CN109640978A - The lung cancer prevention for including using apiolin, curcumin and honokiol as effective component or treatment pharmaceutical compositions - Google Patents
The lung cancer prevention for including using apiolin, curcumin and honokiol as effective component or treatment pharmaceutical compositions Download PDFInfo
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- CN109640978A CN109640978A CN201780052022.4A CN201780052022A CN109640978A CN 109640978 A CN109640978 A CN 109640978A CN 201780052022 A CN201780052022 A CN 201780052022A CN 109640978 A CN109640978 A CN 109640978A
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Abstract
The present invention relates to a kind of using any one of apiolin and curcumin and honokiol prevents as the lung cancer that effective component includes or treatment pharmaceutical compositions.Composition according to the present invention, compared with the case where individually handling apiolin, curcumin or honokiol, when mixed processing, can mutually rise ground cancer cell specific induction of apoptosis.The lung cancer prevention or treatment for including using any one of apiolin and curcumin and honokiol mixture as effective component according to the present invention improve anticancer effect with pharmaceutical compositions, very excellent treatment of cancer reinforcing effect can be shown with cancer cell specific induction of apoptosis.Therefore, composition according to the present invention can be efficiently applied to lung cancer prevention, improve or treat.
Description
Technical field
The present invention relates to the treatment lung cancer effects of any one of apiolin or curcumin and honokiol mixture.
Background technique
Cancer (cancer) refers to being caused by many reasons balance between cell division and apoptosis, by lasting point
Split and be proliferated and the abnormal cell group that generates, also referred to as malignant tumour.In general, cancer can include internal organs, leucocyte,
Multiple positions of 100 kinds or more bodies including bone, lymph node etc. are fallen ill, and the phenomenon that pass through wet periphery (perimeter) tissue and to
The mobile transfer of other organs and develop into serious symptoms, eventually lead to death.Wherein, malignant tumour, that is, lung originating from lung
Cancer-root is broadly divided into Small Cell Lung Cancer (small cell lung cancer) and non-small cell lung cancer according to its tissue morphology
(non-sma ll cell lung cancer).The Small Cell Lung Cancer is divided into lung cancer according to the position of incidence tissue
A part, but with other lung cancer it is clinical pass through, treatment method and in terms of there is the feature clearly distinguished, therefore into
Row is as above distinguished.In addition, non-small cell lung cancer divides into gland cancer, dermoid cancer and large cell carcinoma according to tectotype.
Specifically, Small Cell Lung Cancer substantially lump is big, has canescence, is proliferated along bronchial wall.Small Cell Lung Cancer is big
Part had just had evolved to the degree being difficult through operation excision in diagnosis at that time, and grade malignancy is high, therefore fast-growth, held
It changes places and is shifted by lymphatic vessel or blood circulation to whole body.But significant treatment effect can be obtained by chemotherapy or radiotherapy
Fruit.The main organs of the Small Cell Lung Cancer transfer are reported as brain, liver, bone, lung, adrenal gland, kidney etc., mainly first in gas
Manage (bronchus or bronchiole) morbidity.
On the contrary, as described above, non-small cell lung cancer is divided into gland cancer (adenocarcinoma), dermoid cancer
(squamous cell carcinoma) and large cell carcinoma (large-cell carcinoma).Firstly, gland cancer occurs mainly in
Lung tip position, also often occurs in women or non-smoker, and big slight but transferred situation is more.Recently, it sends out
Sick frequency shows increased trend.Secondly, dermoid cancer is mainly found in lung central part, Xiang Zhiqi in most cases
Tube cavity growth causes to occur blocking bronchial symptom.Male's morbidity is relatively common, has close association with smoking.Finally,
Large cell carcinoma occur mainly in lung surface nearby (lung tip), it is approximately half of big bronchus occur, account for whole lung cancer 4~
10% or so, cell size is generally large.Wherein, a part has a tendency of fast breeding and transfer, large cell carcinoma with it is other
Non-small cell lung cancer is compared, and prognosis situation is poor.
If above-mentioned lung cancer when being diagnosed in early days, can obtain rehabilitation by drug therapy and radiation cure etc., but
Be when condition worse to a certain extent when, so that it may first pass through operation remove lesion, pass through drug therapy and radiation cure etc.
It is treated.So far, the generally acknowledged drug that can be used for treating lung cancer is confined to several, and therefore, it is difficult to execute to be suitable for patient
Treatment, and its side effect is also the big problem faced.It is most of just to have discovered that cancer when observing tumour the 1st time
Transfer, the success rate after performing the operation are low.
Therefore, as the new mean of access for the treatment of cancer, constantly it is being dedicated to utilizing the lower natural materials of toxicity always
It research and development Small side effects and is able to suppress cancer metastasis or makes the efficiency of cancer cell reduction significantly carcinogenic inhibitor and cancer
Therapeutic agent.But these not yet solve (Korean Patent public affairs derived from the bad fundamental drawback of the therapeutic agent therapeutic effect of natural materials
The number of beginning the compilation of 10-2012-0109139).
In this background, the present inventor passes through to develop the preparation for capableing of more safe and effective treatment lung cancer
Arduous research, it is final to confirm apiolin or curcumin；And honokiol mixture can cause the apoptosis of lung cancer cell line simultaneously
The proliferation that can inhibit cancer cell finds that it is effectively used for lung cancer therapy composition, so as to complete the present invention.
Summary of the invention
Technical problem to be solved
The present invention is exactly to research and develop in order to solve the above problem.The present inventor confirms through independent or mixing administration celery
The glycolysis speed that element, curcumin, honokiol can obtain lung cancer cell line reduces, inhibits ANT2 expression, inhibits HK2 table
It reaches, PD-L1 is inhibited to express and reduce the effect of ATP production.Based on this, the present invention is completed.
Therefore, the object of the present invention is to provide one kind with any one of apiolin and curcumin and honokiol is
The lung cancer prevention or treatment pharmaceutical compositions that effective component includes.
In addition, another object of the present invention is to provide one kind with any one of apiolin and curcumin and magnolia obovata
Phenol is the lung cancer prevention or improvement healthy functions food compositions that effective component includes.
But the technical problems to be solved by the invention are not intended to be limited to above-mentioned project, for not yet mentioning
The other projects arrived, those skilled in the art just have specific understanding by following record.
The method for solving technical problem
In order to realize above-mentioned purpose of the invention, the present invention provide it is a kind of with any one of apiolin and curcumin and and
Magnolol is the lung cancer prevention or treatment pharmaceutical compositions that effective component is included.
It is to have that another object of the present invention is to provide one kind with any one of apiolin and curcumin and honokiol
The lung cancer prevention or improvement healthy functions food compositions that effect ingredient is included.
Example is realized as of the invention one, and the composition includes using apiolin and honokiol as effective component.
As another realization example of the invention, the composition includes using curcumin and honokiol as effective component.
As another realization example of the invention, the composition can make ANT2 (Adenine nucleotide translocator 2；
Adenine nucleotide translocator 2) gene expression reduce.
As another realization example of the invention, the composition can make HK2 (Hexokinase 2；Hexokinase 2) or
PD-L1 (programmed death ligand 1；Programmed death-ligand 1) protein expression reduce.
In addition, the present invention provide it is a kind of comprising by the pharmaceutical compositions to the lung cancer of individual dosing step prevent or treat
Method.
In addition, the lung cancer that the present invention provides a kind of pharmaceutical compositions is prevented or therapeutical uses.
The effect of invention
The present invention relates to one kind with apiolin or curcumin；And honokiol is that the lung cancer prevention of effective component or treatment are used
Pharmaceutical compositions.Composition according to the present invention, compared with the case where individually handling apiolin, curcumin or honokiol,
If be mixed or and with processing, can mutually rise ground cancer cell specific induction of apoptosis.The present invention is in apiolin and curcumin
Any and honokiol mixture be effective component lung cancer prevention or treatment with pharmaceutical compositions can be improved anticancer imitate
Fruit, cancer cell specific induction of apoptosis, to show that very good treatment of cancer increases effect.Therefore, combination according to the present invention
Object can be effectively used for lung cancer prevention, improve or treat.
Detailed description of the invention
Fig. 1 is individually or when mixed processing to carry out honokiol, apiolin, curcumin to lung cancer cell line apoptosis effect
The result of confirmation；
Fig. 2 be by honokiol, apiolin, curcumin individually or when mixed processing to the ANT2 expression suppression of lung cancer cell line
The result that effect processed is confirmed；
Fig. 3 is individually or when mixed processing to subtract honokiol, apiolin, curcumin to the ATP production of lung cancer cell line
The result that few effect is confirmed；
Fig. 4 be by honokiol, apiolin, curcumin individually or when mixed processing to the HK2 expression suppression of lung cancer cell line
The result that effect processed is confirmed；
Fig. 5 be by honokiol, apiolin, curcumin individually or when mixed processing to the glycolysis speed of lung cancer cell line
The result that (glycolysis rate) reducing effect is confirmed；
Fig. 6 a be by honokiol, apiolin, curcumin individually or when mixed processing to PD-L1 in lung cancer cell types
The result that expression inhibiting effect is confirmed；
Fig. 6 b be by honokiol, apiolin, curcumin individually or when mixed processing to PD- in lung cancer cell line H2228
The result that L1 expression inhibiting effect is confirmed.
Specific embodiment
Composition according to the present invention includes to confirm using apiolin or curcumin and honokiol mixture as effective component
To the glycolysis speed of reduction lung cancer cell line, inhibition ANT2 expression, HK2 expression, inhibition PD-L1 is inhibited to express and reduce
ATP production is based on this, completes the present invention to have lung cancer prevention, improvement or therapeutic effect.
In the following, the present invention is described in detail.
The present invention provides one kind with apiolin or curcumin；And honokiol is the lung cancer prevention or control that effective component includes
Treatment composition.The composition includes pharmacy and healthy functions food compositions.
Term used in the present invention " prevention " refers to by the way that pharmaceutical compositions inhibition lung cancer phase according to the present invention is administered
All behaviors of related disorders or delayed onset.
Term used in the present invention " treatment ", referring to makes the disease of lung cancer by the way that pharmaceutical compositions according to the present invention are administered
Shape improvement becomes advantageous all behaviors.
The object disease that composition of the invention prevents, treats i.e. " cancer (cancer) " is due to biological tissue's inner cell
It is unlimitedly proliferated and is caused the disease of malignant tumour, more specifically, can be lung cancer, but be not only defined in this.
" honokiol (honokiol) " is a kind of polyphenol compound used in the present invention, can be from Magnoliaceae species
Separation, purification or extraction in (Magnolia species).More specifically, can separate, purify or extract from Cortex Magnoliae Officinalis tree, but
It is not only defined in this, passes through can using for the compound that is chemically synthesized or mercantile-type sale.Furthermore it is possible to be with
Derivative of magnolol or the like, but not only it is defined in this.
" apiolin (apigenin, 5,7,4'- trihydroxyflavone used in the present invention；5,7,4'-trihydrox
Yflavone) " be a kind of flavonoids series compound, can not only be found in locust tree tree extract, but also largely deposit
It is the vegetables such as the fruit such as orange, apple, cherry, grape and onion, caraway, celery, barley, tomato or tea, grape
In the beverages such as wine, it can therefrom be separated, purified or be extracted, but not only be defined in this, pass through the change being chemically synthesized
Close can using for object or mercantile-type sale.Furthermore it is possible to be derivative of apiolin or the like, but not only it is defined in
This.
" curcumin (curcumin) " is a kind of alkaloid compound used in the present invention, can be from turmeric or Radix Curcumae
Middle separation, purification are extracted, but are not only defined in this, pass through all may be used for the compound that is chemically synthesized or mercantile-type sale
To use.Furthermore it is possible to be derivative of curcumin or the like, but not only it is defined in this.
In addition, to can be the lung cancer for including using apiolin and honokiol as effective component pre- for composition according to the present invention
Anti-, improvement or therapeutic composition, but not only it is defined in this.
In addition, to can be the lung cancer for including using curcumin and honokiol as effective component pre- for composition according to the present invention
Anti-, improvement or therapeutic composition, but not only it is defined in this.
In addition, composition according to the present invention, which is characterized in that make ANT2 (Adenine nucleotide
Translocator 2) gene expression reduce.
" ANT2 (Adenine nucleotide translocator 2) " of the invention is a kind of life in cancer cell
Deposit, be proliferated and transfer process in critical function gene.Adenosine acid transporter enzyme/2 protein of transporter (ANT) is
A kind of most protein in mitochondrial inner membrane is formed as six transbilayer helixes.ANT promotes mitochondrial ATP to be converted into cell
Matter ADP plays a significant role during cellular energy metabolism.Mitochondria can be had an impact as a result,.It is all
Mammal all have the isotype (isoform) of ANT1~ANT3, the ANT2 as the isotype family is converted to line
It will increase during ADP in plastochondria and absorbed by the tenuigenin A TP that glycolytic cycle generates, thus, it is possible to keep mitochondrial membrane
The missing (knockdown) of current potential, ANT2 can reduce the membrane potential difference in cancer cell.
In addition, composition according to the present invention, which is characterized in that make HK2 (hexokinase 2) or PD-L1
The expression of (Programmed death-ligand 1) protein is reduced.
" HK2 (hexokinase 2) " of the invention is a kind of will to make it by phosphatizing treatment with the hexoses of 6 carbon
The enzyme of pbosphohexose is converted to, although expression quantity of the HK2 in normal cell is few, the expression quantity in most of cancer cell
But very high, have the function of making glucose phosphorylation, while simultaneously block cell withers in conjunction with the VDAC protein of mitochondria
Mechanism (Apoptosis) is died, has the function of enhancing cancer cell viability.Therefore, it can be effectively used for the cancer using HK2 as target
Treatment.
In addition, to be that one kind is present in cancer thin for " PD-L1 (Programmed death-ligand 1) " protein of the invention
The protein of cellular surface, when the T cell with cancer cell killing effect is tied with the i.e. PD-L1 of protein for being present in cancer cell surfaces
When conjunction, T cell can not just attack cancer cell, to lose the effect for killing cancer cell.Immunity anticancer agent can prevent antibody and PD-
L1 protein combines, to allow T cell active attack cancer cell.The anticancer agent enhances human immune system, and there is no existing
The side effect or patience that anticancer agent generates.Therefore, as one of immune avoidance strategy of cancer cell, by adjusting PD-L1's
Expression, and utilize the variation of immunologic test point (immune checkpoint) function, so that it may inhibit tomour specific T lymph thin
The function of born of the same parents.
In one embodiment of the invention, by by honokiol, apiolin, curcumin individually or mixing it is thin to lung cancer
Born of the same parents' strain is handled, it is thus identified that the apoptosis effect of cancer cell (referring to embodiment 1).Simultaneously, it is thus identified that by honokiol, celery
Element, curcumin individually or when mixed processing the ANT2 expression inhibiting effect (referring to embodiment 2) of lung cancer cell line, ATP produce and subtract
Few effect (referring to embodiment 3), HK2 expression inhibiting effect (referring to embodiment 4), glycolysis speed reducing effect are (referring to implementation
Example 5) and PD-L1 expression inhibiting effect (referring to embodiment 6).
Therefore, according to the present invention include using any one of apiolin and curcumin and honokiol as effective component
Pharmaceutical compositions can reduce the glycolysis speed of lung cancer cell line, inhibit ANT2 expression, inhibits HK2 expression, inhibits PD-L1 table
It reaches and reduces ATP production, be also used as the effective component of lung cancer prevention, improvement or therapeutic composition.
Pharmaceutical compositions according to the present invention other than effective component, may also include allow in pharmacy using load
Body.In this case, allow in pharmacy using carrier be a kind of substance common when deploying preparation, including lactose,
Glucose, sucrose, D-sorbite, mannitol, starch, locust tree glue, calcium phosphate, alginate, gelatin, calcium silicates, microcrystalline cellulose
Element, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl p-hydroxybenzoate, P-hydroxybenzoic acid third
Ester, talcum, magnesium stearate and mineral oil etc., but not only it is defined in this.In addition, other than mentioned component, it can also be further
Including lubricant, wetting agent, sweetener, fumet, emulsifier, suspending agent, preservative agent etc..
Pharmaceutical composition of the invention can use oral administration or non-oral administration according to method as a purpose
(such as: for intravenous, subcutaneous, intraperitoneal or local), state and weight, the degree of disease, medicine of the dosage according to patient
Object form, administration route and time are without same, but those skilled in the art can suitably select.
Pharmaceutical composition of the invention is by pharmaceutically effective amount administration.In the present invention, " pharmaceutically effective amount "
Refer to that effective dose standard can according to sufficient quantity needed for can be used for reasonable benefit/hazard ratio treatment disease of therapeutic treatment
With according to the kinds of Diseases comprising patient, severity, the activity of drug, to the susceptibility, administration time, administration route of drug
And factor including discharge ratio, the drug that uses during treatment, simultaneously and the well-known factor of other medical domains are determined
It is fixed.Pharmaceutical compositions according to the present invention both can be used as single Therapeutic Administration or with other therapeutic agent and with being administered, can
It, can single or multiple administrations in order or to be administered simultaneously with existing therapeutic agent.Importantly, above-mentioned factor is all considered
Under the premise of inside and not generating side effect, to be carried out according to the dosage standard that can obtain maximum efficiency with least amount to
Medicine, this point those skilled in the art can easily determine.
Specifically, the effective quantity of medicament of the present invention composition is according to the age of patient, gender, state, weight, in vivo work
Absorptivity, inertia rate and the drainage rate of property ingredient, the drug of kinds of Diseases and it is different.In general, according to every 1kg
The standard of 0.001~150mg of weight is administered, preferably 0.01~100mg, it is daily or the next day be administered or be divided within 1st 1~3 time
It is administered.However, it is possible to be increased and decreased according to administration route, fat severity, gender, weight, age etc..Cause
This, the dosage will not be limited the scope of the invention in which kind of method.
In addition, composition of the invention can be added to healthy functions food with the prevention of lung cancer related disease or improvement purpose
In.It, can be by describedization if there is the compound of lung cancer prevention or improvement to use as food additives the present invention
It closes object directly to add or be used together with other food or food composition, can suitably use according to conventional methods.Effectively at
The combined amount divided can suitably be determined according to purpose (prevention, health or rapeutic treatment) is used.In general, it is producing
When food or beverage, the compound of the present invention is relative to raw material according to 15 weight % or less, it is preferable that according to 10 weight % or less
Amount be added.But when carrying out taken long-term for the purpose of health and health or for the purpose of health adjusting, the amount
It can be with below for the range.It in terms of safety, does not have any problems, therefore the dosage of effective component can also be
It is more than the range.
The type of the food is not particularly limited.Example as the food that can add the substance has, meat, perfume (or spice)
Intestines, chocolate, confectionery, snack categories, Biscuits, Piza, instant noodles, other noodles, chewing gum class, include ice cream at bread
Dairy products, various soup, drinking water, tea, drink, pick-me-up and compound vitamin including class etc., on ordinary meaning
Healthy functions food is all included.
Healthy beverage composition of the invention as common beverage, can also be contained with supplementary element there are many fumet or
Natural carbohydrate etc..Above-mentioned natural carbohydrate is the disaccharides such as monosaccharide, maltose and the sucrose such as glucose and fructose, paste
The sugar alcohols such as polysaccharide and xylitol, D-sorbite and antierythrite such as essence and cyclodextrin.Talin, sweet tea can be used in sweetener
Synthetic sweeteners such as natural sweeteners or saccharin, Aspartame such as leaf chrysanthemum extract etc..In general, the natural carbon aquation
It is about 0.01-0.20g that the ratio for closing object, which is every 100ml composition its dosage of the invention, it is preferable that its dosage is 0.04-
0.10g。
Other than mentioned component, composition of the invention can contain there are many nutritional agents, vitamin, electrolyte, flavor
Agent, colorant, pectic acid and its salt, alginic acid and its salt, organic acid, protective colloid thickener, pH adjusting agent, stabilizer,
Preservative, glycerol, alcohol, for carbonating agent of soda etc..In addition, composition of the invention can be containing for producing
The pulp of fruit juice, fruit drink and vegetable beverage.These ingredients independent or combined can use.Although these additives
Ratio is not too important, but the present composition of every 100 parts by weight its dosage is generally in the range of 0.01-0.20 parts by weight
Selection.
As another form of the invention, the present invention provides a kind of comprising walking the pharmaceutical compositions to individual administration
Rapid lung cancer therapy method.In the present invention, so-called " individual " refers to the object for needing to implement disease treatment, more specifically, being
Refer to the mammalitys such as people or inhuman primate, rat (mouse), dog, cat, horse and ox.
In the following, some preferred embodiments will be enumerated in order to help to understand the present invention.But it enumerates following
The purpose of embodiment is to be able to be more readily understood that the present invention, rather than is limited by following embodiment of the invention interior
Hold.
[embodiment]
The lung cancer cell line apoptosis effect individually or when mixed processing by honokiol, apiolin, curcumin of embodiment 1.
In order to confirm that honokiol, apiolin, curcumin lead to the effect of lung cancer cell line apoptosis, with human lung carcinoma cell line
A549 (adenocarcinomic human alveolar basal epithelial cells) be object, by honokiol,
Apiolin, curcumin (Sigma-Aldrich) carry out independent or mixed processing.By human lung carcinoma cell line honokiol, celery
When the concentration that element, curcumin are handled is determined as being administered alone by administration concentration curve (dose-concentration curve)
Induce cell apoptosis reach 20% concentration (IC20: inhibitory concentration 20) i.e. 10 μM, it has carried out individually
With mixed processing.After processing 24 hours, CCK8assay (Cell Counting Kit-8, Dojindo Molecular is utilized
Technologies, Inc) the apoptosis effect of lung cancer cell line is analyzed.
Its result is as shown in Figure 1, compared with the case where individually handling honokiol, apiolin or curcumin, at mixing
Apoptic effects dramatically increase when reason.Specifically, Apoptosis caused by honokiol is individually handled is 19%, apiolin list
Apoptosis caused by managing of staying alone is 22%, and Apoptosis caused by curcumin is individually handled is 20%, compared with the above results
Compared with Apoptosis caused by honokiol+apiolin mixture is 79%, cell caused by honokiol+curcumin mixture
Apoptosis is 83%.It is possible thereby to confirm, apoptic effects caused by the mixture are not simple additive effect
(additive effect), but a kind of synergistic effect (synergistic effect).It can thus be seen that suffering to lung cancer
When person treats, compared with the case where being administered alone honokiol, apiolin, curcumin, honokiol+apiolin or and
Lung cancer therapy effect can be enhanced in magnolol+curcumin mixing administration.
By honokiol, apiolin, curcumin, individually or when mixed processing the ANT2 of lung cancer cell line is expressed embodiment 2.
Inhibitory effect
In order to confirm honokiol, apiolin, curcumin ANT2 expression inhibitory effect, with human lung carcinoma cell line A549
For object, honokiol, apiolin, curcumin independent or mixed processing has been subjected to.Then, in order to confirm lung cancer cell line
ANT2 mRNA expresses repressed situation, performs qRT-PCR analysis.More specifically, by human lung carcinoma cell line A549 with 10 μM
Honokiol, apiolin, curcumin carried out individually or mixed processing.After 24 hours, RNAs (TRIzol RNA is extracted
Isolation Reagents, Thermo Sientific), pass through reverse transcription reaction (RT:reverse transcription)
By cDNA synthesis (PrimeScript 1st strand cDNA Synthesis Kit, Takara) and then utilize SYBR
(SYBR Premix Ex Taq, Takara) implements real-time polymerase chain reaction (real-time polymerase chain
reaction:qPCR).ANT2 (adenine nucleot ide translocase 2) as analysis object is a kind of public affairs
Know the gene that extremely important effect is played for existence, proliferation and the transfer to cancer cell.
The analysis and utilization of qRT-PCR experimental result following formula.
[fold change=2- Δ Δ Ct, where Δ Δ Ct=(Ct of gene of interest, treat ed-
Ct of HK gene,treated)-(Ct of gene of interest,control-Ct of HK gene,
control),Ct was the threshold cycle number and HK was the house-keeping
gene.]
In addition, the primer base sequences for qPCR are as described in Table 1.
[table 1]
Its result is as shown in Fig. 2, it has been confirmed that by honokiol, apiolin, curcumin is independent or mixed processing will lead to
ANT2 expression is reduced.Compared with the case where individually handling honokiol, apiolin, curcumin, according to honokiol+apiolin
Or honokiol+curcumin, when being handled, the expression inhibiting effect of ANT2 is relatively higher.
It is possible thereby to judge, honokiol+apiolin or honokiol+curcumin are mixed into administration, can obtain with
The cancer that ANT2 siRNA, that is, shRNA (short hairpin RNA) or siRNA (short interfering RNA) are generated
The similar curative effect of disease therapeutic effect.In addition, by honokiol, ANT2 caused by apiolin, curcumin be independent or mixed processing subtracts
Few effect utilization siRNA reduces ANT2, so as to solve the problems, such as to exist when cancer is implemented and treated, i.e., with
Problem of the siRNA or shRNA to internal transport (delivery system) correlation.
By honokiol, apiolin, curcumin, the ATP production of lung cancer cell line subtracts embodiment 3. individually or when mixed processing
Few effect
By the result in the embodiment 2 it has been confirmed that human lung carcinoma cell line is utilized honokiol, apiolin, ginger
When flavine carries out independent or mixed processing, effectively ANT2 can be inhibited to express.Therefore, because of the function of ANT2 to cancer cell
ATP has produced conclusive effect, it is contemplated that honokiol, apiolin, curcumin independent or mixed processing will to will lead to cancer thin
The ATP of born of the same parents, which is produced, to be reduced.
Therefore, effect is reduced in order to confirm that ANT2 expression inhibiting causes the ATP of lung cancer cell line to produce, by human lung carcinoma cell
Strain A549 has carried out independent or mixed processing using honokiol, apiolin, curcumin.Then, CellTiter-Glo is utilizedTM
Luminescent Cell Viability assay kits (Promega) is analyzed.
Its result is as shown in figure 3, when carrying out independent or mixed processing for honokiol, apiolin, curcumin, it is thus identified that will
The ATP of human lung carcinoma cell line produces the result effectively reduced.In particular, by honokiol+apiolin, honokiol+curcumin
When mixing administration, compared with the case where being administered alone, ATP production reduces effect to be enhanced relatively.
It is possible thereby to judge, the reduction of the required energy, that is, ATP of existence can inhibit the growth of cancer cell, final to induce cancer thin
Born of the same parents' apoptosis, therefore, individually or mixing administration can inhibit the expression of ANT2 by honokiol, apiolin, curcumin, to induce
ATP production is reduced.Therefore, inhibitory effect can be produced by ATP in cancer cell and improves treatment of cancer effect.
By honokiol, apiolin, curcumin, individually or when mixed processing the HK2 of lung cancer cell line expresses suppression to embodiment 4.
Effect processed
In order to confirm honokiol, ANT2 expression inhibiting caused by apiolin, curcumin are independent or mixed processing whether
The expression of enzyme, that is, Hexokinase 2 (HK2) for intervening glycolysis is adjusted, it, will be with using human lung carcinoma cell line A549 as object
Magnolol, apiolin, curcumin individually or mixed processing.Then, it is analyzed using qRT-PCR.
The analysis and utilization of qRT-PCR experimental result following formula.
[fold change=2- Δ Δ Ct, where Δ Δ Ct=(Ct of gene of interest, treated-
Ct of HK gene,treated)-(Ct of gene of interest,control-Ct of HK gene,
control),Ct was the threshold cycle number and HK was the house-keeping
gene.]
In addition, the primer base sequences for qPCR are as described in Table 2.
[table 2]
Its result is as shown in figure 4, can be confirmed, by honokiol, apiolin, curcumin individually or when mixed processing,
The expression of HK2 significantly reduces, compared with the case where individually handling honokiol, apiolin, curcumin, by honokiol+celery
When dish element or honokiol+curcumin mixed processing, the expression inhibiting effect of HK2 is relatively higher.
The HK2 enzyme its expression quantity in normal cell is few, but the expression quantity of HK2 is but very in most of cancer cell
It is high.In addition, the HK2 enzyme not only makes glucose phosphorylation, but also the block cell apoptosis in conjunction with the VDAC protein of mitochondria
Mechanism (Apoptosis).Thus, it is possible to play the function of enhancing cancer cell viability.Therefore, honokiol+apiolin is mixed
Closing object or honokiol+curcumin mixture processing causes HK2 expression to be suppressed significantly, so as to using HK2 as target
In cancer treatment procedure, enhance its therapeutic effect.
The glycolysis speed of the lung cancer cell line individually or when mixed processing by honokiol, apiolin, curcumin of embodiment 5.
Spend (glycolysis rate) reducing effect
By the result of the embodiment 4 it has been confirmed that individually or mixed processing by honokiol, apiolin, curcumin
Have the effect of inhibiting HK2 expression.Therefore, in order to confirm by honokiol, apiolin, curcumin individually or mixed processing whether
The glycolysis speed that can reduce lung cancer cell line, using human lung carcinoma cell line A549 as object, by honokiol, apiolin, ginger
Flavine individually or mixed processing.Then, it is analyzed using Lactate Assay Kit (Biovision).
Its result is as shown in figure 5, can be confirmed, individually or mixed processing by honokiol, apiolin, curcumin, tool
There is the effect for the glycolysis reduction for leading to human lung carcinoma cell line.In particular, individually being given with by honokiol, apiolin, curcumin
The case where medicine, is compared, and when honokiol+apiolin or honokiol+curcumin are mixed administration, glycolysis reduces effect enhancing.
In addition, in the glucose metabolic process of cancer cell, due to the oxidative phosphorylation approach existing defects of mitochondria, because
This it is assumed that it is main ATP is only produced by glycolytic cycle under the premise of, pass through the ATP production efficiency of glycolytic cycle than aoxidizing
Phosphorylation efficiency is lower.Therefore, cancer cell just must execute glycolysis to produce sufficient ATP with very high standard
Journey.Therefore, according to assessment, target of the metabolic inhibition generated by the inhibition with cancer metabolizing enzyme as treatment of cancer,
It is worth very high.Thus expect, glycolysis caused by honokiol+apiolin or honokiol+curcumin mixed processing is subtracted
Few effect will be efficiently applied to lung cancer therapy.
By honokiol, apiolin, curcumin, individually or when mixed processing the PD-L1 of lung cancer cell line is expressed embodiment 6.
Inhibitory effect
In order to confirm honokiol, the PD- of human lung carcinoma cell line caused by apiolin, curcumin be independent or mixed processing
L1 expression inhibiting effect carries out honokiol, apiolin, curcumin single using human lung carcinoma cell line A549 and H2228 as object
Only or mixed processing.Then, by the expression degree in PD-L1 protein standards using Western blotting (Western-blot) into
Analysis (PD-L1antibody is gone；cell-signaling,Actin antibody:santa cruze).
As shown in Figure 6 a, in the lung cancer cell types used in the 1~embodiment of embodiment 5 PD-L1 expression
Very low (PD-L1low), therefore be judged as and be difficult to confirm whether honokiol, apiolin, curcumin cause the expression of PD-L1 to subtract
It is few, so having used the higher lung cancer cell line H2228 (PD-L1 of the expression of PD-L1high)。
Its result is as shown in Figure 6 b, it is observed that by honokiol, apiolin, curcumin individually or when mixed processing,
The expression of PD-L1 can effectively be inhibited.In particular, when honokiol, apiolin or curcumin are individually handled, it can be faintly
It observes that the expression of PD-L1 is reduced, but when by honokiol+apiolin or honokiol+curcumin mixed processing, can observe
Expression to PD-L1 is very strongly suppressed.
If having the T cell for killing cancer cell effect in conjunction with the protein i.e. PD-L1 for being present in cancer cell surfaces, T
Cell can not then attack cancer cell, to lose the effect for killing cancer cell.Immunity anticancer agent can prevent antibody and PD-L1 albumen
Matter combines, to allow T cell active attack cancer cell.The anticancer agent enhances human immune system, therefore there is no existing anti-
The side effect or patience that cancer agent generates.Therefore, as one of immune evasion strategy of cancer cell, pass through the expression tune of PD-L1
Section, and utilize the variation of immunologic test point (immune checkpoint) function, so that it may inhibit tomour specific T lymphocyte
Function.That is, activating this inhibition immunologic test point, in tumour cell so as to escape tomour specific T- lymphocyte
Attack.Recently it is well known that, its function is inhibited using the monoclonal antibody of PD-L1, enhances tomour specific T- lymph
Cell activity and effect, it is possible thereby to obtain antitumous effect.A variety of cancer cells are obtained using PD-L1 as the treatment method of target
The very effective clinical efficacy had no precedent before this.
It is possible thereby to confirm, honokiol+apiolin or honokiol+curcumin are mixed ANT2 caused by being administered or
HK2 expression inhibiting can not only be induced cell apoptosis directly, and inhibit that the immune of lung carcinoma cell can also be overcome by PD-L1
Escape mechanism.Therefore it will eventually enhance the effect for the treatment of of cancer.
The explanation of aforementioned present invention is exemplary, it should be understood that the skill with the technical field of the invention general knowledge
Art personnel can easily be changed to other specific under the premise of not changing technical idea of the invention or mandatory attribute
Form.Therefore, embodiment listed above is all exemplary in structure at all levels, is not delimit the scope of the invention.
Industrial utilizability
Composition according to the present invention, compared with the case where individually handling apiolin, curcumin or honokiol, mixing
Or and mutually rise ground cancer cell-apoptosis with that can induce when handling.According to the present invention with any one of apiolin or curcumin
And honokiol mixture is that lung cancer prevention that effective component includes or treatment pharmaceutical composition improve anticancer effect, it can be with
Cancer cell specific induction of apoptosis shows very excellent treatment of cancer reinforcing effect.Therefore, composition according to the present invention can be with
It is efficiently applied to lung cancer prevention, improves or treats.
<110>hundred Ao Yi good fortune limited liability companies
<120>the lung cancer prevention or treatment pharmacy group for including as effective component using apiolin, curcumin and honokiol
Close object
<130> DFP19KR3534
<150> KR 10-2016-0111383
<151> 2016-08-31
<160> 8
<170> KoPatentIn 3.0
<210> 1
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> ANT2_forward primer
<400> 1
acgtgtctgt gcagggtatt 20
<210> 2
<211> 19
<212> DNA
<213> Artificial Sequence
<220>
<223> ANT2_reverse primer
<400> 2
gtgtcaaatg gataggaag 19
<210> 3
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> GAPDH_forward primer
<400> 3
aaggtgaagg tcggagtcaa 20
<210> 4
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> GAPDH_reverse primer
<400> 4
aatgaagggg tcattgatgg 20
<210> 5
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HK2_forward primer
<400> 5
caaagtgaca gtgggtgtgg 20
<210> 6
<211> 20
<212> DNA
<213> Artificial Sequence
<220>
<223> HK2_reverse primer
<400> 6
gccaggtcct tcactgtctc 20
Claims (12)
1. a kind of lung cancer prevention or treatment pharmaceutical compositions, which is characterized in that
With apiolin or curcumin；And
Honokiol includes for effective component.
2. lung cancer prevention according to claim 1 or treatment pharmaceutical compositions, which is characterized in that
The composition includes using apiolin and honokiol as effective component.
3. lung cancer prevention according to claim 1 or treatment pharmaceutical compositions, which is characterized in that
The composition includes using curcumin and honokiol as effective component.
4. pharmaceutical compositions according to claim 1, which is characterized in that
The composition reduces the expression of ANT2 (Adenine nucleotide translocator 2) gene.
5. pharmaceutical compositions according to claim 1, which is characterized in that
The composition makes HK2 (hexokinase 2) or PD-L1 (Programmed death-ligand 1) protein
Expression is reduced.
6. a kind of lung cancer prevention or treatment method, which is characterized in that including
It will be with apiolin or curcumin；And honokiol is the effective component pharmaceutical composition that includes to the step of individual administration.
7. a kind of lung cancer of pharmaceutical compositions is prevented or therapeutical uses, which is characterized in that
The pharmaceutical compositions include using any one of apiolin and curcumin and honokiol as effective component.
8. a kind of lung cancer prevention improves with healthy functions food compositions, which is characterized in that
With apiolin or curcumin；And
Honokiol includes for effective component.
9. lung cancer prevention according to claim 8 improves with healthy functions food compositions, which is characterized in that
The composition includes using apiolin and honokiol as effective component.
10. lung cancer prevention according to claim 8 improves with healthy functions food compositions, which is characterized in that
The composition includes using curcumin and honokiol as effective component.
11. healthy functions food compositions according to claim 8, which is characterized in that
The composition reduces the expression of ANT2 (Adenine nucleotide translocator 2) gene.
12. healthy functions food compositions according to claim 8, which is characterized in that
The composition makes the table of HK2 (hexokinase 2) or PD-L1 (Programmed death-ligand 1) protein
Up to reduction.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020160111383A KR101803000B1 (en) | 2016-08-31 | 2016-08-31 | Pharmaceutical compositions for preventing or treating lung cancer comprising apigenin, curcumin, and honokiol as active ingredients |
| KR10-2016-0111383 | 2016-08-31 | ||
| PCT/KR2017/009241 WO2018043989A1 (en) | 2016-08-31 | 2017-08-24 | Pharmaceutical composition comprising apigenin, curcumin, and honokiol as active ingredients for preventing or treating lung cancer |
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| KR (1) | KR101803000B1 (en) |
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| CN113952351B (en) * | 2021-09-08 | 2023-02-17 | 隋新兵 | Pharmaceutical composition for treating cancer and preparation method and application thereof |
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| KR101803000B1 (en) | 2017-11-30 |
| CN109640978B (en) | 2021-08-27 |
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