CN102552224A - Application of curcumin derivative C2 in anti-colon cancer medicaments - Google Patents
Application of curcumin derivative C2 in anti-colon cancer medicaments Download PDFInfo
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Abstract
The invention relates to the application of curcumin derivative C2 in anti-colon cancer medicaments. The curcumin derivative C2 is superior in killing colon cancer cells to curcumin and can cause the decline of mitochondrial membrane potentials of colon cancer cells, induce apoptosis of colon cancer cells and induce apoptosis by accumulation of active oxygen free radicals in colon cancer cells. Under certain circumstances, curcumin derivative C2 is more stable and lipophilic than parent compound curcumin. Besides, compared with parent compound curcumin, curcumin derivative C2 is advantageous in killing colon cancer cells without damaging healthy colon cells. The invention provides a theoretical basis for developing new anti-colon cancer medicaments of curcumin derivatives.
Description
Technical field
The present invention relates to biology and medicine and pharmacology field, the particularly application of curcumin derivate C2 in the resistive connection bowelcancer medicine.
Background technology
Curcumin is a kind of hydrophobicity polyphenol that comes from the plant Rhizoma Curcumae Longae rhizome.Present research shows that curcumin has multiple effects such as antiinflammatory, immunomodulating, antitumor.But curcumin dissolubility in vivo is lower; Simultaneously wherein the beta-diketon structure makes the less stable of curcumin; Metabolic process is too fast, thereby its bioavailability is very low, makes when clinical practice, need just can produce a desired effect than heavy dose; These are to limit curcumin further in the main cause of clinical practice, and the derivant of seeking curcumin is a focus in the present antitumor research.
Colon cancer is second largest popular cancer in the world wide, the third-largest cancer cause of death.Its pathogenesis is not clear and definite fully, main relevant with environmental factors and inherited genetic factors as yet at present.Surgical discectomy remains unique radical cure method of colon cancer now.Because only 70% colon cancer tumor can be excised, many patients have to accept auxiliary chemotherapy.In the past 30 years, 5-fluorouracil (5-FU) and be that the chemotherapy on basis is the main method of colon cancer aspect adjuvant treatment with the 5-fluorouracil effectively raises the therapeutic effect of colon cancer, has reduced the recurrence of tumor.But in recent years, the resistance of 5-fluorouracil in therapeutic process is more and more general, and it is a key factor of treatment of colon cancer failure.Simultaneously, only 26% patient responds to the Therapeutic Method of 5-fluorouracil and 5-fluorouracil/folinic acid (LV).Many other patients are to the not reaction or point reaction is only arranged of this method.Medicine that some are new such as Irinotecan (irinotecan) or oxaliplatin (oxaliplatin) are compared the response rate that has improved initial treatment of colon cancer with 5-FU, but new means or new adjuvant medicine still need continue to explore.
Summary of the invention
In order to overcome the deficiency that above-mentioned prior art exists; The object of the present invention is to provide the application of curcumin derivate C2 in the resistive connection bowelcancer medicine; Curcumin has got into the clinical research stage in the application of treatment colon cancer; Curcumin derivate C2 carries out structural modification on the basis of curcumin female parent, keep its drug safety, increased anti-tumor activity and stability, has the potentiality that are developed to new resistive connection bowelcancer medicine.
In order to achieve the above object, technical scheme of the present invention is such:
The application of curcumin derivate C2 in the resistive connection bowelcancer medicine; It is characterized in that; Curcumin derivate C2 is higher than curcumin to the lethal effect of colon cancer cell, and the structural formula of described curcumin derivate C2 is
Curcumin derivate C2 has caused the decline of colon cancer cell mitochondrial membrane potential.
Curcumin derivate C2 has induced the generation of colon cancer cell apoptosis.
Curcumin derivate C2 comes the death of inducing cell through the accumulation of inducing the colon cancer cell reactive oxygen free radical.
Advantage of the present invention: under a stable condition, curcumin derivate C2 is more stable than maternal curcumin itself, and lipotropy is stronger.Simultaneously, curcumin derivate C2 and maternal curcumin compare colon cancer cell and have the stronger toxicity of killing and wounding, and be less to the lethal effect of normal colon cell, and this resistive connection bowelcancer medicine new for curcumin derivate is developed to provides theoretical basis.
Description of drawings
Fig. 1 is that variable concentrations curcumin CO and derivant C2 are to colon cancer cell and normal colon epithelial cell lethal effect comparison diagram, n >=3; As matched group, #, * represent P＜0.05 with the cell that do not add medicine; ##, * * represent P＜0.01; ###, * * * represent P＜0.001; Wherein Fig. 1 a representes variable concentrations curcumin C0 and the derivant C2 lethal effect to colon cancer cell SW620; Fig. 1 b representes variable concentrations curcumin C0 and the derivant C2 lethal effect to colon cancer cell HCT116, and Fig. 1 c representes variable concentrations curcumin C0 and the derivant C2 lethal effect to normal colon epithelial cell HIEC.
Fig. 2 is the variation diagram of the mitochondrial membrane potential behind the curcumin derivate C2 processing colon cancer cell SW620 different time.
Fig. 3-a is the Hoechst testing result figure after variable concentrations curcumin derivate C2 handles colon cancer cell SW620.
Fig. 3-b is the apoptosis molecule protein immunity marking detection figure after variable concentrations curcumin derivate C2 handles colon cancer cell SW620.
Fig. 4-a is the induced map of curcumin derivate C2 to colon cancer cell SW620 active oxygen ROS, n >=3; As contrast, * representes P＜0.05 with the cell that do not add medicine.
Fig. 4-b is the variation diagram of curcumin derivate C2 to the lethal effect of colon cancer cell SW620, n >=3; As contrast, * * * representes P＜0.001 with the cell that do not add medicine; With C2 handle but the cell that do not add NAC as contrast, ### representes P＜0.001.
Fig. 4-c index of correlation detection figure that to be curcumin derivate C2 suppress the C2 effect colon cancer cell SW620 apoptosis induction and ROS inhibitor, Fig. 4-c-1 is the Hoechst testing result; Fig. 4-c-2 is protein immunization marking result.
The specific embodiment
Below in conjunction with embodiment the present invention is done more detailed explanation.
One, the preparation of curcumin derivate C2 and pharmaceutical research
The method for preparing of derivant:
2-methoxybenzaldehyde (51mmol) and acetone (25mmol) are dissolved in the 8mL dehydrated alcohol, drip the NaOH solution of 15mL 20% (wt) under the vigorous stirring, stirring at normal temperature reaction 48h; Add the 40mL distilled water; Add dilute hydrochloric acid again and transfer to faintly acid, sucking filtration, deposition vacuum drying; Column chromatography for separation, ethyl acetate/petroleum ether (3: 1) is as eluant.Pharmaceutical research:
1. stable
Through the ultraviolet-uisible spectrophotometer monitoring, confirmed that at 25 ℃ in PBS (pH=7.4) buffer system, derivant is more stable than curcumin itself.
2. lipotropy
CLog P (logarithm value of n-octyl alcohol/water partition coefficient P): derivant (CLogP=3.77) is stronger than the lipotropy of Curcumin (CLog P=2.56).Calculate CLog P through Bio-Loomsoftware.
3. purity analysis
The purity of measuring derivant through HPLC (HPLC) is 99%.Eluant is methanol=70/30; Retention time is 7min; Test column is Zorbax CN, 4.6 * 250mm, P/N 880952.705 reversed-phase columns.
Two, the active test of Tuberculosis in vitro intestinal cancer
More active in order to explain that curcumin derivate C2 has than the better resistive connection intestinal cancer of curcumin itself; Utilize its growth inhibited ability of tetramethyl azo azoles salt colorimetry (MTT) method test, represent the active power of Tuberculosis in vitro intestinal cancer with half-inhibition concentration value (IC50) to the colon cancer tumor cell.
Method of testing and step:
(1) material
Tetrazolium salts (MTT) mother solution (5mg/ml): the tetrazolium salts powder is dissolved in the phosphate buffer (PBS), is made into 5mg/ml concentration, after fully mixing dissolves on the eddy mixer, uses the filtration sterilization of disposable aspiration needle filter, keeps in Dark Place in 4 ℃ of refrigerators.
Dimethyl sulfoxide (DMSO), phosphate buffer (PBS), 10%RPMI1640 culture medium
(2) method
1. with cell inoculation (10000/hole) in 96 orifice plates, do not add culture fluid in the hole of periphery, replenish with 150 μ l phosphate buffers (PBS).At 37 ℃, contain 5%CO
2Incubator in cultivate;
Add compound treatment when 2. treating cell attachment and density suitable (50%-60%).At first remove culture medium, by series concentration preparation Compound C 2 solution, every hole 100 μ l cultivated 24 hours with 1640 culture medium that contain 2% serum.
3. remove and contain C2 culture medium and phosphate buffer (PBS) on every side, the tetrazolium salts solution (0.5mg/ml) that adding 100 μ l dilute with serum-free medium in every hole, 37 ℃, 5%CO
2Incubator in cultivated 1 hour;
4. inhale and remove tetrazolium salts solution, in every hole, add 200 μ l DMSO, blow even with liquid-transfering gun.Measure the light absorption value in each hole at the 550nm place with ELIASA, thereby obtain the relative energy value of cell in each hole.
(3) result and discussion
Following Fig. 1 of experimental result and table 1; This derivant C2 and maternal curcumin compare colon cancer cell and have the stronger toxicity of killing and wounding; Less to the lethal effect of normal colon cell simultaneously, proved that curcumin derivate C2 is developed to the probability of resistive connection bowelcancer medicine.
Table 1 curcumin and this derivant C2 are to the IC50 value (μ mol/L) of various cells
Three, kill and wound the colon cancer cell Mechanism Study
The decline of mitochondrial membrane potential:
The decline of mitochondrial membrane potential is one of early stage significant incident of apoptosis.In order to probe into the influence of curcumin derivate C2, utilize the variation of JC-1 method detection line mitochondrial membrane potential for the colon cancer cell mitochondrial membrane potential.
Method of testing:
(1) material
The JC-1 dyestuff
(2) mitochondrial membrane potential detection method
1. with cell inoculation (10000/hole) in 96 orifice plates, do not add culture fluid in the hole of periphery, replenish with 150 μ l phosphate buffers (PBS).At 37 ℃, contain 5%CO
2Incubator in cultivate;
Add compound treatment when 2. treating cell attachment and density suitable (50%-60%).By concentration preparation Compound C 2 solution, every hole 100 μ l cultivate different time with 1640 culture medium that contain 2% serum.
3. remove and contain C2 culture medium and phosphate buffer (PBS) on every side, the JC-1 solution (1: 1000) that adding 100 μ l dilute with serum-free medium in every hole, 37 ℃, 5%CO
2Incubator in cultivated 1 hour;
4. inhale and remove JC-1 solution; In every hole, add 200 μ l PBS, suction is gone, and in every hole, adds 100 μ l PBS again; With ELIASA 485/538, the 485/585nm place measures the light absorption value in each hole, weighs the ratio of mitochondrial depolarization with the relative scale of red green fluorescence.
(3) result and discussion
Experimental result such as Fig. 2.Can prove that through above experiment curcumin derivate C2 has caused the decline of mitochondrial membrane potential.
The generation of apoptosis
In order to probe into the mechanism of curcumin derivate C2 in killing and wounding the colon cancer cell process, at first detect this chemical compound and whether induced apoptotic generation.The method of utilizing the Hoechst dyeing and the protein immunization marking is respectively from form and apoptosis developed by molecule horizontal detection.
Method of testing:
(1) material
Hoechst 33258 staining kits; Western and IP cell pyrolysis liquid; 5 * sample-loading buffer: 250mmol/L Tris-HCl (PH 6.8); 10% dodecyl sodium sulfate (SDS); 30% glycerol; 5% beta-mercaptoethanol; 0.05% bromophenol blue;
SDS-PAGE separation gel (12%) is (10ml): the 3.3ml pure water; 4.0ml 30% acrylamide mixed liquor; 2.5ml 1.5mol/L Tris (PH 8.8); 0.1ml 10%SDS; 0.1ml 10% Ammonium persulfate.; 0.004ml TEMED;
SDS-PAGE concentrates glue (4ml): the 2.7ml pure water; 0.67ml 30% acrylamide mixed liquor; 0.5ml 1.0mol/L Tris (PH 6.8); 0.04ml 10%SDS; The 0.04ml10% Ammonium persulfate.; 0.004ml tetramethylethylenediamine (TEMED);
10 * electrophoretic buffer (1L): 30.3g Tris; The 144g glycine; 10g SDS; 1 * commentaries on classics film buffer (1L): 3.03g Tris; 14.4g glycine; Mentioned reagent is dissolved in and adds the 200ml dehydrated alcohol in the 800ml pure water behind the mixing, joins existing usefulness behind the mixing at present;
10×TBST(1L)：24.4g?Tris；80g?NaCl；10ml?Tween-20。Regulate pH to 7.6-8.0 with hydrochloric acid behind the mentioned reagent mixing;
5% skim milk; 1% bovine serum albumin (BSA);
Protein antibodies: Caspase-3 (rabbit source, Cell Signal Technology); PARP (rabbit source, Cell Signal Technology)
(2) a-Hoechst dyeing detection method
1. seed cells in 6 orifice plates, place 37 ℃, contain 5%CO
2Incubator in cultivate;
2. treat suitably dosing when (50-60%) of cell attachment and density, inhale go after the former culture medium 6 orifice plates wherein a hole add contain 2% serum culture medium as contrast, adding final concentration in all the other holes is the The compounds of this invention C2 of 5,10 μ mol/L.6 orifice plates after handling are placed 37 ℃, contain 5%CO
2Incubator in cultivated 24 hours;
3. utilize Hoechst 33258 staining kits to detect the generation of apoptosis.Suction cleans twice with PBS after going to contain in 6 orifice plates culture medium of Compound C 2, in every hole, adds 500 μ l fixatives, on shaking table fixing 15 minutes;
4. remove fixative, clean cell twice with PBS, add every hole and add 500 μ l dyeing liquors, lucifuge dyeing is 30 minutes on shaking table, inhales and removes dyeing liquor, and reuse PBS washes twice, exhausts liquid, observes down in fluorescence microscope.
The b-protein immunization marking (Western blot)
1. the preparation of protein sample:, utilize the BCA albuminimetry to measure protein sample concentration, and utilize each histone concentration of lysate trim with extracting albumen after the lysis.
2. PAGE (SDS-PAGE)
3. change film
4. sealing
5. add one and resist, wash film
6. add two and resist, wash film
7. chemiluminescence
(3) result and discussion
Experimental result such as Fig. 2, processed group is compared with matched group, and the apoptotic cell number rises, and protein immunization marking result shows the expression rising of Cleaved-Caspase-3 simultaneously, and spliced body appears in its substrate DNA repairase PARP.Can prove that through above experiment curcumin derivate C2 has caused apoptotic generation.
The variation of active oxygen (ROS)
In order further to probe into the mechanism of The compounds of this invention C2 in killing and wounding the colon cancer cell process; Utilize dichlorofluorescein method (DCF) test to kill and wound the variation of active oxygen in the process; And (N-acetylcysteine, NAC) whether detection of active oxygen is the key factor of killer cell to utilize active oxygen (ROS) inhibitor N-acetylcystein.
Method of testing:
(1) material
H2DCFDA mother solution (10mmol/ml): generally be formulated in the dimethyl sulfoxide (DMSO), mother liquid concentration 10mmol/ml keeps in Dark Place in-20 ℃ of refrigerators.Using the serum-free medium dilution during use is 10 μ mol/ml to final concentration for 1000 times.
(N-acetylcysteine, NAC): the storage mother solution is 100mmol/L to active oxygen inhibitor N-acetylcystein, is stored in-20 ℃ of refrigerators.Be diluted to desired concn with the culture medium that contains 2% serum during use.
ROS cell pyrolysis liquid: 10mmol/L Tris; 150mmol/L NaCl; 0.1mmol/L EDTA; 0.5%Triton *-100.Regulate pH to 7.5 behind the mentioned reagent mixing, be stored in 4 ℃ of refrigerators.
(2) ROS detection method
1. seed cells in 6 orifice plates, place 37 ℃, contain 5%CO
2Incubator in cultivate;
Dosing when 2. treating cell attachment and density suitable (50-60%); Suction go after the former culture medium 6 orifice plates wherein a hole add contain 2% serum culture medium as contrast; The adding final concentration is the The compounds of this invention C2 of 5 μ mol/L or the mixed liquor of this Compound C 2 and ROS inhibitor NAC in all the other holes, and wherein the final concentration of NAC is 4mmol/L.6 orifice plates after handling are placed 37 ℃, contain 5%CO
2Incubator in cultivated 24 hours;
3. clean twice with PBS after inhaling the culture medium go to contain in 6 orifice plates Compound C 2, in every hole, add 1.5ml H2DCFDA working solution (10 μ mol/mL),, contain 5%CO in 37 ℃
2Incubator in continue to cultivate 30min;
4. remove working solution, clean cell twice, add certain volume ROS lysate with PBS; Placed 10 minutes, with scraper with cell transfer to the 1.5mL centrifuge tube, 15000g; 4 ℃ of centrifugal 10min get supernatant in new centrifuge tube, behind the mix homogeneously amount of supernatant with every hole 40 μ l are joined in 96 orifice plates; As blank, at the 485nm exciting light, the 538nm scattered light detects its fluorescence OD value down with fluorescence microplate reader with protein lysate;
5. use bicinchoninic acid method (BCA) that the sample of doing fluoroscopic examination is carried out the quantification of protein analysis, calculate wherein Protein content;
6. active oxygen (ROS) content is fluorescence OD value/protein content.
(3) result and discussion
Experimental result such as Fig. 4, processed group is compared oxygen-derived free radicals ROS level and is raise with matched group, and ROS inhibitor N-acetylcystein (N-acetylcysteine NAC) can suppress its rising.In addition, the result of Hoechst method and Western method is presented at and adds after the NAC, and the apoptosis level descends.The result of tetramethyl azo azoles salt colorimetry is presented at and adds after the NAC simultaneously, and this derivant C2 is suppressed for the lethal effect of cell.The rising that can prove ROS in the cell that this derivant C2 causes through this experiment plays a key effect in the apoptotic process that kills and wounds and cause of its pair cell.
Claims (4)
1. the application of curcumin derivate C2 in the resistive connection bowelcancer medicine; It is characterized in that; Curcumin derivate C2 is higher than curcumin to the lethal effect of colon cancer cell, and the structural formula of described curcumin derivate C2 is
2. the application of curcumin derivate C2 according to claim 1 in the resistive connection bowelcancer medicine is characterized in that curcumin derivate C2 has caused the decline of colon cancer cell mitochondrial membrane potential.
3. the application of curcumin derivate C2 according to claim 1 in the resistive connection bowelcancer medicine, curcumin derivate C2 has induced the generation of colon cancer cell apoptosis.
4. the application of curcumin derivate C2 according to claim 1 in the resistive connection bowelcancer medicine, curcumin derivate C2 comes the death of inducing cell through the accumulation of inducing the colon cancer cell reactive oxygen free radical.
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| CN103910616A (en) * | 2014-03-20 | 2014-07-09 | 浙江工业大学 | Curcumin derivative and preparation and application thereof |
| CN114478256A (en) * | 2022-01-26 | 2022-05-13 | 安徽理工大学环境友好材料与职业健康研究院(芜湖) | Preparation method of novel curcumin derivative and application of novel curcumin derivative in resisting liver cancer |
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Application publication date: 20120711 |