CN107951892A - Zinc protoporphyrin is preparing enhancing Human colorectal cancer cells to the application in 5 FU 5 fluorouracil chemosensitivity medicine - Google Patents
Zinc protoporphyrin is preparing enhancing Human colorectal cancer cells to the application in 5 FU 5 fluorouracil chemosensitivity medicine Download PDFInfo
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Abstract
The invention discloses zinc protoporphyrin to prepare enhancing Human colorectal cancer cells to the application in 5 fluorouracil chemotherapy sensitive drugs, belongs to chemotherapeutics technical field.The present invention provides basis for new drug development and innovative treatments, suitable for carrying out chemotherapy to Human colorectal carcinoma patient, improves the Chemotherapy of 5 fluorouracil medicines.
Description
Technical field
The present invention relates to zinc protoporphyrin to prepare enhancing Human colorectal cancer cells to 5 FU 5 fluorouracil chemosensitivity medicine
In application, belong to chemotherapeutics technical field.
Background technology
Colorectal cancer is one of common tumor in digestive tract, according to World Health Organization's International Cancer Research Center
(International Agency for Research on Cancer, IARC) data shows that the whole world there are about in 2012
1360000 colorectal cancer new cases, occupy malignant tumour the 3rd, after lung cancer, breast cancer；It is about 690,000 dead, positioned at lung
After cancer, liver cancer and stomach cancer, malignant tumour the 4th is occupied.China is the Di Fa areas of colorectal cancer, in recent years, with China's economy
Development, dietary structure and living-pattern preservation, the incidence of colorectal cancer is in rising trend.According to statistics by 2016,
For China's colorectal cancer neopathy number of cases up to 33.1 ten thousand, wherein death is 15.9 ten thousand.
Treatment at present is mainly the tumour of surgery excision original site, and postoperative to be aided with chemotherapy, radiotherapy, immunization therapy etc. a variety of
Means carry out it auxiliary treatment, and effective chemotherapy can not only kill residual cancer cell, can also prevent the further expansion of cancer cell
Dissipate and shift.Common chemotherapy regimen is the combined chemotherapy based on 5 FU 5 fluorouracil (5-FU).
The content of the invention
The present invention provides zinc protoporphyrin to prepare enhancing Human colorectal cancer cells to 5 FU 5 fluorouracil chemosensitivity medicine
Application in thing, basis is provided for new drug development and innovative treatments.The technical solution of use is as follows：
The present invention provides a kind of zinc protoporphyrin (Zinc protoporphyrin, ZnPP) to prepare enhancing people's Colon and rectum
Cancer cell is to the application in 5 FU 5 fluorouracil chemosensitivity medicine.
Present invention Heme oxygeanse-1 (heme using Human colorectal carcinoma RKO, HT29, HCT8 cell line as investigation of materials
Oxygenase-1, HO-1) influence to 5 FU 5 fluorouracil (5-FU) chemosensitivity and its possible mechanism, inventor's application
5-FU acts on Human colorectal cancer cells alone or in combination for various concentrations zinc protoporphyrin (ZnPP), Copp (CoPP),
Alaram Blue methods observe medicine cell growth inhibitory action；Quantitative PCR analysis HO-1 changes in gene expression；Fluidic cell
Art detects apoptosis rate；Its possible molecular mechanism is analyzed by detecting Caspase-3 and active oxygen (ROS).The results show：
Various types of cells has HO-1 expression, can make its expression enhancing after alone 5-FU or 5-FU combination CoPP, but CoPP lures it
Effect is led, 5-FU combinations ZnPP can reduce the expression of HO-1, and can substantially suppress Human colorectal cancer cells growth, in dose-dependant
Property；5-FU is combined ZnPP compared with alone 5-FU, hence it is evident that improves inhibitory rate of cell growth and apoptosis rate (P ＜ 0.05), 5-FU
It is combined CoPP then faint reduction inhibitory rate of cell growth and apoptosis rate (P>0.05)；Alone 5-FU compared with blank control group,
Intracellular ROS activity substantially increases, and intracellular ROS activity (P ＜ 0.05) is can further improve after 5-FU combinations ZnPP, and is combined
CoPP can reduce intracellular ROS activity levels (P ＜ 0.05).
In summary：Inventor has found that ZnPP can strengthen Human colorectal cancer cells to 5-FU chemosensitivities first, this
One effect may be related with increasing the intracellular active and intracellular Caspase-3 activity of ROS.
The present invention provides basis for new drug development and innovative treatments, and the present invention is suitable for Human colorectal carcinoma patientization
Treat, improve the Chemotherapy of 5 FU 5 fluorouracil.
Brief description of the drawings
Fig. 1 is that RT-PCR analyzes HO-1 expression conditions in each treatment group of RKO cells；
(A, HO-1；B, β-Actin；In A and B：M is Marker DL2000；1 is blank control group；2 be addition DMSO
Group；3 be addition 5-FU groups；4 be 0.5 μm of ol CoPP+5-FU group of addition；5 be 1 μm of ol CoPP+5-FU group of addition；6 be addition 5
μm ol CoPP+5-FU groups；7 be 10 μm of ol CoPP+5-FU groups of addition；8 be 0.5 μm of ol ZnPP+5-FU group of addition；9 be addition
1 μm of ol ZnPP+5-FU group；10 be 5 μm of ol ZnPP+5-FU groups of addition；11 be 10 μm of ol ZnPP+5-FU groups of addition).
Fig. 2 is that RT-PCR analyzes HO-1 expression conditions in each treatment group of HCT8 cells；
(A, HO-1；B, β-Actin；In A and B：M is Marker DL2000；1 is blank control group；2 be addition DMSO
Group；3 be addition 5-FU groups；4 be 0.5 μm of ol CoPP+5-FU group of addition；5 be 1 μm of ol CoPP+5-FU group of addition；6 be addition 5
μm ol CoPP+5-FU groups；7 be 10 μm of ol CoPP+5-FU groups of addition；8 be 0.5 μm of ol ZnPP+5-FU group of addition；9 be addition
1 μm of ol ZnPP+5-FU group；10 be 5 μm of ol ZnPP+5-FU groups of addition；11 be 10 μm of ol ZnPP+5-FU groups of addition).
Fig. 3 is that RT-PCR analyzes HO-1 expression conditions in each treatment group of HT29 cells；
(A, HO-1；B, β-Actin；In A and B：M is Marker DL2000；1 is blank control group；2 be addition DMSO
Group；3 be addition 5-FU groups；4 be 0.5 μm of ol CoPP+5-FU group of addition；5 be 1 μm of ol CoPP+5-FU group of addition；6 be addition 5
μm ol CoPP+5-FU groups；7 be 0.5 μm of ol ZnPP+5-FU group of addition；8 be 1 μm of ol ZnPP+5-FU group of addition；9 be addition 5
μm ol ZnPP+5-FU groups；).
Fig. 4 analyzes each treatment group HO-1 gene relative expression quantities of RKO cells for quantitative PCR method.
Fig. 5 analyzes each treatment group HO-1 gene relative expression quantities of HCT8 cells for quantitative PCR method.
Fig. 6 analyzes each treatment group HO-1 gene relative expression quantities of HT29 cells for quantitative PCR method.
Fig. 7 detects cell inhibitory rate for Alaram Blue methods.
Fig. 8 is each treatment group flow cytomery Apoptosis of HCT8 cells；
(a, 1 μm of ol ZnPP combine 200 μm of ol 5-FU groups；B, 5 μm of ol ZnPP combine 200 μm of ol5-FU groups；c,10μ
Mol ZnPP combine 200 μm of ol5-FU groups；D, 1 μm of ol CoPP combine 200 μm of ol5-FU groups；E, 5 μm of ol CoPP combine 200 μ
Mol 5-FU groups；F, 10 μm of ol CoPP combine 200 μm of ol 5-FU groups；G, blank control group；H, DMSO group；I,200μmol 5-
FU groups.
Each treatment group Apoptosis ratio of Fig. 9 flow cytometer detections.
Figure 10 is influence of each treatment group to cell ROS activity.
Figure 11 is influence of each treatment group to HCT8 cells Caspase-3 activity.
Embodiment
With reference to specific embodiment, the present invention will be further described, but the present invention should not be limited by the examples.
Embodiment 1：
1 materials and methods
1.1 material
1.1.1 reagent
RKO cells；HT29 cells；The cells such as HCT8 cells are preserved by laboratory；RPMI-1640 culture mediums, DMEM cultures
Base, dual anti-, hyclone, Alaram Blue kits are purchased from life technology companies；It is active oxygen, Caspase3, thin
Born of the same parents' apoptosis detection kit, Bradford protein concentrations detection kit are purchased from green skies Bioisystech Co., Ltd；HO-1 and
Internal reference β-actin primers transfer to Shanghai Ying Jun Bioisystech Co., Ltd to synthesize；RT-PCR kit is purchased from Thermo
Scientific companies.
1.1.2 instrument
Autoclave (HVE-50, Japanese Hariyama companies)；Double single side clean work station (SW-CJ-2FD, Suzhou
Cleaning equipment Co., Ltd)；Global function micropore board detector (SYNERGY/H1, Biotek companies of the U.S.)；CO2Incubator
(BB150, Thermo companies of the U.S.)；Inverted microscope (DMi8, German LEICA companies)；Centrifuge (5810R, Germany
Eppendorf companies).
1.2 method
1.2.1 cell recovery, culture
Cryopreservation tube equipped with HCT8, RKO, HT29 cell is taken out from -80 DEG C of refrigerators, Thin film glove is put on, in 37 DEG C of water
Quick-thawing in bath, is transferred to centrifuge tube, 1000rpm centrifugation 5min, abandon supernatant, by cell suspension by the suspension to have thawed
It is transferred to afterwards in the culture dish containing complete culture solution, puts CO into2Culture in incubator.Observation cell daily, if cell attachment converges
It is right to 80%, pancreatin had digestive transfer culture can be used.
1.2.2 medicine optimum concentration is definite
Taking a 50ml centrifuge tubes, zeroing, thing (ZnPP, ZnPP, 5-FU) is got it filled in centrifuge tube with spoon on assay balance
It is interior, take out and fully dissolved with DMSO, it is 0.01mol/L to make concentration, is dispensed into 1.5ml centrifuge tubes, carries out mark.Use sealed membrane
- 20 DEG C of refrigerators are placed after sealing to preserve.According to the experimental result of Alaram Blue, it is 200 μm of ol to determine 5-FU drug concentrations,
The activity of CoPP medicines is that the activity of 0.5 μm of ol to 10 μm of ol, ZnPP medicine is 0.5 μm of ol to 10 μm of ol.Respectively
DMSO groups are set, 200 μm of ol 5-FU medicine groups are used alone, 200 μm of ol 5-FU are separately added into 0.5 μm of ol after adding 24h
CoPP, 1 μm of ol CoPP, 5 μm of ol CoPP, 10 μm of ol CoPP, ZnPP groups are added after 24h using 200 μm of ol 5-FU to be added respectively
Enter 0.5 μm of ol ZnPP, 1 μm of ol ZnPP, 5 μm of ol ZnPP, 10 μm of ol ZnPP, detection indices are collected after handling 24h.
1.2.3 cell prepares
The cell of well-grown exponential phase is taken, is digested with pancreatin, nutrient solution is diluted to concentration as 5 × 104/ mL's
Cell suspension, is inoculated into 6 orifice plates by every hole 2mL, CO is moved to after having spread2Incubator culture.It is adherent thin after being incubated overnight
The original fluid of born of the same parents, which is washed, to be abandoned, and adds the new complete culture solutions of 1mL, is added in addition to DMSO groups outside the DMSO of corresponding 5-FU volumes,
Remaining each hole adds the 5-FU of final concentration of 200 μm of ol so that nutrient solution volume 2mL.After cultivating 24h, nutrient solution is discarded,
PBS is washed 3 times, DMSO groups, exclusive use 5-FU medicine groups, each concentration C oPP groups that each group in 1.2.2 is set, each concentration
ZnPP group 2mL drug containing nutrient solutions are added in orifice plate again, and each concentration 3 is parallel, and indices are detected after cultivating 24h.
1.2.4 quantitative PCR detection Human colorectal cancer cells HO-1mRNA is expressed
With reference to the reverse transcription specification of Thermo Scientific, using 1 μ g total serum IgEs as template in 20 μ L systems, carry out
The synthesis of cDNA.5 '-CTTCAAGCTGGTGATGGC-3 ' of HO-1 sense primers (SEQ ID NO.1), anti-sense primer 5 '-
TGGAGCCGCTTCACATAG-3 ' (SEQ ID NO.2), product 219bp；β-Actin sense primers 5 '-
TCCCTGGAGAAGAGCTACGA-3 ' (SEQ ID NO.3), anti-sense primer 5 '-AGCACTGTGTTGGCGTACAG-3 ' (SEQ
ID NO.4), product 194bp.Gene expression amount is detected with the fluorescent quantitation reagent of Takara.The response procedures of quantitative fluorescent PCR
For 95 DEG C, 30s；95 DEG C, 5s；60 DEG C, 30s；72 DEG C, 34s；40cycles.
1.2.5 the detection of Cellular Oxidation stress level ROS, Caspase3 and Apoptosis
By the cell that drug combination is handled well in 96 orifice plates, with reference to green skies active oxygen detection kit (S0033)
Method, detects Cellular Oxidation stress level.The cell that drug combination is handled well in 6 orifice plates, with reference to green skies Caspase 3
The method of activity detection kit (C1115), detects the expression of cell Caspase3 activity.Drug combination is handled in 6 orifice plates
Good cell, with reference to the method for green skies Annexin V-FITC cell apoptosis detection kits (C1063), uses fluidic cell
Instrument detects the apoptosis situation of cell.
2 results
The expression of HO-1 genes in 2.1 different pharmaceutical treatment groups
HO-1 gene expression amounts with RT-PCR and quantitative PCR to each drug-treated group HCT8, RKO, HT29 cell respectively
Analyzed, as a result as shown in Figures 1 to 6.The results show that visible HO-1 is expressed on a small quantity in control group in each treatment group, application
The expression that 5-FU medicines can induce HO-1mRNA is significantly raised, and HO-1mRNA expression is further after 5-FU drug combinations CoPP rises
Height, and as the rise of combination CoPP concentration, the gene expression of HO-1 also increase.And 5-FU drug combinations ZnPP can be reduced
The expression of HO-1mRNA, and as the rise of combination ZnPP concentration, the expression of HO-1mRNA are gradually lowered.Show exogenous
ZnPP can reduce the expression of HO-1 genes, and CoPP can increase the expression of HO-1 genes.But due to 0.5 μm of ol in HT29 cells
CoPP combines 5-FU groups and 0.5 μm of ol ZnPP joint 5-FU group cell detachment is more, is not detected by the expression of gene.
The influence of 2.2 each drug concentration cell proliferations
Alaram Blue detection displays, various concentrations 5-FU and ZnPP can substantially suppress Human colorectal cancer cells propagation
Activity, has concentration dependent, as concentration increase inhibiting rate is strengthened (Fig. 7).CoPP breeds Human colorectal cancer cells
Influence is smaller, compared with the control group no significant difference.5-FU is taken to combine various concentrations ZnPP, each group cell proliferation rate is equal
Significantly lower than alone 5-FU groups (P ＜ 0.05), and it is in concentration gradient dependence；And 5-FU joint various concentrations CoPP, each group are thin
Born of the same parents' appreciation rate is slightly above alone 5-FU groups.
2.3 each treatment group apoptosis rates compare
Flow cytometry (FCM) analysis Apoptosis ratiometric result is shown (Fig. 8 and Fig. 9)：Alone 5-FU is to colorectal cancer
Impact cell is smaller, compared with not adding medicine group, non-viable apoptotic cell quantity showed increased；After being combined with ZnPP, colorectal cancer
The apoptosis rate increase of cell, in concentration dependent, the difference extremely significantly (p compared with alone 5-FU groups<0.01)；And it is combined with CoPP
Afterwards, the apoptosis rate of cell decreases, more not notable (p than difference with control group>0.05).
As shown in Figure 10, alone 5-FU cells ROS activity is significantly higher than blank control group (P ＜ 0.05), in RKO cells and
Particularly evident in HT29 cells, cell ROS activity raises again after 5-FU combination various concentrations ZnPP raises in HCT8 cells
Become apparent from, and be in concentration gradient, (P ＜ 0.05) statistically significant with alone medicine group comparing difference；And 5-FU combinations are different
ROS activity is obvious after concentration C oPP reduces, particularly evident in RKO cells and HT29 cells, and is in concentration gradient (P ＜
0.05).Caspase-3 relative activities are analyzed in 2.5 each groups
As shown in Figure 11, alone 5-FU cells Caspase-3 activity is significantly higher than Normal group (P ＜ 0.05), combination
The rise of cell Caspase-3 activity is more obvious after various concentrations ZnPP, and in ZnPP low concentrations, performance is not notable, but is in concentration
Gradient, (P ＜ 0.05) statistically significant with alone medicine group comparing difference；And Caspase- after 5-FU combination various concentrations CoPP
3 activity are obvious to be reduced, unobvious during CoPP low concentrations in HCT8 cells, and is in concentration gradient (P ＜ 0.05), in HT29 cells
Middle Caspase-3 activity reduces unobvious.
3 discuss
HO-1 has the function of cytoprotection, i.e. antioxidation, anti-inflammatory effect and Anti-G value, and in tumour
Acted in occurrence and development more and more important.Recent researches find, the high expression of the visible HO-1 of many entity tumors, in anoxic and
Expression becomes apparent during chemicotherapy.In tumour cell, the expression of HO-1 and the diffusion transfer of tumour, Anti-G value have closely
Contact.Fang etc. points out that HO-1 can suppress apoptosis of tumor cells, so as to promote tumour growth.HO-1 can be by reducing cell
Interior enzymatic oxidation material, increases the horizontal of bilirubin and suppresses Apoptosis.Zhang Juan, which is opened etc., is reported in drug resistance liver cancer Bel/Fu cell lines
Middle suppression HO-1 can reduce the expression of the concentration and mRNA of chemotherapeutics, and suppress HO-1 influence MCR-1 expression.
Cell after this experiment handles different medications carries out HO-1 gene level detections, makes the results show that 5-FU combines
After ZnPP, the expression downward (Fig. 1 to Fig. 6) of HO-1 genes, cytoactive reduce in cell, and showing, which reduces HO-1, can suppress to tie
The activity of rectum cancer cell, and after applying CoPP effect colorectal cancer cells, the up-regulated expression of HO-1 genes in cell, the carcinoma of the rectum
Cytoactive changes unobvious (Fig. 7).After treatment with chemotherapy medicine 5-FU, intracellular HO-1 expression is increased；After use in conjunction CoPP
Further HO-1 can be induced to express, while cell inhibitory rate and the more alone 5-FU of apoptosis rate are decreased obviously, and it is combined ZnPP suppression
After cell HO-1 expression, cell inhibitory rate and apoptosis rate dramatically increase.This represents that CoPP induction HO-1 expression is thin to colorectal cancer
The effect of sensitiveness decline is deposited in the damage of born of the same parents 5-FU chemotherapy, and applies ZnPP thin by blocking HO-1 expression to strengthen colorectal cancer
Born of the same parents are to 5-FU chemosensitivities.Illustrate that HO-1 derivants CoPP can actually induce the expression of HO-1 on cell and cell is risen
Protective effect, and HO-1 inhibitor ZnPP can then suppress the expression of HO-1, promote its apoptosis.
In addition, acted on using 5-FU after colorectal cancer cell has inhibitory action to its growth.After being combined with ZnPP, carefully
Born of the same parents are rounded even apoptosis phenomenon and become apparent, and illustrate that ZnPP and chemotherapeutics 5-FU combinations have effect of enhanced sensitivity.And and CoPP
After combination, cell growth state is better than opposite with alone 5-FU groups, illustrates that CoPP can weaken 5-FU cell growth states
Influence.
Found after being detected using flow cytometer to Apoptosis, after 5-FU combinations ZnPP, apoptotic cell has increased
Add；And after using CoPP, apoptotic cell reduces (Fig. 9).This experimental result illustrates that ZnPP increases cell due to inhibiting HO-1
Apoptosis, CoPP suppress Apoptosis due to protecting cell induction of the expression of HO-1.
For active oxygen to promoting cell mitogen, induced cell proliferation is vital, in the range of a certain concentration, this
Kind promotees the ability of cell Proliferation and the level of active oxygen is proportionate, the intracellular too low mitosis for then suppressing cell, shadow
Ring the propagation of cell.Confirmed in Bai Hua is on influences of the NAC to fetal hepatocytes proliferation activity intracellular ROS level with it is thin
There are positive correlation for born of the same parents' propagation.Generally believe that Apoptosis is a series of highly regulated cysteine proteinases now
Caspase cascade reactions (cascade) event (also known as CPP32, apopain) is proved to be in the level as a result, caspase-3
Join the downstream of reaction, it makes cell death by corresponding substrate in degradation of cell.Illustrate that ZnPP can increase 5-FU medicines to thin
The inhibitory action of intracellular growth situation, and ZnPP is to be influenced by suppressing the expression of HO-1 genes and cell growth situation.
Because HO-1 and cytoprotection, anti-oxidation stress etc. are closely related.We to different medications handle after RKO cells,
HCT8 cells, HT29 cells carry out the detection of intracellular reactive oxygen level, 3 Activity determinations of Caspase and Apoptosis detection.
The results show：With alone 5-FU groups ratio, after ZnPP and 5-FU drug combinations, the rise of intracellular reactive oxygen level, Caspase
3 increased activities, the obvious increase for corresponding to apoptosis rate；And CoPP and 5-FU drug combinations with alone 5-FU groups phase
Than intracellular reactive oxygen level has declined, the activity of Caspase 3 and apoptosis rate reduce.
In conclusion this Experimental Research Heme oxygeanse-1 is to Human colorectal cancer cells 5 FU 5 fluorouracil chemosensitivity
Influence, in 0.5 to 10 μm of ol concentration range in an experiment, HO-1 inhibitor ZnPP can increase Human colorectal cancer cells pair
The sensitiveness of 5-FU medicines, and HO-1 activators CoPP can then slow down the Chemotherapy effect of 5-FU medicines.Its mechanism of action
The expression quantity that may be by changing HO-1 genes is lived to influence to produce reactive oxygen species into the cell, suppress Caspase 3 indirectly
Property, so as to reduce apoptosis rate.Classical chemotherapeutics of the 5-FU as oncotherapy, can be suppressed by ZnPP etc. in vitro
The medicines of HO-1 gene expressions reduces the expression quantity of HO-1 genes and increases the sensitiveness of the chemotherapeutics such as 5-FU, which can be with
A new approaches are provided for the medication or clinical practice of follow-up colorectal carcinoma or other class treatments of cancer.
Although the present invention is disclosed as above with preferred embodiment, it is not limited to the present invention, any to be familiar with this
The people of technology, is not departing from spirit and scope of the invention, can do various change and modification, therefore, guarantor of the invention
Shield scope should be subject to what claims were defined.
Claims (1)
1. zinc protoporphyrin is preparing enhancing Human colorectal cancer cells to the application in the medicine of 5 FU 5 fluorouracil chemosensitivity.
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Citations (2)
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|---|---|---|---|---|
| CN102753162A (en) * | 2009-10-22 | 2012-10-24 | 南加利福尼亚大学 | Methods and nutritional formulations to increase the efficacy and reduce the side effects of cancer treatment |
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- 2018-01-19 CN CN201810052563.3A patent/CN107951892A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102753162A (en) * | 2009-10-22 | 2012-10-24 | 南加利福尼亚大学 | Methods and nutritional formulations to increase the efficacy and reduce the side effects of cancer treatment |
| CN107184586A (en) * | 2017-06-25 | 2017-09-22 | 浙江大学 | Heme oxygenases-1 inhibitor is preparing the application in suppressing doxorubicin cardiotoxicity medicine |
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| Title |
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| DOMINIKA NOWIS ET AL.: ""Zinc protoporphyrin IX, a heme oxygenase-1 inhibitor, demonstrates potent antitumor effects but is unable to potentiate antitumor effects of chemotherapeutics in mice"", 《BMC CANCER》 * |
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