivative thereof is selected alone, luteolin or a derivative thereof is selected alone, eriodictyol or a derivative thereof is selected alone, and ginsenoside Rg3 or a derivative thereof is selected alone, but the invention is not limited thereto, and the above compounds may be used in combination.
Preferably, the resistant BRAF (V600E) mutant tumor is an acquired resistant BRAF (V600E) mutant tumor.
Preferably, the resistant BRAF (V600E) mutant tumor is an inherently resistant BRAF (V600E) mutant tumor.
Preferably, the drug-resistant BRAF (V600E) mutant tumor-resistant BRAF (V600E) targeted drug.
Preferably, the BRAF (V600E) targeted drug is selected from at least one of vemurafenib and dabrafenib.
Preferably, the drug-resistant BRAF (V600E) mutant tumor tolerates a MEK targeting drug downstream of BRAF.
Preferably, the BRAF downstream MEK-targeting drug is selected from at least one of trametinib and cobitinib.
It is understood that the tumor described in the embodiments of the present invention is not limited in kind, and may be any tumor in which BRAF (V600E) mutation exists, including but not limited to: papillary thyroid carcinoma, leukemia, melanoma, anaplastic thyroid carcinoma, serous ovarian carcinoma, breast carcinoma, large intestine carcinoma, glioma, or non-small cell lung carcinoma, among others.
Preferably, the medicament comprises the compound and pharmaceutically acceptable excipients. It is understood that the "adjuvant" as referred to herein may be various carriers, various adjuvants and the like added according to the requirements for preparing a dosage form and the like, including but not limited to diluents, wetting agents, binders, disintegrants, lubricants, color, flavor modifiers, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, topical analgesics, pH modifiers, isotonic or isotonic modifiers, and the like. Further: diluents such as starch, sucrose, celluloses, inorganic salts, etc.; wetting agents such as water, ethanol, and the like; adhesives such as starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone, polyethylene glycol, and the like; disintegrants, such as starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium croscarmellose, crospovidone, surfactants, transpiration disintegrants, and the like; lubricants such as talc, calcium stearate, magnesium lauryl sulfate, colloidal silica, polyethylene glycol, and the like; color, flavor and taste modifiers such as pigment, perfume, sweetener, mucilage, and flavoring agent, specifically fuchsin and xylitol; solvents such as water, oil, ethanol, glycerin, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, ethyl acetate, etc.; solubilizers such as tweens, maizes, polyoxyethylene fatty alcohol ethers, soaps, sulfates, sulfonates, and the like; cosolvents such as organic acids (e.g., citric acid) and salts thereof, amides and amines, inorganic salts, polyethylene glycol, povidone, glycerol, and the like; emulsifying agents, such as span, tween, maize, benze, glycerin fatty acid ester, higher fatty acid salt, sulfate, sulfonate, gum arabic, tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, hydroxide, silica, bentonite, etc.; suspending agents such as glycerol, syrup, acacia, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol, thixotrope, etc.; antioxidants such as sulfites, pyrosulfites, bisulfites, ascorbic acid, gallic acid and esters thereof, and the like; metal complexing agents such as disodium ethylenediaminetetraacetate, polycarboxylic acid compounds, and the like; inert gases such as nitrogen, carbon dioxide, and the like; preservatives, such as parabens, organic acids and salts thereof (e.g., sodium benzoate), quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols, volatile oils, and the like; local analgesics such as benzyl alcohol, chlorobutanol, lidocaine, and procaine; pH regulators such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetate, citric acid, citrate, etc.; isotonic or isotonic regulator, such as glucose, sodium chloride, sodium citrate, sorbitol, xylitol, etc.
Preferably, the medicament comprises 0.1-99% of the compound by mass.
The invention can be prepared into any dosage form of tablets, capsules, granules, suspensions, oral liquid, injections, paste and the like. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field. The present invention is not limited by the above listed dosage forms.
The drugs of the present invention may be administered by injection, orally or by external application, and the administration route is not limited by the above examples.
Parthenolide, luteolin, and ginsenoside Rg3 used in this example were obtained from Won Massa Biotechnology Ltd (China) and Halloween was obtained from Extrasynthese (France). The four natural products have purity of more than 98% by HPLC detection.
The present invention will be further described with reference to specific examples so that those skilled in the art may better understand the present invention, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above-described contents of the present invention belong to the scope of the present invention.
Example 1 varying concentrations of parthenolide, luteolin, chrysoeriol and ginsenoside Rg3 to resistance
Effect of BRAF mutant melanoma cell proliferation
1.1 Experimental materials
(1) Parthenolide: purchased from Kyormant Biotech, Inc.; accurately weighing a certain amount of parthenolide, dissolving with dimethyl sulfoxide (DMSO) to obtain 20mM parthenolide solution (mother liquor), subpackaging, and placing in a refrigerator at-20 deg.C for use.
(2) Luteolin: purchased from Kyormant Biotech, Inc.; accurately weighing a certain amount of luteolin, dissolving with dimethyl sulfoxide (DMSO) to obtain 80mM luteolin solution (mother liquor), subpackaging, and placing in a refrigerator at-20 deg.C for use.
(3) Chrysoeriol: available from Extrasynthese company; precisely weighing a certain amount of Halloween, dissolving with dimethyl sulfoxide (DMSO) to obtain Halloween solution (mother solution) of 40mM, subpackaging, and storing in refrigerator at-20 deg.C for use.
(4) Ginsenoside Rg 3: purchased from Kyormant Biotech, Inc.; precisely weighing a certain amount of ginsenoside Rg3, dissolving in dimethyl sulfoxide (DMSO) to obtain 60mM ginsenoside Rg3 solution (mother liquor), packaging, and refrigerating at-20 deg.C.
(5) Vemurafenib: manufactured by LC Laboratories, Inc.; precisely weighing a certain amount of vemurafenib, dissolving into 1mM vemurafenib solution (mother solution) by DMSO, subpackaging, and placing in a refrigerator at-20 ℃ for later use.
(6) A375 cell line [ human melanoma cells carrying BRAF (V600E) mutation ]: purchased from ATCC cell bank, usa, and stored in liquid nitrogen.
(7) Cells resistant to acquired vemurafenib a 375-VR: a375 cells were cultured in DMEM with 5% FBS and increasing concentrations (0.1. mu.M → 1. mu.M) of Verofinib for 3 months to give Verofinib resistant melanoma cells A375-VR, which were subsequently cultured in DMEM with 1. mu.M of Verofinib and 5% FBS to maintain resistance.
(8) A2058 cell line [ human melanoma cells carrying a BRAF (V600E) mutation; intrinsic resistance to BRAF (V600E) inhibitor ]: purchased from ATCC cell bank, usa, and stored in liquid nitrogen.
(9) HaCaT human immortalized keratinocytes: purchased from ATCC cell bank, usa, and stored in liquid nitrogen.
(10) HDFa human dermal fibroblasts: purchased from ATCC cell bank, usa, and stored in liquid nitrogen.
(11) Fibroblast growth kit: purchased from ATCC company, usa.
(12) DMEM medium powder: manufactured by Gibco corporation of usa.
(13) 0.5% Trypsin-EDTA (10X) (Trypsin): 100 mL/bottle, manufactured by Gibco, USA.
(14) Fetal bovine serum: 500 mL/bottle, manufactured by Gibco, USA.
(15) 96-well flat-bottom culture plates: manufactured by the Korea SPL company;
(16) MTT reagent powder: manufactured by Affymetrix corporation.
1.2 Experimental instruments
(1) A carbon dioxide incubator: model nu-4750e, manufactured by Nuaire corporation.
(2) A centrifuge: centrifuge model 5702, manufactured by Eppendorf corporation.
(3) The biological safety cabinet: nu-425 and 400e, manufactured by Nuaire.
(4) An electronic balance: manufactured by Mettler Toledo corporation.
(5) And (3) inverting the microscope: manufactured by Leica corporation.
(6) A water bath device: WNB 14, manufactured by Memmert GmbH + Co.
(7) Microplate reader: manufactured by BIO-RAD corporation.
1.3 Experimental methods and results
(1) Adjusting the cell suspension concentration to 3X 10 3 Per well, adding into 96-well culture plate, placing 100 μ L per well at 37 deg.C with 5% CO 2 The cell culture box was cultured for 24 hours.
(2) The old culture medium is removed by suction, 5% FBS corresponding cell culture media containing different drug concentrations are added, a control group and a zero adjustment group are arranged, each group is provided with 5 multiple wells, and the culture is continued for 24 hours.
Parthenolide addition group: the final concentration of the drug in the medium was 1.25. mu.M, 2.5. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, respectively.
Luteolin adding medicine group: the final concentration of the drug in the culture medium was 5. mu.M, 10. mu.M, 20. mu.M, 40. mu.M, 80. mu.M, respectively.
Jinshengmu medicine adding group: the final concentration of the drug in the medium was 5. mu.M, 10. mu.M, 20. mu.M, 30. mu.M, 40. mu.M, respectively.
Ginsenoside Rg3 dosing group: the final concentration of the drug in the culture medium was 20. mu.M, 30. mu.M, 40. mu.M, 50. mu.M, and 60. mu.M, respectively.
Control group: a culture medium containing 1 per mill of DMSO is adopted.
And (3) zero setting group: and (4) no cells are added, and culture media with different drug concentrations or culture media containing 1 thousandth of DMSO are added in the same volume as the additive group and the control group.
(3) After the administration, MTT solution at a concentration of 5mg/mL was added to each well in an amount of 10. mu.L, and after 4 hours, the supernatant was aspirated, 100. mu.L of DMSO solution was added thereto, and the mixture was shaken for 10 minutes to dissolve the crystals sufficiently. The OD of each well was measured at 570 nm.
Cell viability was calculated using the following formula:
the cell survival rate is [ (the OD average value of the drug addition group-the OD average value of the zeroing well)/(the OD average value of the control group-the OD average value of the zeroing well) × 100% ]; wherein:
the average value of the addition medicine groups OD is the sum of the addition medicine groups OD value/the number of the addition medicine groups;
the average value of the zero-setting holes OD is equal to the sum of the OD values of all the zero-setting holes/the number of the zero-setting holes;
the average value of the control group OD is equal to the OD value of each control group/the number of blank control groups;
the OD value is the optical density absorbed by the detected object, and is used for directly reading data on an instrument.
The experiment was repeated 3 times. The results are shown in FIGS. 1, 2, 3 and 4.
As can be seen from fig. 1, parthenolide significantly inhibited the proliferation of melanoma cells resistant to both acquired vemurafenib (a375-VR) and intrinsic (a2058) resistance, and had a dose-effect relationship; and has less killing effect on human normal dermal fibroblasts HDFa.
As can be seen from FIG. 2, luteolin significantly inhibits proliferation of A375-VR melanoma cells resistant to acquired vemurafenib, and has a dose-effect relationship; and has less killing effect on human normal dermal fibroblasts HDFa.
As can be seen from fig. 3, chrysoeriol significantly inhibited the proliferation of a375-VR melanoma cells that were resistant to vervafenib acquired, and had a dose-effect relationship; and the killing effect on human keratinocyte HaCaT is small.
As can be seen from fig. 4, ginsenoside Rg3 significantly inhibited the proliferation of a375-VR melanoma cells that are resistant to vemurafenib acquired, and had a dose-effect relationship; and the killing effect on human keratinocyte HaCaT is small.
Example 2 Effect of parthenolide on growth of drug-resistant BRAF (V600E) mutant melanoma in nude mice
2.1 Experimental materials
Experimental animals: male BALB/c-nu/nu nude mice (about 8 weeks in size) were provided by the animal testing center, university of Chinese, hong Kong. The experiment was conducted 1 week after free intake of drinking water in a constant temperature, constant pressure, sterile environment at the laboratory animal center of hong Kong university of Dipper.
A375-VR cells resistant to acquired Verofinib: vemurafenib resistant melanoma cells a375-VR were established in example 1, and subsequently the cells were cultured in DMEM containing 1 μ M vemurafenib and 5% FBS to maintain their resistance.
Parthenolide intraperitoneal injection: weighing 5mg parthenolide, dissolving in 1mL DMSO, diluting with PBS to 20mL to obtain 0.25mg/mL parthenolide solution, filtering, sterilizing, packaging, and storing in 4 deg.C refrigerator.
Vemurafenib intraperitoneal injection: weighing 12.5mg of vemurafenib, dissolving in 0.5mL of DMSO, diluting to 10mL with PBS to obtain 1.25mg/mL of vemurafenib solution, filtering, sterilizing, packaging, and storing in a refrigerator at 4 ℃.
2.2, experimental methods and results:
A375-VR cells (concentration 3X 10) 6 ) Resuspended in 0.1mL Phosphate Buffered Saline (PBS) and inoculated subcutaneously into the back of BALB/c-nu/nu nude mice.
In the case of tumor growth to about 50mm 3 At that time, the mice were randomly divided into 3 groups of 4 mice each and dosing was started. Wherein: one group is a vemurafenib group, and the vemurafenib is injected into the abdominal cavity of the mouse at 10 mg/kg/day every day; one group is a parthenolide group, and 2 mg/kg/day of parthenolide is administered to the abdominal cavity of the mice every day; one group was a control group: mice were given daily intraperitoneal injections of PBS solution containing 5% DMSO; the administration was continued for 21 days.
At the end of the experimental period, mice were weighed, sacrificed, solid tumors were exfoliated, tumor weight was weighed, and tumor inhibition rate (%) was calculated, and the results are shown in fig. 5.
The tumor weight of the nude mice of the parthenolide group is obviously lower than that of the control group (P <0.01), the inhibition rate of the parthenolide on the A375-VR tumor growth is 86.61%, and the body weight of the nude mice has no obvious influence, so that the parthenolide can safely and effectively inhibit the growth of the Verofinib-resistant melanoma.
Example 3 Effect of Halichorin on growth of BRAF (V600E) mutant melanoma resistant in nude mice
3.1 Experimental materials
Experimental animals: male BALB/c-nu/nu nude mice (about 8 weeks in size) were provided by the animal testing center, university of Chinese, hong Kong. The experiment was conducted 1 week after free intake of drinking water in a constant temperature, constant pressure, sterile environment at the laboratory animal center of hong Kong university of Dipper.
A375-VR cells resistant to acquired Verofinib: vemurafenib resistant melanoma cells a375-VR were established in example 1, and subsequently the cells were cultured in DMEM containing 1 μ M vemurafenib and 5% FBS to maintain their resistance.
Jinshengmu intraperitoneal injection: weighing 25mg of chrysoeriol, dissolving in 20mL of PBS solution containing 5% PEG400 and 5% Tween 80 to obtain 1.25mg/mL chrysoeriol solution, filtering, sterilizing, packaging, and storing in refrigerator at 4 deg.C.
Trametinib intraperitoneal injection: weighing 2.5mg trametinib, dissolving in 10mL PBS solution containing 5% PEG400 and 5% Tween 80 to obtain 0.25mg/mL trametinib solution, filtering, sterilizing, packaging, and storing in refrigerator at 4 deg.C.
3.2, experimental methods and results:
A375-VR cells (concentration 3X 10) 6 ) Resuspended in 0.1mL Phosphate Buffered Saline (PBS) and inoculated subcutaneously into the back of BALB/c-nu/nu nude mice.
Mice were randomly divided into 4 groups of 4 mice on the first day after cell inoculation and dosing was started. Wherein: one group is a chrysoeriol group, and the chrysoeriol is injected into the abdominal cavity of the mouse by 10mg/kg every day; one group is a trametinib group, and 2mg/kg of trametinib (positive control group) is injected into the abdominal cavity of a mouse every day; one group was a control group, and mice were given 2mg/kg of PBS solution containing 5% PEG400 and 5% Tween 80 per day for intraperitoneal injection; the administration was continued for 14 days.
At the end of the experimental period, mice were weighed, sacrificed, solid tumors were exfoliated, tumor weight was weighed, and tumor inhibition rate (%) was calculated. Fig. 6 shows the largest and smallest tumors in each group.
The tumor weight of the nude mice of the Jineriodictyol group and the trametinib group is obviously lower than that of the control group (P <0.05), the inhibition rate of the Jineriodictyol on the A375-VR tumor growth is 59.8%, and the tumor weight of the nude mice has no obvious influence on the weight of the mice, which indicates that the Jineriodictyol can safely and effectively inhibit the growth of the melanoma resistant to the Verofinib.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The application of the ginsenoside Rg3 or the derivative thereof in preparing the medicine for preventing and/or treating drug-resistant BRAF (V600E) mutant tumors.
2. The use according to claim 1, wherein said resistant BRAF (V600E) mutant tumor is an acquired resistant BRAF (V600E) mutant tumor.
3. The use according to claim 1, wherein said drug-resistant BRAF (V600E) mutant tumor is an inherently drug-resistant BRAF (V600E) mutant tumor.
4. The use according to any of claims 1 to 3, characterized in that said drug-resistant BRAF (V600E) mutant tumor-resistant BRAF (V600E) targeted drug.
5. The use according to any of claims 1 to 3, wherein said drug-resistant BRAF (V600E) mutant tumor-tolerant BRAF downstream MEK-targeting drug.
6. Use according to any one of claims 1 to 3, wherein the tumour is papillary thyroid carcinoma, leukaemia, melanoma, anaplastic thyroid carcinoma, serous ovarian carcinoma, breast carcinoma, carcinoma of the large intestine, glioma or non-small cell lung carcinoma.
7. Use according to any one of claims 1 to 3, characterized in that the medicament comprises the compound and a pharmaceutically acceptable adjuvant.
8. Use according to claim 7, wherein the medicament comprises the compound in an amount of 0.1-99% by mass.
9. Use according to any one of claims 1 to 3 and 8, wherein the medicament is in the form of tablets, capsules, granules, suspensions, oral liquids, injections or ointments.
10. Use according to any one of claims 1 to 3 and 8, wherein the medicament is administered by injection, orally or topically.
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