CN117018056A - A composition prepared from fructus Psoraleae and herba Epimedii for treating cancer - Google Patents

A composition prepared from fructus Psoraleae and herba Epimedii for treating cancer Download PDF

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Publication number
CN117018056A
CN117018056A CN202310794973.6A CN202310794973A CN117018056A CN 117018056 A CN117018056 A CN 117018056A CN 202310794973 A CN202310794973 A CN 202310794973A CN 117018056 A CN117018056 A CN 117018056A
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psoralen
cancer
epimedin
composition
icariside
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李国辉
李春雨
曹波
李蓥滢
林蒙蒙
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Cancer Hospital and Institute of CAMS and PUMC
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Cancer Hospital and Institute of CAMS and PUMC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/487—Psoralea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
    • A61K36/296—Epimedium
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present application relates to a composition for treating cancer, comprising a component derived from psoralea fruit and a component derived from epimedium, such as psoralen and icariside ii, epimedin B or epimedin C. The application digs the components of the psoralea and the epimedium medicinal materials, and determines the synergistic effect of the components in the psoralea and the epimedium on treating cancers. The composition of the present application inhibits cell proliferation against various common cancers such as liver cancer, lung cancer, breast cancer, etc., and thus it can be effectively used for treating cancer.

Description

A composition prepared from fructus Psoraleae and herba Epimedii for treating cancer
Technical Field
The application belongs to the fields of natural medicines and tumor treatment, and particularly provides a composition derived from fructus psoraleae and epimedium for treating cancers.
Background
Herba Epimedii and fructus Psoraleae are common tonic Chinese medicinal herbs, both of which are pungent and warm in nature and can warm and tonify kidney yang, and are combined with other deficiency-tonifying herbs to be used in prescriptions for treating deficiency of kidney yang, deficiency of liver and kidney, deficiency of lung and kidney qi or deficiency of spleen and kidney yang. Fructus Psoraleae has effects of warming kidney, supporting yang, warming spleen, and relieving diarrhea, and is a common traditional Chinese medicine for treating kidney-spleen yang deficiency. Psoralen is coumarin and coumarin related benzofuran glycoside, and has antioxidant, antitumor and antibacterial effects. The research shows that the psoralen can inhibit proliferation of SMMC-7721 cells of human liver cancer, MCF-7 cells of human breast cancer and MDA-MB-231 cells, promote apoptosis, and suggest that the psoralen is a novel treatment method for preventing and treating liver cancer. In view of the above, fructus Psoraleae has great potential for treating tumors, and further research is necessary to explore the anti-tumor effect of fructus Psoraleae.
Herba Epimedii is the key herb for warming yang and tonifying kidney, and research shows that herba Epimedii can inhibit the migration of mononuclear malignant glioma cells. Icariin is a compound extracted from Epimedium plants, and research shows that ICA induces B16 mouse melanoma cell differentiation by inhibiting ERK1/2-p38-JNK dependent pathway, so that cell cycle is blocked in G0/G1 phase. Researches show that icariin can induce apoptosis of ovarian cancer cells of xenograft tumor and inhibit tumor growth. The research shows that icariin has anti-tumor effect in vitro and in vivo in P815 tumor-bearing mice, and can up-regulate LMP/TAP related molecules and induce MHC-I expression, thereby enhancing immune monitoring, relieving tumors, and indicating that icariin can become an effective antigen adjuvant for tumor treatment. The research shows that the epimedium is hopeful to provide clues for the treatment of related tumors and can provide new opportunities for the treatment of tumors in future.
Disclosure of Invention
Since the chemical substances in the fructus psoraleae and the herba epimedii for inducing cancer cells are not clear, the fructus psoraleae and the herba epimedii are required to be screened for anti-tumor active ingredients. The research is used for excavating the components of the medicinal materials of the epimedium and the fructus psoraleae, and aims to clarify the material basis of the synergistic treatment of the components in the fructus psoraleae and the epimedium so as to provide guidance and support for the prevention and treatment of the cancers of the fructus psoraleae and the epimedium and lay a foundation for guiding the research and development of original innovative medicaments of the traditional Chinese medicines and the clinical reasonable medicaments.
In one aspect, the present application provides a composition for treating cancer comprising a component derived from fructus Psoraleae and a component derived from herba Epimedii.
Further, the components derived from fructus Psoraleae are selected from one or more of bakuchiol, psoralen, isopsoralen, neo-psoralen, psoralen-dihydroflavone methyl ether, psoralen, and psoralen.
Further, the component derived from epimedium is selected from one or more of icariin, icaritin, icariside I, icariside II, epimedin A1, epimedin B, epimedin C, dehydrated icaritin and icariside A.
Further, the component derived from fructus Psoraleae is psoralen, and the component derived from herba Epimedii is icariside II, epimedin B or epimedin C.
Further, the effective component in the composition is psoralen, icariside II, epimedin B or epimedin C; preferably, no other active ingredient is included in the composition.
Further, the weight ratio of psoralen to icariside II, epimedin B or epimedin C in the composition is 8:1-1:2.
Further, the weight ratio of psoralen to icariside II, epimedin B or epimedin C in the composition is 4:1-1:2.
Further, the weight ratio of psoralen to icariside II in the composition is 2:1; alternatively, the weight ratio of psoralen to epimedin B in the composition is 2:1; alternatively, the weight ratio of psoralen to epimedin C in the composition is 1:1.
In another aspect, the application provides the use of the above composition in the manufacture of a medicament for the treatment of cancer.
Further, the cancer is liver cancer, lung cancer, breast cancer, ovarian cancer, stomach cancer, colorectal cancer, kidney cancer, thyroid cancer, pancreatic cancer, prostate cancer, and bladder cancer.
Further, the cancer is liver cancer.
The composition of the application is in any clinically acceptable dosage form. Including various dosage forms for oral and parenteral administration. For oral administration, the composition can be tablet, capsule, soft capsule, oral liquid, syrup, granule, dripping pill, orally disintegrating tablet, sustained release capsule, controlled release tablet, controlled release capsule, etc.; when used for parenteral administration, the composition can be water injection, freeze-dried powder injection, sterile powder injection, infusion solution and the like.
Those skilled in the art can construct the above dosage forms using various pharmaceutically acceptable carriers or excipients, such as solvents, co-solvents, pH adjusting agents, osmotic pressure adjusting agents, stabilizers, antioxidants, fillers, binders, lubricants, disintegrants, coating agents, sustained release agents, controlled release agents, adsorption carriers, and the like.
Drawings
FIG. 1A shows the cytostatic rates of psoralen at various concentrations;
FIG. 1B shows the cytostatic rates of bakuchiol at various concentrations;
FIG. 1C shows the cytostatic rates of psoralen at various concentrations;
FIG. 1D shows the cytostatic rates of isopsoralen at different concentrations;
FIG. 1E shows the cytostatic rates of psoralen at different concentrations;
FIG. 1F shows the cytostatic rates of isopsoralen at different concentrations;
FIG. 1G shows the cell inhibition of psoralen at various concentrations;
FIG. 1H shows the cytostatic rates of psoralen at various concentrations;
FIG. 1I shows the cytostatic rates of isopsoralen flavanone at various concentrations;
FIG. 1J shows the cytostatic rates of the novel psoralen isoflavones at different concentrations;
FIG. 1K shows the cytostatic rates of bavachin methyl ether at various concentrations;
FIG. 2A shows the cell inhibition rate of icariin and icaritin;
FIG. 2B shows the cell inhibition rate of icariside I and icariside II;
FIG. 2C shows the cell inhibition of epimedin A, epimedin A1;
FIG. 2D shows the cell inhibition of epimedin B, C;
FIG. 2E shows the cell inhibition rates of anhydroicaritin and icariin A;
FIG. 3A shows the cell inhibition of psoralen in combination with 8.33. Mu.M epimedium monomer;
FIG. 3B shows the values of the formula q for psoralen in combination with 8.33. Mu.M of epimedium monomer;
FIG. 3C shows the cell inhibition of psoralen in combination with 16.67. Mu.M epimedium monomer;
FIG. 3D shows the value of the formula q for psoralen in combination with 16.67. Mu.M of epimedium monomer;
FIG. 3E shows the cell inhibition of psoralen in combination with 33.33. Mu.M epimedium monomer;
FIG. 3F shows the value of the formula q for psoralen in combination with 33.33. Mu.M of epimedium monomer;
FIG. 3G shows the cell inhibition of psoralen in combination with 66.67. Mu.M epimedium monomer;
FIG. 3H shows the values of the formula q for psoralen in combination with 66.67. Mu.M of epimedium monomer;
FIG. 4A shows the cytostatic rate of psoralen in combination with epimedin B;
FIG. 4B shows the cytostatic rate of psoralen in combination with icariside II;
FIG. 4C shows the cytostatic rate of psoralen in combination with epimedin C;
FIG. 4D shows the values of the gold equation q for psoralen in combination with epimedin B, icariside II, and epimedin C;
FIG. 5A shows the effect of psoralen in combination with icariside II on tumor quality;
FIG. 5B shows the effect of psoralen in combination with icariside II on tumor volume;
FIG. 5C shows the effect of psoralen in combination with icariside II on mouse body weight;
FIG. 5D shows the effect of psoralen in combination with icariside II on organ coefficients.
Detailed Description
Example 1 materials and basic methods
1. Cell culture
HepG2 cells respond similarly to primary mouse hepatocytes and primary human hepatocytes. The culture medium used for HepG2 cells was DMEM medium containing 10% fetal bovine serum and 1% penicillin, and was cultured in a humidified incubator at 37 ℃ with 5% carbon dioxide. The experiment was performed using 3-7 passages of cells and only cells with a viability of greater than 90% were used.
2. Preparation of medicaments
Selecting 11 fructus Psoraleae monomer components, namely bakuchiol, psoralen, bakuchiol, isopsoralen, psoralen, isopsoralen, new psoralen isoflavone, psoralen dihydroflavone methyl ether, psoralen and psoralen B, and 10 herba Epimedii monomer components, namely icariin, icariside I, icariside II, epimedin A1, epimedin B, epimedin C, dehydrated icariside and icariside A, and screening. Precisely weighing appropriate amount of each reference substance, dissolving with cell-grade DMSO, preparing into 50mg/mL mother liquor, subpackaging, and storing at-80deg.C.
3. Cytotoxicity assays
HepG2 cells at 9×10 4 The cells/well density was inoculated in 96-well plates, and the cells were dosed after incubation in an incubator for 24 hours using complete medium. After 24h exposure of the cells to the drug or DMEM, absorbance (a) was detected with a microplate reader at 450nm using CCK8 kit. Experiments were repeated 3 times. And then calculating the inhibition rate of the drug to the HepG2 cell according to a formula. The inhibition ratio of the cells was calculated as follows.
Cell inhibition% = (a Is not added with medicine －A Dosing )/(A Is not added with medicine －A Blank space )×100％
In the formula A Is not added with medicine Indicating that it is not addedAbsorbance values for drug groups (containing cells and CCK-8 solution); a is that Dosing Absorbance values representing the dosing group (containing cells, drug and CCK-8 solution); a is that Blank space Absorbance values are shown for the blank (CCK-8 solution only).
The combined drug effect is evaluated according to the golden formula: q value=e (a+b) /(E a +E b –E a ×E b )，E a+b Tumor inhibiting rate, E a 、E b Tumor inhibition rate, q for single use of two drugs>1.15 shows that the two medicaments act synergistically; q<0.85 indicates that the two drugs act antagonistically; q is 0.85-1.15, which means that the two drugs act together.
4. Animal experiment verification
Establishing a HepG2 liver cancer animal model: each mouse was inoculated subcutaneously with HepG2 cells (2X 10) 5 days after 18-20g BALB/c-nu male mice were fed adaptively 7 ) After two weeks, the tumor growth was seen (50-100 mm 3 ). Tumor mice were randomly divided into 4 groups: model group, psoralen group, icariside II group and combination group. The dosing groups were drawn and statistically data after 14 days of continuous dosing: (1) tumor volume and weight: the length and width of each group of mouse tumors were measured using vernier calipers, and the length/width was measured using the formula (length x width 2 ) 2, calculating the tumor volume; the tumor weights of the mice in each group are weighed by using a balance and recorded, thus obtaining the tumor weight. (2) Tumor inhibition rate: the average (m 1) of the tumor weights of the mice in each group and the average (m) of the tumor weights of the mice in the model group were calculated 2 ) According to the formula (1-m 1/m 2 ) Calculating the X100 percent to obtain the tumor inhibition rate of each administration group. (3) Organ coefficients: the weight of each organ tissue such as heart, liver, spleen, lung, kidney, etc. of the mouse is weighed and divided by the weight of the corresponding mouse, and the percentage of each organ, namely the coefficient of each organ, is calculated. All experiments and procedures involving mice were performed according to guidelines of the animal ethics committee of tumor hospitals of the national academy of medical science.
The measurement data are expressed by Mean ± standard deviation (Mean ± SD), the comparison between the groups is by one-way ANOVA, the comparison between the two groups is by t-test, p <0.05 indicates significant differences, and p <0.01 indicates extremely significant differences.
EXAMPLE 2 experimental results
As shown in FIGS. 1A-K, psoralen and psoralen are components in the psoralen in a certain concentration range, cytotoxicity is in a dose-dependent relationship, and the inhibition rate of the psoralen is larger at a low dose, so that the psoralen is selected for subsequent researches.
As shown in FIGS. 2A-E, the ingredients in epimedium have little effect on HepG2 cell growth at low concentrations. The icariside II has strong effect on inhibiting the growth of HepG2 cells in a higher concentration range and has a dosage relationship.
Psoralen (33.33 mu M) at nontoxic concentration is respectively combined with 10 kinds of epimedium monomers at different concentrations to determine the cell inhibition rate and the q value of a gold formula. As shown in FIGS. 3A-H, icariside II has synergistic inhibition effect (q.gtoreq.1.15) in combination with psoralen at doses of 8.33 and 16.67. Mu.M; both epimedin B and epimedin C have synergistic inhibition effect (q.gtoreq.1.15) in combination with psoralen at doses of 8.33, 16.67, 33.33 and 66.67. Mu.M. In conclusion, icariside II, epimedin B, epimedin C and psoralen with different concentrations have synergistic inhibition effect on HepG2 cell growth after being combined. In addition, icariside II, epimedin B and epimedin C were the largest in the gold formula q values when 16.67. Mu.M, 16.67. Mu.M and 33.33. Mu.M were combined with psoralen (33.33. Mu.M), respectively. Preferably, the optimal concentration ratios of psoralen to icariside ii, epimedin B and epimedin C are respectively: 2: 1. 2:1, 1:1.
To further screen the optimal composition, in vitro validation was performed on the compositions (psoralen + epimedin B, psoralen + epimedin C, psoralen + icariside ii) at different concentration gradients. As shown in figures 4A-D, the synergistic inhibition effect of psoralen and icariside II on HepG2 cell growth is the strongest (q is more than or equal to 1.15) after the final determination.
As shown in fig. 5A-D, mice were significantly reduced in tumor mass and volume (p < 0.01) with no significant change in body weight and organ coefficients after administration of psoralen in combination with icariside ii, as compared to psoralen or icariside ii alone. In vivo experiments further prove that the composition of psoralen and icariside II has better anti-liver cancer effect.

Claims (10)

1. A composition for treating cancer, comprising a component derived from malaytea scurfpea fruit and a component derived from epimedium herb.
2. The composition of claim 1, wherein the ingredient derived from psoralen is selected from one or more of bakuchiol, psoralen, isopsoralen, neopsoralen, psoralen dihydroflavone, psoralen methyl ether, psoralen, and psoralen.
3. The composition according to claim 1 or 2, wherein the component derived from epimedium is selected from one or more of icariin, icaritin, icariside i, icariside ii, epimedin A1, epimedin B, epimedin C, anhydroicaritin and icariin a.
4. The composition of claim 1, wherein the psoralea-derived component is psoralen and the epimedium-derived component is icariside ii, epimedin B or epimedin C.
5. The composition of claim 4, wherein the weight ratio of psoralen to icariside ii, epimedin B, or epimedin C in the composition is 8:1-1:2.
6. The composition of claim 5, wherein the weight ratio of psoralen to icariside ii, epimedin B, or epimedin C in the composition is 4:1-1:2.
7. The composition of claim 6, wherein the weight ratio of psoralen to icariside ii in the composition is 2:1; alternatively, the weight ratio of psoralen to epimedin B in the composition is 2:1; alternatively, the weight ratio of psoralen to epimedin C in the composition is 1:1.
8. Use of a composition according to any one of claims 1-7 in the manufacture of a medicament for the treatment of cancer.
9. The use of claim 8, wherein the cancer is liver cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, colorectal cancer, renal cancer, thyroid cancer, pancreatic cancer, prostate cancer, or bladder cancer.
10. The use of claim 9, wherein the cancer is liver cancer.
CN202310794973.6A 2023-06-30 2023-06-30 A composition prepared from fructus Psoraleae and herba Epimedii for treating cancer Pending CN117018056A (en)

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CN202310794973.6A CN117018056A (en) 2023-06-30 2023-06-30 A composition prepared from fructus Psoraleae and herba Epimedii for treating cancer

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