CN110237080A - Low polarity rare ginsenoside mixture and application thereof - Google Patents
Low polarity rare ginsenoside mixture and application thereof Download PDFInfo
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- CN110237080A CN110237080A CN201810189845.8A CN201810189845A CN110237080A CN 110237080 A CN110237080 A CN 110237080A CN 201810189845 A CN201810189845 A CN 201810189845A CN 110237080 A CN110237080 A CN 110237080A
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Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
- A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention belongs to field of medicaments, be related to a kind of low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture and preparation for treat and/or pre- preventing tumor and/or the drug and/or health care product of cancer in purposes；And its preparation for immunological regulation, improve microcirculation, improve quality of life drug and/or health care product in purposes.Invention further provides the compositions and application thereof for including low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of low polarity rare ginsenoside mixture and application thereof, and
Its pharmacological mechanism in anti-tumor aspect.
Background technique
Cancer is to torture the second-biggest-in-the-world disease of human life, and the death rate is only second to cardiovascular and cerebrovascular disease, is that the mankind are dead
One of main factor died.Organize cancer mechanism, the official International Cancer Research Center (IARC) of subordinate negative by World Health Organization
The latest edition " report of world's cancer " of duty predicts that swift and violent proliferation situation will be presented in global cases of cancer, by 2012 14,000,000
People, fast 19,000,000 people for increasing to 2025, were up to 24,000,000 people by 2035 year by year.Report also shows that the whole world was new in 2012
Increasing cases of cancer has nearly half to appear in Asia, and wherein most ranks first in China, the newly-increased cases of cancer height of China.2012
Newly-increased 3,070,000 cancer patients of China simultaneously cause about 2,200,000 people dead, account for the 21.9% and 26.8% of global total amount respectively.WHO
Data be slightly below China statistics.2012 annual datas of national tumour Register publication show that China is annual newly-increased
Cases of cancer about 3,500,000, it is therefore dead that there are about 2,500,000 people.
There are mainly three types of modes for the common method for the treatment of of cancer now: operation, radiotherapy and drug therapy, and which is selected and is controlled
Treatment method then depends on position, grade malignancy, development degree and the patient body state of tumour.In Three models, operation
Treatment method, the invasion of Chang Yinwei cancer cell spreads to adjacent tissue or far-end transfer and effect is limited；The treatment method of radiotherapy, then
It is limited to the injury caused by other internal normal tissues；The treatment method of drug, it is pernicious for advanced stage dispersivity and metastatic
Tumour is most basic treatment method.In past decades, though the chemotherapy for being conceived to direct killing tumour cell has significantly
Development and progress becomes the backbone of tumor pharmacother, but this treatment mode is poor to the slow solid tumor effect of proliferation, drug
Selectivity is small, toxicity is more and serious defect becomes the important limiting factor in clinical treatment.After operation, radiation and chemotherapy
The 4th kind of mode later is the biological therapy of tumour, mainly passes through the effect of tumor host defense mechanism or biological agent
The biologically of body itself is adjusted, to suppress or eliminate tumour；Although biological therapy without too big toxic side effect,
Since technical requirements are tight, complex process, price is high, and numerous cancer patients and family members are difficult to bear, influence it and control in cancer
It popularizes in treatment field.
Since there are above-mentioned various limitations, the research and development of natural antitumor drug achieve more and more concerns.It is natural anti-
Cancer drug either in inhibition or killing tumor cell, adjustment body's immunity, improvement symptom and feature and mitigates chemicotherapy
In toxic side effect, or in the conditioning after being ill of tumour, all have important function.As a result, natural plants new treatment will become after
The 5th kind of mode after operation, radiotherapy, chemotherapy and biotherapy.
Araliaceae (araliaceae) Panax (Pana ×) plant, such as ginseng (P.ginseng), American Ginseng
(P.quenquefolinus), Radix Notoginseng (P.notoginseng), panax japonicus (P. uaponicus), Curcurbitaceae gynostemma pentaphyllum genus are planted
Object gynostemma pentaphylla (Gynostemma oentaphyllum Thrunb Mak) etc. is the rare traditional medicinal plant of China, master
Wanting effective component is dammarane type four-ring triterpenoid ginseng saponin series compound.Have now been found that the archetypal man in Araliaceae
Ginseng saponin(e has more than 60 kinds, can be divided into two major classes: 1) glycol group ginsenoside (Ra, Rb1, Rb2, Rb3, Rc, Rd etc.)；2) triol group
Ginsenoside (Re, Rf, Rg1, Rg2, Rh1 etc.), is all made of glucoside member and sugar, is generally dissolved easily in water, curative effect specifically includes that
Immunoloregulation function, improving micro_circulation effect adjust digestive function, enhancing memory and learning ability, anti-aging, tranquilizing the mind etc., but
Apparent anti-tumor activity is not shown.
Low polarity rare ginsenoside content in former panax species is little, exists only in wild ginseng or red ginseng, black
In ginseng and the ginseng and Radix Notoginseng product of processings such as ripe Radix Notoginseng, it is also only ten thousand/it is several, and it is insoluble in water, usually only it is dissolved in ethyl alcohol
Or in the low polar organic solvents such as ethyl acetate, referred to as low polarity rare ginsenoside mainly includes that prototype ginsenoside is logical
Cometabolism derivative (C-k, Rg3, Rh2, Rh1, PPD, PPT etc.) and the side chain desugar simultaneously crossing glycosidic bond degradation and generating
Dehydration formed with more double bond structures conversion derivative (Rg5, Rh3, Rk1, Rk2, Δ (20-21) PPD, Rh4, Rk3,
F4, Rg6, Δ (20-21) PPT etc.).Low polarity rare ginsenoside is in addition to the common original biology of prototype ginsenoside
Except activity, the completely new pharmaceutical activity such as antitumor, antiviral for also showing that prototype saponin(e do not have, with high medicinal
Value and application prospect.
Due to each comfortable wide spectrum of two kinds of saponin monomers anticancer activity and validity in terms of do not embody yet it is absolute excellent
Gesture, the research significance for combining anticancer for them are great.
Summary of the invention
The rare people of low polarity for the high anticancer validity with wide spectrum that the technical problem to be solved in the present invention is to provide a kind of
Join saponin(e Δ (20-21) PPT/ Δ (20-22) PPT mixture, the present invention provides the low poles of industrialization manufacture high-content
Compositing monomer Δ (20-21) PPT and Δ (20-22) PPT method and mixture Δ (20- of property rare ginsenoside mixture
21) PPT/ Δ (20-22) PPT is in being used to prepare treatment and/or pre- preventing tumor and/or the drug and/or health care product of cancer
Purposes, and be used to prepare immunological regulation, improve microcirculation, improve quality of life drug and/or health care product in purposes.This
Invention further provides mixture Δ (20-21) PPT/ Δ (20-22) PPT and makees in the part pharmacology of its broad spectrum anticancer on the way
Use mechanism.It includes low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixing that the present invention, which finally provides,
Composition of object and application thereof.
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture of the present invention is by having such as
Flowering structure formula
Low polarity rare ginsenoside monomer Δ (20-21) PPT and have following structural
Low polarity rare ginsenoside monomer Δ (20-22) PPT mix, Δ (20-21) PPT and Δ (20-22)
PPT belongs to isomer in chemical structure.
The weight of low polarity ginsenoside monomer Δ (20-21) PPT and low polarity ginsenoside Δ (20-22) PPT
Than for 7:1~1:5, preferably 1:2~1:5, further preferably 1:3.We are in an experiment it is surprisingly found that two kinds same
The combination of enantiomers produces significant synergistic function in drug effect, and anticancer cancer resistant effect is better than Δ (20- significantly
21) PPT and Δ (20-22) PPT monomer.
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixture is being prepared for controlling
Treat and/or the drug of pre- preventing tumor and/or cancer and/or use in health care product on the way,
Wherein the tumour and/or cancer are selected from:
Malignant tumour, including but not limited to bladder cancer, breast cancer, colon cancer, kidney, liver cancer, lung cancer (including cellule lung
Cancer, non-small cell lung cancer), head and neck cancer, the cancer of the esophagus, gallbladder cancer, oophoroma, cancer of pancreas, gastric cancer, cervix cancer, thyroid cancer,
Prostate cancer and cutaneum carcinoma (including squamous cell carcinoma)；
It is the hematopoetic tumor of lymphatic system, including but not limited to leukaemia, acute lymphoblastic leukemia, acute thin at lymph
Born of the same parents' leukaemia, B- cell lymphom, T- cell lymphom, Huo Qijin lymph cancer, non-Huo Qijin lymph cancer, hairy cell lymphom,
Mantle cell lymphoma, myeloma and BurkettShi lymph cancer；
The hematopoetic tumor of marrow system, including but not limited to acute and chronic myelocytic leukemia, myeloproliferative disorder
Syndrome and promyelocytic leukemia；
The tumour of the interstitial origin cause of formation, including but not limited to fibrosarcoma and rhabdomyosarcoma；
The tumour of maincenter and peripheral nervous system, including but not limited to astrocytoma, at fibroneuroma, neuroglia
Tumor and neurinoma；And
Other tumours, including but not limited to melanoma, seminoma, teratocarcinoma, osteosarcoma, exophytic pigment neck tumor,
Thyroid gland filters capsule cancer and Kaposi's sarcoma.
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixture is in anticancer purpose
Pharmacological mechanism is that it can be raw by reducing cell cycle regulating protein Cyclin D1 and CDK4 effectively blocks cellular
It is longer than the G1 phase；And certainly by the different degrees of promotion of the activation caspase 3 tumour cell directly proportional to Drug level
Body apoptosis.
Another purposes of low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixture is
Preparation for immunological regulation, improve microcirculation, improve quality of life drug and/or health care product in purposes.
The present invention also provides a kind of compositions, including low polarity rare ginsenoside Δ (20-21) the PPT/ Δ
(20-22) PPT mixture.
The composition is preferably pharmaceutical preparation, and it includes treatment and/or the low rare ginsengs of polarity of prevention effective dose
Saponin(e Δ (20-21) PPT/ Δ (20-22) PPT mixture and optional pharmaceutically acceptable diluent, carrier, excipient,
Auxiliary material or medium.
The dosage form of the pharmaceutical preparation is any one of peroral dosage form, injection type or Topical application forms.
The peroral dosage form includes but is not limited to tablet, pulvis, suspension, emulsion, capsule, granule, sugar coated tablet, medicine
Ball, liquid, spirit, syrup or limonada.
The injection type includes but is not limited to aqua, suspension or solution.
The Topical application forms include but is not limited to ointment, solid, suspension, aqua, spirit, pulvis, paste, bolt
Agent, aerosol, opoultice, liniment, lotion, enema or emulsion.
Alternatively, the composition is preferably health care product, it includes the low polarity for the treatment of and/or prevention effective dose is rare
Acceptable carrier in ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture and optional health care product.
One purposes of the composition is in preparation for treating and/or the drug of pre- preventing tumor and/or cancer
And/or the purposes in health care product.
Wherein the tumour and/or cancer are selected from:
Malignant tumour, including but not limited to bladder cancer, breast cancer, colon cancer, kidney, liver cancer, lung cancer, head and neck cancer, food
Pipe cancer, gallbladder cancer, oophoroma, cancer of pancreas, gastric cancer, cervix cancer, thyroid cancer, prostate cancer and/or cutaneum carcinoma；
It is the hematopoetic tumor of lymphatic system, including but not limited to leukaemia, acute lymphoblastic leukemia, acute thin at lymph
Born of the same parents' leukaemia, B- cell lymphom, T- cell lymphom, Huo Qijin lymph cancer, non-Huo Qijin lymph cancer, hairy cell lymphom,
Mantle cell lymphoma, myeloma and/or BurkettShi lymph cancer；
The hematopoetic tumor of marrow system, including but not limited to acute and chronic myelocytic leukemia, myeloproliferative disorder
Syndrome and/or promyelocytic leukemia；
The tumour of the interstitial origin cause of formation, including but not limited to fibrosarcoma and/or rhabdomyosarcoma；
The tumour of maincenter and peripheral nervous system, including but not limited to astrocytoma, at fibroneuroma, neuroglia
Tumor and/or neurinoma；And
Melanoma, seminoma, teratocarcinoma, osteosarcoma, exophytic pigment neck tumor, thyroid gland filter capsule cancer and/or card wave
Sarcoma.
Another purposes of the composition is to be used to prepare immunological regulation, improve microcirculation, improve quality of life
Purposes in drug and/or health care product.
Terminology used in the present invention have it is defined below, unless otherwise described:
The term as used herein " low polarity ", refers to for general ginsenosides, Rg3, Rh2 of content rareness,
Δ (20-21) PPT, Δ (20-22) PPT etc. are insoluble in water, are only dissolve in low polar organic solvent.
The term as used herein " composition " mean include comprising specified amount each specified ingredient product, and directly or
Any product generated indirectly from the combination of each specified ingredient of specified amount.The Topical application forms include ointment, solid, hang
Turbid, aqua, spirit, pulvis, paste, suppository, aerosol, opoultice, liniment, lotion, enema or emulsion.Sterile
Under the conditions of by reactive compound and pharmaceutically acceptable carrier and any desired preservative, buffer or propellants.Eye
It is also considered within the scope of the present invention with preparation, eye ointment, powder and solution.
When being used for above-mentioned treatment or other treatment, a kind of the compounds of this invention for the treatment of and/or prevention effective dose can be with
It applies, or is applied by pharmaceutically acceptable salt, ester or prodrug forms (in the case where in the form of there are these) in a pure form.Or
Person, the compound can be with the pharmaceutical compositions containing the purpose compound Yu one or more pharmaceutically acceptable excipient
Administration.The compounds of this invention of word " treatment and/or prevention effective dose " refer to be suitable for the reasonable effect of any therapeutic treatment/
Hazard ratio treats the compound of the sufficient amount of obstacle.It is to be understood that total consumption per day of the compounds of this invention and composition must be by
Attending physician makes decision in reliable medical judgment scope.For any specific patient, specific treatment and/or prevention
Effective dose level must be depending on many factors, and the factor includes the severity of treated obstacle and the obstacle；Institute
The activity of the particular compound of use；Used concrete composition；Age of patient, weight, general health, gender and
Diet；Administration time, administration route and the excretion rate of used particular compound；Duration for the treatment of；With used tool
The drug that body compound combination is used or used simultaneously；And similar factor well known to medical field.For example, the way of this field
It is that the dosage of compound gradually increases dosage, until obtaining since less than obtaining required therapeutic effect and desired level
Required effect.
The present invention also provides comprising optionally with the acceptable diluent of one or more non-toxic pharmaceuticals, carrier, excipient,
The pharmaceutical preparation of auxiliary material or medium the compounds of this invention formulated together.The pharmaceutical preparation can especially particular formulation at
Solid or liquid form is for oral administration, for parental injection or for rectally.
Pharmaceutical composition of the invention can by oral, rectum, parenteral, pond, in intravaginal, peritonaeum, part is (as logical
Cross powder, ointment or drops), buccal give the mankind and other mammals, or as oral spray or nasal spray
Agent is given.Terms used herein " parenteral " refer to including in intravenous, intramuscular, intraperitoneal, breastbone, subcutaneous and intra-articular injection
With the administration mode of infusion.
On the other hand, the present invention provides the pharmaceutical composition comprising present component and physiologically tolerable diluent.
The present invention includes one or more above compounds, with one or more nontoxic physiologically tolerable or acceptable diluents,
Carrier, auxiliary material or medium (they are referred to as diluent herein) are configured to composition together, for parental injection, intranasally
Transmitting, in solid or liquid form oral administration, rectum or local administration etc..
The composition for being suitable for parental injection may include physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersion
Agent, suspension or emulsion, and the sterile powders for being reconstructed into Sterile injectable solution or dispersing agent.It is suitable aqueous or non-aqueous
Carrier, diluent, solvent or medium example include water, ethyl alcohol, polyalcohol (propylene glycol, polyethylene glycol, glycerol etc.), plant
Oily (such as olive oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositions can also contain auxiliary material, such as preservative, wetting agent, emulsifier and dispersing agent.Pass through various antibacteriums
Agent and antifungal agent, such as parabens, anesin, phenol, sorbic acid etc., it can be ensured that prevent the effect of microorganism.
It is also expected to including isotonic agent, such as carbohydrate, sodium chloride etc..By using can postpone absorb substance, such as aluminum monostearate and
Gelatin, the extension that can reach injectable drug form absorb.
Suspending agent, such as ethoxylation i-octadecanol, polyoxyethylene mountain can also be contained in suspension in addition to the active compound
The pure and mild polyoxyethylene sorbitan esters of pears, microcrystalline cellulose, inclined aluminium hydroxide, bentonite, agar and bassora gum or this
The mixture etc. of a little substances.
In some cases, to extend the effect of drug, it is expected that slowing down the absorption for subcutaneously or intramuscularly injecting drug.This can lead to
It crosses using the liquid suspension of the crystal of poorly water-soluble or amorphous substance and realizes.In this way, the infiltration rate of drug depends on
Its solution rate, and solution rate may depend on crystal size and crystal form.Alternatively, the delay of the medicament forms of parenteral
Absorption is realized by the way that the drug to be dissolved in or be suspended in oily medium.
Injectable depot formulations form can be by biodegradable polymer such as polylactide-polyglycolide
(polylactide-polyglycolide) microcapsule matrix of drug is formed in prepare.Can according to drug and polymer it
Than the property with used specific polymer, drug releasing rate is controlled.The reality of other biological degradable polymer
Example includes polyorthoester class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations
Can also by by drug be embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can for example by with bacteria filter filtering or pass through incorporation aseptic solid composite form bactericidal agent
It sterilizes, the solid composite can be dissolved or dispersed in front of use sterile water or other sterile injectable mediums.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In such solid dosage forms
In, reactive compound can be at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or Dicalcium Phosphate
And/or following material mixing: a) filler or incremental agent such as starch, lactose, sucrose, glucose, mannitol and silicic acid；B) it glues
Mixture such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic；C) moisturizer is for example sweet
Oil；D) disintegrating agent such as agar, calcium carbonate, potato or tapioca, alginic acid, certain silicates and sodium carbonate；E) solution hinders
Stagnant dose such as paraffin；F) absorbsion accelerator such as quaternary ammonium compound；G) wetting agent such as cetanol and glyceryl monostearate；H) it adsorbs
Agent such as kaolin and bentonite and i) lubricant such as talcum powder, calcium stearate, magnesium stearate, solid polyethylene glycol, dodecane
The mixture of base sodium sulphate and they.It also may include buffer in the dosage form in the case where capsule, tablet and pill.
The solid composite of similar type uses excipient such as lactose and high molecular weight polyethylene glycol etc., it is also possible to make soft
Filler in capsule and hard capsule.
Tablet, dragee (dragees), capsule, pill and granule solid dosage forms can be with coating and shell material such as
Other clothing materials well known to enteric coating material and field of medicine preparations are prepared together.These solid dosage forms can optionally contain opacifier, and
It, which is formed, can also make it only or preferentially at some position of enteron aisle optionally with delayed mode discharge active component.It can be used
The example of embedding composition include polymer substance and wax class.If be suitble to, reactive compound can also with it is one or more on
It states excipient and is made into microencapsulated form.
Liquid dosage form for oral administration includes pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.
Liquid dosage form, which is removed, also contains inert diluent commonly used in the art, such as water or other solvents containing active ingredient beyond the region of objective existence, increases
Solvent and emulsifier such as ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, benzylalcohol, Ergol, propylene glycol, 1,3- fourth two
Alcohol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, embryo oil, olive oil, castor oil and sesame
Oil), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyethylene glycol and sorbitan fatty acid
Ester and their mixture.Orally administered composition also may include auxiliary material in addition to comprising inert diluent, such as wetting agent, emulsification and outstanding
Floating agent, sweetener, corrigent and flavouring agent.
Suppository is preferably for the composition of rectum or vagina administration.Suppository can by by the compounds of this invention with it is suitable non-
To prepare, they are solid at room temperature for irritation excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax mixing, but
It is then under body temperature liquid, therefore can be melted in rectal cavity or vaginal canal and release reactive compound.
The compounds of this invention can also be administered with liposomal form.As it is known in the art, liposome usually use phosphatide or its
He is made lipid material.Liposome is formed by the single-layer or multi-layer aquation liquid crystal being scattered in water-bearing media.It is any being capable of shape
At liposome it is nontoxic, be physiologically subjected to and metabolizable lipid can be used.The present composition of liposomal form removes
Outside containing the compounds of this invention, it can also contain stabilizer, preservative, excipient etc..Preferred lipid is natural and synthesis phosphorus
Rouge and phosphatidyl choline (lecithin), they can be used individually or together.The method for forming liposome is well known in the art.
The prodrug that the term as used herein " pharmaceutically acceptable prodrug " represents the compounds of this invention, in reliable medicine
It is suitable for being contacted with the tissue of the mankind and lower animal without there is excessive toxicity, stimulation, allergic reaction in determination range
Deng matching with reasonable effect/Hazard ratio and effective to its intended purpose, also represent the compounds of this invention in the conceived case
Zwitterionic form.Prodrug of the invention can for example be rapidly converted into the parent of above formula in vivo and hydrolyzing in blood
Compound.
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture of the invention and corresponding combination
Object has the anti-tumor activity for inhibiting human tumor cells (17 kinds have been surveyed tumour cell) and cell proliferation of human umbilical vein, through reality
It verifies bright because mixture synergistic effect keeps its wide spectrum high anti-cancer activity significantly rare low better than similar comparison medicine, including low polarity
Polarity rare ginsenoside monomer Rg3, Δ (20-21) PPT monomer and Δ (20-22) PPT monomer, validity are also significantly better than
Non- similar control drug taxol.In addition, experiment finds low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT
Mixture can have in Non-small Cell Lung Cancer A 549 by reducing cell cycle regulating protein Cyclin D1 and CDK4
Retarding cell growth is imitated in the G1 phase；And the mixture also can be by activating caspase 3 in liver gland cancer SK-HEP-1 cell
And the tumour cell autologous apoptotic that different degrees of promotion is directly proportional to Drug level.Many experiments confirm that the low polarity is rare
Ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture can be made for treating and/or preventing various cancers
And/or the drug and/or health care product of tumour, and for immunological regulation and/or improve microcirculation and/or improve quality of life
Drug and/or health care product, focus on the application has broad application prospects in the treatment of malignant tumour.
Figure of description explanation
Fig. 1 is to scheme Δ (20-21) PPT/ Δ (20-22) PPT (1:3) the adjusting A549 cell cycle.
Fig. 2 is Δ (20-21) PPT/ Δ (20-22) PPT (1:3) to Cyclin D1 and CDK4 albumen table in A549 cell
Up to horizontal influence diagram.
Fig. 3 is that Δ (20-21) PPT/ Δ (20-22) PPT (1:3) promotes SK-HEP-1 Apoptosis figure.
Fig. 4 is that Δ (20-21) PPT/ Δ (20-22) PPT (1:3) is active to caspase 3 in SK-HEP-1 cell
Influence diagram.
Specific embodiment
Unless specifically indicated, term used herein has the general sense in fields of the present invention.
Below with reference to specific embodiment, the present invention will be described, it should be noted that these embodiments are only explanation
Property, and be not considered as limiting the invention.Particular technique or condition are not specified in embodiment, according in the art
Technology or conditions described in document are carried out according to product description.Reagents or instruments used without specified manufacturer,
Being can be with conventional products that are commercially available.
Embodiment 1: low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture and preparation method thereof
A kind of low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture is present embodiments provided,
It is by having the following structure formula
Low polarity rare ginsenoside monomer Δ (20-21) PPT and have following structural
Low polarity rare ginsenoside monomer Δ (20-22) PPT with weight ratio 7:1；1:5；The ratio of 1:2 and 1:3 is mixed
It closes.
It is specific the preparation method is as follows:
(1) weigh low polarity rare ginsenoside monomer Δ (20-21) PPT of 8.75mg (is had by Canadian imperial botanical medicine
Limit company Canada Royal Enoch Phytomedicine Ltd is provided) and the low polarity rare ginsenoside list of 1.25mg
Body Δ (20-22) PPT is (by Canadian imperial botanical medicine Co., Ltd Canada Royal Enoch Phytomedicine Ltd
There is provided), it is uniformly mixed with the ratio of weight ratio 7:1, obtains low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22)
PPT mixture (7:1).
(2) low polarity rare ginsenoside monomer Δ (20-21) PPT of 1.67mg is weighed (by Canadian imperial botanical medicine
Co., Ltd Canada Royal Enoch Phytomedicine Ltd provide) and 8.33mg low polarity rare ginsenoside
Monomer Δ (20-22) PPT is (by Canadian imperial botanical medicine Co., Ltd Canada Royal Enoch Phytomedicine
Ltd is provided), it is uniformly mixed with the ratio of weight ratio 1:5, obtains low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-
22) PPT mixture (1:5).
(3) low polarity rare ginsenoside monomer Δ (20-21) PPT of 2.50mg is weighed (by Canadian imperial botanical medicine
Co., Ltd Canada Royal Enoch Phytomedicine Ltd provide) and 7.50mg low polarity rare ginsenoside
Monomer Δ (20-22) PPT is (by Canadian imperial botanical medicine Co., Ltd Canada Royal Enoch Phytomedicine
Ltd is provided), it is uniformly mixed with the ratio of weight ratio 1:3, obtains low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-
22) PPT mixture (1:3).
(4) low polarity rare ginsenoside monomer Δ (20-21) PPT of 3.33mg is weighed (by Canadian imperial botanical medicine
Co., Ltd Canada Royal Enoch Phytomedicine Ltd provide) and 6.67mg low polarity rare ginsenoside
Monomer Δ (20-22) PPT is (by Canadian imperial botanical medicine Co., Ltd Canada Royal Enoch Phytomedicine
Ltd is provided), it is uniformly mixed with the ratio of weight ratio 1:2, obtains low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-
22) PPT mixture (1:2).
Embodiment 2: low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT of different mixing proportion is mixed
It closes and inhibits the experiment of multiclass tumor cell proliferation outside object
Laboratory sample:
Testing drug: low polarity rare ginsenoside Δ (20-21) PPT/ for the first three ratio that embodiment 1 is prepared
Δ (20-22) PPT mixture.
Control drug: taxol (SELLECK；Cat.#S1150)；Low polarity rare ginsenoside monomer Rg3 is (from Shanghai
The purchase of Yuan Ye Biotechnology Co., Ltd, commodity article No. are B21059)；Low polarity rare ginsenoside monomer Δ (20-21)
PPT (from embodiment 1)；Low polarity rare ginsenoside monomer Δ (20-22) PPT (from embodiment 1).
Experimental procedure:
With 18 kinds of cell lines (including 17 kinds of tumor cell lines and a kind of human umbilical vein endothelial cell line) for experiment cell
System, logarithmic growth phase cell (3 × 104/ mL to 2.5 × 105/ mL), it is seeded in 96 orifice plates with every 100 μ L of hole, each cell
It is 96 orifice plates；Then taking 7 logarithmic decrease concentration with 150 μM to 2 μM of low concentration of high concentration, (each concentration sets two again
Hole), it is separately added into testing drug solution and control drug solution (testing drug solution or the preparation of control drug solution: is adopted respectively
0.5% DMSO solution is dissolved in testing drug or control drug) 500nL.The addition concentration of taxol be by 1 μM of high concentration extremely
0.0014 μM of low concentration of 7 three times decreasing concentrations.After after tested/control drug solution effects 72 hours, use(Promega；Cat.#G7573) luminescent cell viability examination method finds out every kind of drug in each cell line
Each concentration to this be the Proliferation Ability percentage of cell, and draw dose-effect relationship figure, IC finally calculated according to curve in figure50
Inhibit percentage (E with highestma×), as shown in Table 1 and Table 2.
Table 1: low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixture of different mixing proportion with
And comparison medicine Rg3, Δ (20-21) PPT and Δ (20-22) PPT inhibit cell-proliferation activity testing result
Table 2: low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixture of different mixing proportion
And control drug taxol, Rg3, Δ (20-21) PPT and Δ (20-22) PPT inhibit cell Proliferation validation checking result
Note: the meaning for the term expression that table 1, table 2 and context occur is as follows:
Δ (20-21) PPT/ Δ (20-22) PPT (7:1) represents low polarity rare ginsenoside Δ (20-21) PPT/ Δ
The weight ratio of Δ (20-21) PPT and Δ (20-22) PPT in (20-22) PPT mixture are 7:1, i.e. embodiment 1 obtains
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture.
Δ (20-21) PPT/ Δ (20-22) PPT (1:5) represents low polarity rare ginsenoside Δ (20-21) PPT/ Δ
The weight ratio of Δ (20-21) PPT and Δ (20-22) PPT in (20-22) PPT mixture are 1:5, i.e. embodiment 2 obtains
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture.
Δ (20-21) PPT/ Δ (20-22) PPT (1:3) represents low polarity rare ginsenoside Δ (20-21) PPT/ Δ
The weight ratio of Δ (20-21) PPT and Δ (20-22) PPT in (20-22) PPT mixture are 1:3, i.e. embodiment 3 obtains
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture.
It is mentioned using SPSS Statistics software (supplier: IBM corporation, software version: × L fit 21)
For statistical analysis.With duplicate measurements analysis of variance (Rep eated measure ANOVA) detection table 1 into table 2 every group
Whether the difference between average value is presented statistically significant (P < 0.05 or P < 0.01), then subsequent with Bonferroni T test s
Every class mean reason of discrepancies is further sought in calibrating.
Analyze result:
(1) table 1 is shown, when low polarity rare ginsenoside Δ (20-21) the PP T/ Δ (20-22) of different mixing proportion
Average IC of the PPT mixture in 18 cell lines50Polarity rare ginsenoside monomer Rg3 low with control drug, Δ respectively
The average IC of (20-21) PPT and Δ (20-22) PPT in 18 cell lines50When comparing, low polarity rare ginsenoside Δ
Between (20-21) PPT/ Δ (20-22) PPT mixture (7:1) and the low polarity rare ginsenoside monomer Rg3 of control drug
Difference, which is presented, counts extremely significant (P < 0.01), and itself and low polarity rare ginsenoside Δ (2 0-21) PPT/ Δ (20-22) PPT
Also there is notable difference (P < 0.0 1) between mixture (1:5)；And low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-
22) the rare ginseng of low polarity that PPT mixture (1:3) and control drug Rg3, Δ (20-22) PPT and mixed proportion are 1:5
(Δ (20-21) PPT/ Δ (20-22) PPT (1:5) is than Rg3, Δ (20-21) PPT/ compared to there is notable difference for saponin mixture
P < 0.01 of Δ (20-22) PPT (1:3)；P of Δ (20-21) P PT/ Δ (20-22) PPT (1:5) than Δ (20-22) PPT <
0.05)；Finally, low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:3) and three kinds of comparison medicines
The low polarity rare ginsenoside monomer Rg3 of object, Δ (20-21) PPT, Δ (20-22) PPT, and with two kinds of ratios (7:1 and 1:
5) difference of low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture present statistically significant (P <
0.01).In addition, the combination between control drug except Δ (20-21) PPT and Δ (20-22) PPT is without significant difference (P > 0.05)
Outside, remaining combination has notable difference (P < 0.01).
(2) table 2 is shown, when low polarity rare ginsenoside Δ (20-21) the PP T/ Δ (20-22) of different mixing proportion
Average highest of the PPT mixture in 18 cell lines inhibit percentage respectively with control drug taxol, the rare people of low polarity
Join the average highest of saponin monomer Rg3, Δ (20-21) PPT and Δ (20-22) PPT in 18 cell lines and inhibits percentage ratio
Compared with when, low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (7:1) and control drug taxol,
Statistically significant (P < 0.01) is presented in difference between low polarity rare ginsenoside monomer Rg3, and itself and other two kinds of ratios
Also there is notable difference between low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixture of (1:5 and 1:3)
(P<0.01)；And low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:5) and Δ (20-
21) the low polarity rare ginsenoside Δ of PPT/ Δ (20-22) PPT (1:3) and all four control drugs and remaining ratio
Average highest between (20-21) PPT/ Δ (20-22) PPT mixture inhibits percentage to have notable difference (P < 0.01)；Most
Afterwards, between control drug in addition to the combination of Δ (20-21) PPT and Δ (20-22) PPT are without significant difference (P > 0. 05), remaining group
Conjunction mode has notable difference (P < 0.01).
Experiment conclusion:
(1) low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the P PT mixture of different proportion is all
In 18 kinds of surveyed cell lines inhibit cell-proliferation activity and validity it is different degrees of be higher than non-similar control drug Japanese yew
The monomer of alcohol and the low polarity rare ginsenoside monomer Rg3 of similar control drug polarity rare ginsenoside mixture low with this
Δ (20-21) PPT, Δ (20-22) PPT show the low polarity rare ginsenoside monomer Δ (20-21) of two kinds of isomers
The combination of PPT, Δ (20-22) PPT produce significant synergistic effect in drug effect.(2) in all tested cell systems, when low
Δ (20-21) PPT and Δ (20-22) in polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture
When PPT is mixed with weight ratio for the ratio of 1:3, activity and validity are higher than other two kinds of mixed proportions (7:1 and 1:5), because
Δ (20-21) PPT and Δ (20- in this low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture
22) weight ratio of PPT is low polarity rare ginsenoside Δ (20-21) the PPT/ Δ (20-22) surveyed at present by the ratio of 1:3
The optimal proportion that Δ (20-21) PPT in PPT mixture is mixed with Δ (20-22) PPT.
(3) in all tested cell systems, low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT is mixed
Closing object (1:3) in fibrosarcoma cell system there is highest to inhibit cell-proliferation activity (IC50=7.57 μM)；Inhibit cell Proliferation
The cell line that activity comes next is Human umbilical vein endothelial cells (IC50=9.20 μM).
(4) low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:3) is to all tested
The highest of cell line inhibits percentage (validity) all very close 100%, it means that it has extensive high anticancer effective
Property.And the low polarity rare ginsenoside monomer Rg3 of similar control drug only has nearly 100% inhibiting rate to a kind of cell line；This is low
Monomer Δ (20-21) PPT, the Δ (20-22) of polarity rare ginsenoside mixture though the validity of PPT be apparently higher than it is non-similar
Control drug taxol and the low polarity rare ginsenoside monomer R g3 of similar control drug, but it is rare to be still below low polarity
The validity of ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:3).
In addition, by low polarity rare ginsenoside Δ (20-21) the PPT/ Δ (20-22) of the 4th kind of ratio in embodiment 1
PPT mixture (1:2) carries out above-mentioned external inhibition multiclass tumor cell proliferation experiment, finds it to all 18 kinds of surveyed cell lines
In inhibit cell-proliferation activity and validity it is different degrees of be higher than non-similar control drug taxol and similar control
Monomer Δ (20-21) PPT of the low polarity rare ginsenoside monomer Rg3 of drug polarity rare ginsenoside mixture low with this,
Δ (20-22) PPT, activity and validity are higher than the mixed proportion that monomer Δ (20-21) PPT, Δ (20-22) PPT are 7:1,
It is suitable with the mixed proportion of 1:5, it is slightly poorer than the mixed proportion that two kinds of monomers are 1:3.
Embodiment 3: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) adjusts cell cycle distribution experiment
Laboratory sample:
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixture that embodiment 1 is prepared
(1:3)；
Experimental procedure:
Using non-small cell lung cancer cell A549 as experiment cell line, every hole is inoculated with 5000 in 96 orifice plates, places
It is cultivated in cell incubator adherent overnight；Then, to the A549 cell of 96 orifice plates, with Tecan D300e digital
Final concentration of 32 μM of plate hole of dispenser addition, 64 μM, 128 μM, 192 μM (i.e. Δ (20-21) PPT/ Δ (20-22) PPT (1:
3) act on after A549 cell 72h and inhibit 1 times, 2 times, 4 times and 6 times concentration of the IC50 value of the cell Proliferation) test medicine
Object Δ (20-21) PPT/ Δ (20-22) PPT (1:3).Testing drug is dissolved in DMSO solution, and each concentration sets two multiple holes,
The final content in the every hole DMSO is 0.5% in 96 orifice plates, and is blank control wells containing only 0.5% DMSO solution.After tested drug/
After contrast solution acts on 48 hours, cell culture fluid in 96 orifice plate to be detected is removed, every hole is added 100 μ L and contains 80% ethyl alcohol
Cold (- 20 DEG C) phosphate solution (PBS) be placed in 4 DEG C of refrigerators.After fixed cell 30min, 100 μ L phosphate are added in every hole
The phosphate solution that 100 μ L 0.2mg/ml ribalgilases (RNase) are added after removing phosphate solution twice is rinsed,
And it is cultivated 45 minutes in 37 DEG C of environment.Finally, sucking the iodine that Ribonuclease in Aqueous Solution and every hole 100 μ L concentration of addition are 10 μM
Change the third pyridine (Propidium iodide), after room temperature is protected from light culture 15 minutes, sample to be tested fluorescence microplate cytoanalyze
Acumen e × 3 detects the percentage of fluorescence signal and quantitative analysis each cell cycle, as shown in Figure 1.
It uses SPSS Statistics software (supplier: IBM corporation, software version: × L fit 21)
Statistical analysis is provided.(independent-sample T-test) is examined to detect each cell cycle distribution with independent sample
Medicine group and control group mean difference statistically significant (P < 0.05 or P < 0.01) whether is presented.
Such as Fig. 1: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) adjusts A549 cell cycle laboratory test results.Data
It is shown with the form for testing duplicate mean+SD twice.Histogram graph representation A549 cell contrast solution (containing only
0.5% DMSO solution) and it is 16 μM final concentration of, 32 μM (i.e. Δ (20-21) PPT/ Δ (20-22) PPT (1:3) is acted on
Inhibit 1 times and 2 times of concentration of the IC50 value of the cell Proliferation after A549 cell 72h) Δ (20-21) PPT/ Δ (20-22) PPT
The percentage of each cell cycle distribution after being acted on 48 hours in (1:3) solution.(Δ (20-21) PPT/ Δ of 4 times and 6 times concentration
(20-22) PPT (1:3) effect 48 hours after result do not show because the concentration it is excessively high inhibit A549 cell
Proliferation, lead to remaining cell lazy weight to complete the cell cycle analysis of Acumen e × 3).Error line generation on histogram
Table standard deviation.* or * * indicates P < 0.05 or P < 0.01 compared with the control in corresponding period.
Analyze result:
Fig. 1 is shown, when concentration is 32 μM and 64 μM of low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22)
PPT mixture (1:3) acted on 48 hours in A549 cell after cell cycle distribution compared with the control group that no drug is added
When, the cell quantity percentage in cell cycle G1 and the S phase, relatively control are obviously increased and are reduced respectively, and system is presented in difference
Count significant (P < 0.01)；Cell quantity percentage in phase cell cycle G2/M, relatively control also have statistical significant reduction
(when concentration is 32 μM, P < 0.05；When concentration is 64 μM, P < 0.01).
Experiment conclusion:
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:3) can be in A549 cell
It can produce the increase of G1 phase cell number ratio and the subtracting of the cell number ratio of S phase and G2/M phase directly proportional to Drug level
It is few.In general, cell will do it cell growth in the G1 phase, makes division and determine, and prepare for the DNA replication dna of next step.Through G1/S
Cell will enter S phase (synthesis phase) after phase test point (DNA damage inspection) detection, carry out DNA and centriole duplication, chromatin group
Dress.Later, cell enters the G2 phase after the checkpoint S/G2 (DNA replication dna inspection) detection, protein needed for synthesizing mitosis,
It prepares for the division of next step.Finally, cell is after the checkpoint G2/M (mitotic spindle assembly and chromosome distribution check) detection
Into M phase (division stage).Because low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:3) can
G1 phase cell number ratio is raised in A549 cell, and lowers the cell number ratio of S phase and G2/M phase, this indicates them
Effective blocks cellular is in the G1 phase, so that the transition of blocks cellular phase from G1 to S, the loop cycle of final blocks cellular are split into
Journey.It may be that itself meeting an urgent need after DNA of tumor cell is impaired shows that the G1 phase, which blocks, when retardance still can not repair its damage, swell
Oncocyte will enter autologous apoptotic.
Embodiment 4: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) adjusts tumour cell associated period modulin table
It is tested up to amount
Laboratory sample:
Low polarity rare ginsenoside mixture Δ (20-21) PPT/ Δ (20-22) PPT that embodiment 1 is prepared
(1:3)；
Experimental procedure:
Using non-small cell lung cancer cell A549 as cell line used is tested, it is inoculated with 1.5 × 106Cell in 10cm cultivate
In ware, be placed in cell incubator cultivate it is adherent overnight；Second day, the compound to be tested containing respective concentration was added in every ware
2mL culture medium so that final concentration of 32 μM of every ware in the culture dish of final 10mL, 64 μM, 96 μM of (i.e. Δ (20-21) PPT/
Δ (20-22) PPT (1:3) acts on after A549 cell 72h 1 times, 2 times and 3 times concentration for inhibiting the IC50 value of the cell Proliferation)
Testing drug Δ (20-21) PPT/ Δ (20-22) PPT (1:3).Each concentration sets three multiple wares, the every ware of DMSO in culture dish
Final content is 0.5%, and the another cell that three wares are arranged containing only 0.5% DMSO is blank control.Compound/blank pair after tested
After effect 12 hours, the cell in every ware is cracked by RIPA and PI, protein quantification is carried out with BCA method and prepares sample.Most
Afterwards, Cyclin D1 and CDK4 albumen are detected under drug effect in the expression of A549 cell with Western-style pastry method.As a result such as Fig. 2
It is shown.
Such as Fig. 2: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) adjusts Cyclin D1 and C DK4 egg in A549 cell
White expression testing result.Data are shown with the form for testing duplicate mean+SD three times.Histogram graph representation
A549 cell is in contrast solution (DMSO solution containing only 0.5%) and 32 μM final concentration of, and 64 μM, 96 μM of (i.e. Δs (20-21)
PPT/ Δ (20-22) PPT (1:3) acts on after A549 cell 72h 1 times, 2 times and 3 times of the IC50 value for inhibiting the cell Proliferation
Concentration) Δ (20-21) PPT/ Δ (20-22) PPT (1:3) solution in act on 12 hours after C yclin D1 and CDK4 in cell
Protein expression level.Error line on histogram represents standard deviation.* is indicated compared with the control of corresponding protein expression level
P<0.01。
Analyze result:
Fig. 2 is shown, when concentration is 32 μM, 64 μM and 96 μM of low polarity rare ginsenoside Δ (20-21) PPT/ Δ
(20-22) PPT mixture (1:3) acted on 12 hours in A549 cell after cell in Cyclin D1 and CDK4 protein expression
When compared with the horizontal control group being added with no drug, two kinds of protein expression levels compared with compare have it is different degrees of be substantially reduced,
And statistically significant (P < 0.01) is presented in difference.
Experiment conclusion:
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:3) can in A549 cell
The reduction of the different degrees of generation Cyclin D1 and CDK4 protein expression level directly proportional to Drug level.Cyclin D1
It is the key protein of cell cycle regulation G1 phase, has been acknowledged as a kind of proto-oncogene.The overexpression of Cyclin D1 and swollen
Tumor and cancer have certain connection, and cell cycle regulation plays a very important role.Cyclin D1 can pass through
In conjunction with CDK4 molecule and the mode that is activated drives the cell cycle to enter next period from a period jointly.Therefore,
CDK4 molecule is like " engine " for controlling the cell cycle, and cyclin D1 then seems the throttle for controlling " engine ".Research is found
The overexpression of both albumen can promote the division and development of tumour cell, and tumour can be effectively suppressed in the expression for reducing them
The growth of cell.
Embodiment 4: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) promotes apoptosis of tumor cells experiment
Laboratory sample:
Low polarity rare ginsenoside mixture Δ (20-21) PPT/ Δ (20-22) PPT that embodiment 1 is prepared
(1:3)
Experimental procedure:
Using liver adenocarcinoma cell SK-HEP-1 as experiment cell line, every hole 1mL system inoculation 30000 in 24 orifice plates
A SK-HEP-1 cell, be placed in cell incubator cultivate it is adherent overnight；Then, cell culture fluid is replaced, and to 24 orifice plates
Final concentration of 0.2 μM of plate hole interior of SK-HEP-1 cell addition, 0.3 μM, 0.5 μM of (i.e. Δ (20-21) PPT/ Δ (20-22)
PPT (1:3) acts on after SK-HEP-1 cell 72h IC25, IC50 and the IC75 concentration for inhibiting the cell Proliferation) test medicine
Object Δ (20-21) PPT/ Δ (20-22) PPT (1:3).Testing drug is dissolved in DMSO solution, and each concentration sets two multiple holes,
The final content in the every hole DMSO is 0.2% in 24 orifice plates.It is control wells containing only 0.2%DMSO solution.Drug/control after tested
After solution effects 48 hours, the culture solution (containing the cell floated on culture solution) in every hole is extracted, and attached cell is used
After 0.05% trypsase separation, the culture solution that this extraction is added is resuspended cell and is collected in centrifuge tube, 2000rpm revolving speed from
The heart 5 minutes.Supernatant is removed later, it is secondary with PBS buffer solution resuspension washing, finally according to annexin V-isosulfocyanic acid fluorescence
Plain (FITC) and propidium iodide (PI) staining kit (Invitrogen-V13242) specification handles cell sample.
Cell sample without drug-treated also by double staining and is used as control.FACS fluidic cell is used immediately after cell sample processing
Instrument (BD FACS Canto II) carries out Dual channel detection (FL1:530nm and FL3: > 575nm), and each sample at least detects
10000 cells.As a result as shown in Figure 3.
It uses SPSS Statistics software (supplier: IBM corporation, software version: × L fit 21)
Statistical analysis is provided.(independent-sample T-test) is examined to detect each cell cycle distribution with independent sample
Medicine group and control group mean difference statistically significant (P < 0.05 or P < 0.01) whether is presented.
Such as Fig. 3: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) promotes SK-HEP-1 cell apoptosis assay testing result.
Data are shown with the form for testing duplicate mean+SD twice.Histogram graph representation SK-HEP-1 cell is in contrast solution
It is (DMSO solution containing only 0.2%) and 0.2 μM final concentration of, 0.3 μM, 0.5 μM of (i.e. Δ (20-21) PPT/ Δ (20-22) PPT
(1:3) acts on after SK-HEP-1 cell 72h IC25, IC50 and the IC75 concentration for inhibiting the cell Proliferation) Δ (20-21)
The cell percentages in each stage apoptosis phase are in after acting on 48 hours in PPT/ Δ (20-22) PPT (1:3) solution.On histogram
Error line represent standard deviation.* or * * indicates P < 0.05 or P < 0.01 compared with the control in corresponding stage apoptosis phase.
Analyze result:
Fig. 3 is shown, when low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) the PPT mixing of three kinds of concentration
The control group that the cell in each stage apoptosis phase is added with no drug after object (1:3) acts on 48 hours in SK-HEP-1 cell
When comparing, the cell quantity percentage in early apoptosis and total apoptosis is obviously increased compared with control, and statistically significant is presented in difference
(when Δ (2 0-21) PPT/ Δ (20-22) PPT (1:3) concentration is 0.2 μM and 0.3 μM, P < 0.01；As Δ (20-21) PPT/
When Δ (20-22) PPT (1:3) concentration is 0.5 μM, P < 0.05)；It is also bright that cell quantity percentage in late apoptic compares control
It is aobvious to increase, and statistically significant (P < 0.05) is presented in difference.
Experiment conclusion:
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT mixture (1:3) is in liver adenocarcinoma cell SK-
The increase of generation that can be different degrees of in the HEP-1 each apoptosis phase phase cell number percent directly proportional to Drug level.This
Indicate Δ (20-21) PPT/ Δ (20-22) P PT (1:3) can be different degrees of in SK-HEP-1 cell promotion its wither self
It dies.
Embodiment 5: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) enhances caspase 3 (cas pase-3) activity
Experiment
Laboratory sample: low polarity rare ginsenoside Δ (20-21) the PPT/ Δ (20-22) that embodiment 1 is prepared
PPT mixture (1:3)
Experimental procedure:
Using liver adenocarcinoma cell SK-HEP-1 as experiment cell line, every hole is inoculated with 6000 cells in 96 orifice plates, puts
Set cultivated in cell incubator it is adherent overnight；Then, to the SK-HEP-1 cell in 96 orifice plates, with Tecan D300e
Final concentration of 0.3 μM of plate hole of digital dispenser addition, 0.5 μM, 2.5 μM of (i.e. Δ (20-21) PPT/ Δs (20-22)
PPT (1:3) acts on after SK-HEP-1 cell 72h IC50, IC75 and the IC100 concentration for inhibiting the cell Proliferation) test medicine
Object Δ (20-21) PPT/ Δ (20-22) PPT (1:3).Testing drug is dissolved in DMSO solution, and each concentration sets two again
Hole, the final content in the every hole DMSO is 0.2% in 96 orifice plates.It is blank control wells containing only 0.2%DMSO solution.Later, it shakes up3/7 buffer is simultaneously lyophilized3/7 substrate is to room temperature, and then both mixing make
Substrate, which thoroughly dissolves, forms Caspase detection reagent, saves in 4 DEG C of incubators.Drug/contrast solution is made after tested
After 6 hours, 12 hours and 24 hours, extracting raji cell assay Raji plate from incubator makes itself and equilibrium at room temperature.Then 100 μ L are added
Caspase detection reagent covers sealing plate and shakes 30 seconds into each hole of raji cell assay Raji plate.Finally, cultivating at room temperature
After 30 minutes, opposite photoreading (RLU) is detected with Envision to measure the activity of caspase 3 in sample to be tested.As a result
As shown in Figure 4.
It uses SPSS Statistics software (supplier: IBM corporation, software version: × L fit 21)
Statistical analysis is provided.It is detected with independent sample inspection (independent-sample T-test) under each time point effect,
Average relative brightness number difference between the medicine group and control group of various concentration whether present statistically significant (P < 0.05 or P <
0.01).And testing time point and drug concentration and their phase interaction are detected with two-way ANOVA (Two-way ANOVA)
With the influence (P < 0.05 or P < 0.01) that whether there is statistically significant to every group of average relative brightness number.
Such as Fig. 4: Δ (20-21) PPT/ Δ (20-22) PPT (1:3) is active to caspase 3 in SK-HEP-1 cell
Influence testing result.Data are shown with the form for testing duplicate mean+SD twice.Histogram graph representation SK-HEP-1
Cell is in contrast solution (DMSO solution containing only 0.2%) and 0.3 μM final concentration of, and 0.5 μM, 2.5 μM of (i.e. Δs (20-21)
PPT/ Δ (20-22) PPT (1:3) acts on after SK-HEP-1 cell 72h the IC50 for inhibiting the cell Proliferation, IC75 and
IC100 concentration) SK-HEP-1 solution in act on 6 hours, 12 hours, 24 hours after, the active phase of caspase 3 in cell
To photoreading.Error line on histogram represents standard deviation.* P < 0.05 compared with the control at corresponding time point is indicated.
Analyze result:
Fig. 4 is shown, when 6 hours, 12 in low 1 cell of polarity rare ginsenoside Δ (20-22) PPT to SK-HEP- of addition
Hour and after 24 hours, in cell caspase 3 active and no drug addition control group compared with when, only in medication
When concentration is 2.5 μM, the control at the caspase 3 activity more corresponding time point in cell is obviously increased, and system is presented in difference
Count significant (P < 0.05)；Caspase 3 activity more corresponding time point when Drug level is 0.3 μM and 0.5 μM, in cell
Control without marked difference.Two-way ANOVA result (without on the diagram show) display testing time point and drug concentration and
Interaction between them has a significant effect (P < 0.01) to the activity of caspase 3 in SK-HEP-1 cell.
Experiment conclusion:
Low polarity rare ginsenoside Δ (20-21) PPT/ Δ (20-22) PPT (1:3) is in liver adenocarcinoma cell SK-HEP-1
In can produce the active increase of caspase 3 relevant to testing time point and Drug level.This indicates Δ (20-21)
PPT/ Δ (20-22) PPT (1:3) causes the mechanism of its autologous apoptotic and the activation of caspase 3 to have in the tumour cell
It closes.Caspase 3 is referred to as apoptotic proteins enzyme, and core position is in protease cascade cutting process.Different eggs
Caspase 3 proenzyme is respectively cut in white enzyme, to activate caspase 3, the caspase 3 of activation is further cut
Different substrates leads to protease cascade cutting amplification, finally makes cell deathward.
Claims (10)
1. a kind of low polarity rare ginsenoside mixture, which is characterized in that it is by low polarity rare ginsenoside monomer Δ
(20-21) PPT and low polarity rare ginsenoside monomer Δ (20-22) PPT are mixed.
2. low polarity rare ginsenoside mixture according to claim 1, which is characterized in that the low rare people of polarity
Ginseng saponin monomer Δ (20-21) PPT has the following structure formula:
Low polarity rare ginsenoside monomer Δ (20-22) PPT has the following structure formula:
3. low polarity rare ginsenoside mixture according to claim 2, which is characterized in that the low rare people of polarity
The weight ratio for joining saponin monomer Δ (20-21) PPT and low polarity rare ginsenoside monomer Δ (20-22) PPT is 7:1~1:5.
4. low polarity rare ginsenoside mixture according to claim 2, which is characterized in that the low rare people of polarity
The weight ratio for joining saponin monomer Δ (20-21) PPT and low polarity rare ginsenoside monomer Δ (20-22) PPT is 1:2~1:5.
5. low polarity rare ginsenoside mixture according to claim 2, which is characterized in that the low rare people of polarity
The weight ratio for joining saponin monomer Δ (20-21) PPT and low polarity rare ginsenoside monomer Δ (20-22) PPT is 1:3.
6. low polarity rare ginsenoside mixture described in any one of claims 1 to 5 is in preparation for treating and/or pre-
The drug and/or the purposes in health care product of preventing tumor and/or cancer.
7. purposes according to claim 6, which is characterized in that the tumour and/or cancer is selected from malignant tumour, lymph
It is the hematopoetic tumor of system, the hematopoetic tumor of marrow system, the tumour of the interstitial origin cause of formation, the tumour of maincenter and peripheral nervous system, black
In plain tumor, seminoma, teratocarcinoma, osteosarcoma, exophytic pigment neck tumor, thyroid gland filter capsule cancer and Kaposi's sarcoma, wherein
The malignant tumour includes but is not limited to bladder cancer, breast cancer, colon cancer, kidney, liver cancer, lung cancer, head and neck cancer, oesophagus
Cancer, gallbladder cancer, oophoroma, cancer of pancreas, gastric cancer, cervix cancer, thyroid cancer, prostate cancer and/or skin cancer；
The hematopoetic tumor of the lymphatic system includes but is not limited to leukaemia, acute lymphoblastic leukemia, acute thin at lymph
Born of the same parents' leukaemia, B- cell lymphom, T- cell lymphom, Huo Qijin lymph cancer, non-Huo Qijin lymph cancer, hairy cell lymphom,
Mantle cell lymphoma, myeloma and/or BurkettShi lymph cancer；
The hematopoetic tumor of the marrow system includes but is not limited to that acute and chronic myelocytic leukemia, myeloproliferative disorder are comprehensive
Simulator sickness and/or promyelocytic leukemia；
The tumour of the interstitial origin cause of formation includes but is not limited to fibrosarcoma and/or rhabdomyosarcoma；
The tumour of the maincenter and peripheral nervous system includes but is not limited to astrocytoma, at fibroneuroma, neuroglia
Tumor and/or neurinoma.
8. low polarity rare ginsenoside mixture according to any one of claims 1 to 5 is preparing for immunological regulation, is changing
Kind microcirculation and/or the drug for improving quality of life and/or the purposes in health care product.
9. a kind of composition, which is characterized in that mixed including low polarity rare ginsenoside described in any one of claims 1 to 5
Close object.
10. composition according to claim 9, which is characterized in that the composition is pharmaceutical preparation, the pharmaceutical preparation
Comprising as described in any one of claims 1 to 5 low polarity rare ginsenoside mixture and pharmaceutically acceptable dilution
Agent, carrier, excipient, auxiliary material or medium,
The dosage form of the pharmaceutical preparation be peroral dosage form, injection type or Topical application forms,
The peroral dosage form be tablet, pulvis, suspension, emulsion, capsule, granule, sugar coated tablet, pill, liquid, spirit,
Syrup or limonada,
The injection type includes aqua, suspension or solution,
The Topical application forms include ointment, solid, suspension, aqua, spirit, pulvis, paste, suppository, aerosol, mud apply
Agent, liniment, lotion, enema or emulsion；
Alternatively, the composition is health care product, it includes polarity rare ginsenosides low as described in any one of claim 1-5
Acceptable carrier in mixture and health care product.
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| Title |
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