CN104083382A - Synergistic effect and application of ergosterol peroxide and paclitaxel in aspect of killing Hela cancer cells - Google Patents
Synergistic effect and application of ergosterol peroxide and paclitaxel in aspect of killing Hela cancer cells Download PDFInfo
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- CN104083382A CN104083382A CN201410311586.3A CN201410311586A CN104083382A CN 104083382 A CN104083382 A CN 104083382A CN 201410311586 A CN201410311586 A CN 201410311586A CN 104083382 A CN104083382 A CN 104083382A
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Abstract
The invention relates to a composition for killing Hela cancer cells. The composition consists of ergosterol peroxide and paclitaxel and has the effect of inhibiting Hela cancer cell proliferation in a synergistic mode, particularly has an obvious synergistic effect in a concentration range according to a ratio of 6.25-12.5mu g/ml of ergosterol peroxide to 0.025-0.1mu g/ml of paclitaxel. The composition can greatly reduce the amount of paclitaxel and reduce the cost and toxic and side effects and is possibly effective on cancer cell strains with drug resistance on paclitaxel.
Description
Technical field
The invention belongs to Natural Medicine Chemistry and Food Chemistry technical field, relate to 2 kinds of natural products: ergosterol peroxide and paclitaxel.Ergosterol peroxide can strengthen the inhibitory action of paclitaxel to cancer cell multiplication.
Background technology
Ergosterol peroxide (EP) (
fig. 1) be natural component (the Chen Y. K. extensively existing in medicinal fungi and edible mushroom, Kuo Y. H., Chiang B. H., Lo J. M., Sheen L. Y. (2009). Cytotoxic activities of 9,11-dehydroergosterol peroxide and ergosterol peroxide from the fermentation mycelia of
ganoderma lucidumcultivated in the medium containing leguminous plants on Hep 3B cells. Journal of agricultural & food chemistry, 57 (13), 5713-5719.; Kobori M., Yoshida M., Kameyama, M. O., Shinmoto. H. (2007). Ergosterol peroxide from an edible mushroom suppresses inflammatory responses in RAW264.7 macrophages and growth of HT29 colon adenocarcinoma cells. British Journal of Pharmacology, 150 (2), 209-219).The medicinal fungis such as Ganoderma as cancer patient's food supplement (Sliva D. (2003).
ganoderma lucidum(Reishi) in cancer treatment. Integrative Cancer Therapies, 2 (4), 358-364.). it has been generally acknowledged that polysaccharide and Triterpenoid are the anticancer active constituent of Ganoderma, still do not report about the activity contribution of ergosterol peroxide in Ganoderma.The EP in other biological source once reported activity (the Takei T. of cancer cell specific induction of apoptosis, Yoshida M., Kameyama M. O., Kobori M. (2005). Ergosterol peroxide, an apoptosis – inducing component isolated from
sarcodon aspratus(Berk.) S. Ito. Bioscience, Biotechnology & Biochemistry, 69 (1), 212-215.), but not about ergosterol peroxide and the symphyogenetic report of clinical cancer therapy drug.
Paclitaxel (
fig. 1) be clinical conventional broad-spectrum anti-cancer drug, especially to effective (the Wang T. H. of breast carcinoma and uterus carcinoma, Wang H. S., Soong Y. K. (2000). Paclitaxel-induced cell death, where the cell cycle and apoptosis come together. Cancer, 88 (11), 2619-2628.).Paclitaxel is attached to the G2/M phase that microtubule suppresses cell, thus cell death inducing.The greatest problem of clinical use paclitaxel is its toxic and side effects and drug resistance, and in addition, expensive price also causes burden to patient.In recent years, Drug combination became the New Policy for the treatment of cancer.Combine and use the medicine that acts on different target spots often can produce synergism to make medicine can bring into play drug effect compared with low dosage, thereby reduce the toxic and side effects of medicine; Drug combination also can be effective to some drug resistance cancer strains.See that clinically paclitaxel combines the example of use with other drug, as, the coupling of bibliographical information paclitaxel-cyclophosphamide is (the Mcguire W. P. of the better effects if to uterus carcinoma than cyclophosphamide-Cisplatin, Hoskins W. J., Brady M. F., Paul B. S., Kucera R., Partridge E. E., Look K. Y., Pearson D. C., Davidson M. (1996). Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. The New England Journal of Medicine, 334 (1), 1-6.).The coupling of paclitaxel-bevacizumab can significant prolongation metastatic breast cancer compared with alone paclitaxel the Progression free survival phase, but, these are combined anticancer scheme and also usually produce some side effect, as: cause neuropathy, infect and tired (Miller K., Wang M. M., Gralow J., Dickler M., Cobleigh M., Perez E. A., Shenkier T., Cella D., Davidson N. E. (2007). Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. The New England Journal of Medicine, 357 (26), 2666-2676.).Natural product very low or nontoxic toxicity and paclitaxel coupling may be become to the new hope for the treatment of of cancer.
Summary of the invention
The object of the present invention is to provide one to there is synergism, thereby can reduce paclitaxel consumption and reduce the composition of medicine of its chemotherapy side effect and expense.
Composition of medicine of the present invention is made up of ergosterol peroxide and paclitaxel, and in ergosterol peroxide-paclitaxel ratio is the concentration of 6.25-12.5 μ g/ml:0.025-0.1 μ g/ml, synergism is remarkable.
Experiment showed, that ergosterol peroxide can increase paclitaxel and enter cancerous cell concentration, increase the selective inhibitory to cancerous cell, reduce Normocellular toxicity.The collaborative Hela growth and proliferation of cell that suppresses of composition of medicine of the present invention, aobvious same when active the consumption of required paclitaxel significantly reduce (can reach the independent use amount of paclitaxel 1/10), thereby significantly reduce the toxic and side effects of expense and paclitaxel.
brief description of the drawings:
fig. 1the chemical structural formula of ergosterol peroxide and paclitaxel;
fig. 2paclitaxel, ergosterol peroxide and the paclitaxel+ergosterol peroxide proliferation inhibition rate to Hela cell (72 hours; Concentration μ g/ml);
fig. 3 .A: use paclitaxel (10 μ g/ml) or paclitaxel (10 μ g/ml)+ergosterol peroxide (10 μ g/ml) to process Hela cell after 2.5 hours, the paclitaxel peak detecting with UHPLC-MS;
b. process content of taxol in the cell that Hela or GES-1 cell detect after 2.5 hours with paclitaxel (10 μ g/ml) or paclitaxel (10 μ g/ml)+ergosterol peroxide (10 μ g/ml);
fig. 4.ergosterol peroxide is processed after 72 hours different carcinoma cell and Normocellular cytotoxicity, the concentration (μ g/ml) that X-axis is ergosterol peroxide;
fig. 5.total SOD activity in Hela cancerous cell and GES-1 normal cell; (+): with 20 μ g/ml ergosterol peroxides processing 18 hours;
fig. 6. A: the reacted relative concentration of ergosterol peroxide and SOD in cell-free system (ergosterol peroxide is defined as 1 in the concentration not containing in the buffer of SOD);
b: with the ergosterol peroxide relative amount (ergosterol peroxide content in GES-1 normal cell be defined as 1) of 20 μ g/ml ergosterol peroxides processing cells after 6 hours.
table 1. the content of ergosterol peroxide in medicinal fungi and edible mushroom
a medicinal fungi;
b edible mushroom
* regression equation: Y=1.5468X+0.145; Correlation coefficient (R
2)=0.99; The range of linearity: 8.33-0.31 μ g/ml; The concentration of interior mark hydrogenation of compounds cortisone is 2.5 μ g/ml.
?
Detailed description of the invention
cell culture
Hela (human cervical carcinoma cell), A431 (application on human skin cancerous cell), GES-1 (people MG53 gastric epithelial cell), HBE (human bronchial epithelial cell) cultivates in DMEM culture medium; MGC-803 (gastric carcinoma cells), HUEVC (people's umbilicus MG53 vein epithelial cell) cultivates in PRMI 1640 culture medium.All culture medium are all containing 10% calf serum, 100 U/ml mycillins.Cell is at 37 DEG C of 5% CO
2in incubator, cultivate.
cytotoxic activity
Cell is inoculated on 96 orifice plates, 5000, every hole cell, after cell attachment, add compound to continue to cultivate 72 hours, every hole adds 20 μ l MTT (5 mg/ml) to cultivate 4 hours, adds 150 μ l DMSO and measure light absorption value at 570 nm after sucking-off culture fluid;
fig. 2shown when paclitaxel and ergosterol peroxide use separately respectively, and paclitaxel is combined the suppression ratio to Hela cell proliferation while use with ergosterol peroxide.Can see, paclitaxel concentration is respectively 10% and 38% to the proliferation inhibition rate of Hela cell below 0.025 and 0.05 μ g/ml time; Ergosterol peroxide concentration is 23% to the proliferation inhibition rate of Hela cell below 12.5 μ g/ml time.But, it is 66% with the ergosterol peroxide of 12.5 μ g/ml to the proliferation inhibition rate of Hela cell that the paclitaxel of 0.025 μ g/ml is combined while use, the twice of the suppression ratio sum (10%+23%=33%) while use separately for same concentration 2 materials, suppression ratio more than 6 times while use separately for same concentration paclitaxel.In the time that 0.05 μ g/ml paclitaxel and 12.5 μ g/ml ergosterol peroxides share, the proliferation inhibition rate of Hela cell is reached to 80%, suitable to the proliferation inhibition rate of Hela cell during with independent use 0.5 μ g/ml paclitaxel, the amount that, the proliferation inhibition rate of Hela cell is reached to 80% required paclitaxel is in the time of associating ergosterol peroxide only 1/10 of the paclitaxel consumption when using paclitaxel separately.
Content of taxol in cell
Cell is inoculated on 6 orifice plates, grow to 90% converge after, add ergosterol peroxide (10 μ g/ml) or paclitaxel (10 μ g/ml) individual processing 2.5 hours with paclitaxel (10 μ g/ml). remove culture medium, PBS cleans 2 times for cell.With after trypsinization by cell harvesting in centrifuge tube, centrifugal abandoning supernatant.Collecting cell suspends in water and centrifugal abandoning supernatant again.In every porocyte, add ultrasonication cell after 500 μ l methanol, mixture under 12000g gravity centrifugal 20 minutes, the supernatant obtaining is with 0.22 μ m membrane filtration after ODS pillar, and filtrate is analyzed with UHPLC-MS.
Fig. 3 A has shown that dosing processing is after 2.5 hours, the peak area of paclitaxel in the Hela cell detecting with UHPLC-MS.Can find out, after processing with paclitaxel (10 μ g/ml)+ergosterol peroxide (10 μ g/ml), in cell, the content of paclitaxel is apparently higher than the cell by paclitaxel (10 μ g/ml) individual processing.While using as can be seen from Figure 3B paclitaxel (10 μ g/ml) individual processing, the amount that paclitaxel enters Hela cancerous cell is starkly lower than the Normocellular amount that enters.Paclitaxel (10 μ g/ml) and ergosterol peroxide (10 μ g/ml) Combined Treatment, can obviously increase paclitaxel and enter the amount of Hela cancerous cell and affect not obvious on the amount that enters GES-1 cell.Total SOD activity
Hela cancer and GES-1 normal cell are cultivated in 6-cm culture dish, and every ware is divided into ergosterol peroxide processing (20 μ g/ml) and untreated two parts.After 18 hours, by cell dissociation to ultrasonication in water, centrifugal 20min under 12000g gravity.Supernatant is measured SOD activity at 450nm.
SOD suppression ratio (%)=100 × [(A
blank1-A
blank2)-(A
sample-A
blank3)]/(A
blank1-A
blank2)
Blank1: substrate+xanthine enzyme+water; Blank2: substrate+buffer+water; Blank3: substrate+buffer+sample; Sample: substrate+enzyme+sample
SOD activity (U/mg protein)=[SOD inhibition/ (1-SOD inhiition)]/M
SOD inhibition:SOD suppression ratio; M: total protein quality (mg) in sample.
ergosterol peroxide content in cell-free system under SOD existence
SOD is dissolved in kaliumphosphate buffer, regulates pH to 7.8.Reactant liquor containing 100 μ g ergosterol peroxides and 500 μ l SOD is reacted 30 minutes at 25 DEG C.After mixture lyophilization, be again dissolved in acetonitrile and within centrifugal 20 minutes, remove inorganic salt with precipitation in 12000 g.After supernatant liquid filtering, analyze the content of ergosterol peroxide with UHPLC-MS.
Ergosterol peroxide has cytotoxic activity and ergosterol does not have the activity of this respect, and the cytotoxic activity of steroid compound may be relevant with peroxy-radical.In addition, from
fig. 4can find out, ergosterol peroxide was processed cell after 72 hours, and the inhibited proliferation of cancerous cell is obviously greater than Normocellular effect.Whether these phenomenons are because the SOD specific activity normal cell of cancerous cell is low, as containing the normal cell of high-caliber SOD, effectively ergosterol peroxide reduced into the material that there is no cytotoxicity? investigate result as
fig. 5shown in, the Normocellular SOD level of GES-1 is apparently higher than the SOD level of Hela cancerous cell.Process and intracellular SOD was produced and has certain activation in 18 hours with 20 μ g/ml ergosterol peroxides, but there is no notable difference compared with untreated cell.SOD is also verified the cell-free system that acts on of ergosterol peroxide.As
fig. 6shown in, the SOD combined experiments of constant ergosterol peroxide and variable concentrations shows, the concentration that increases ergosterol peroxide along with the concentration of SOD, reducing, shows that SOD can change ergosterol peroxide into other materials.Intracellular measurement result has been verified guess above, that is: the amount of ergosterol peroxide in GES-1 normal cell is starkly lower than the amount (p<0.01) in Hela cancerous cell, be likely due to the Normocellular high-level SOD activity of GES-1 effectively metabolism ergosterol peroxide.
the quantitative analysis of ergosterol peroxide
UPLC-ESIMS(ultra high efficiency liquid phase-Electrospray Mass Spectrometry) in Agilent Agilent 1290 infinity UPLC and Agilent 6430 triple Quad MS (ESI ion source) systems, analyze.Chromatographic column is agilent ZORBAX RRHD Eclipse Plus C18 (50 mm × 2.1 mm; M), column temperature is controlled at 30oC to 1.8 μ.Hydrocortisone is as interior mark.Standard substance (EP) are dissolved in DMSO and with becoming series concentration so that bioassay standard curve containing interior target DMSO solution dilution.50 mg sample extraction things contain interior target methanol solution supersound extraction 2 times with 2 ml, each 10 minutes, then centrifugal.Supernatant by after ODS pillar with 0.22 μ m membrane filtration, filtrate is analyzed with UHPLC-MS.It is the pure water containing 0.1% formic acid that UPLC-ESIMS analyzes mobile phase: A, and B is methanol; Flow velocity is 0.4 ml/min, and injection volume is 2 μ l.Elution program: 60 % B when 0 min, 90 % B when 1.5 min, 4-6 min 100% B.With the MRM(mass spectrum multiple-reaction monitoring of positive ion mode) quantitative EP, parent ion is 429 [M+H], because there is no the daughter ion fragment of sufficient intensity, daughter ion is also set as 429.Fragmentor after optimization is 170 V, and collision energy is 1 eV; Show by the ergosterol peroxide UHPLC-MS quantitative approach measurement result of above-mentioned optimization, the 5 kinds of medicinal fungis and the 6 kinds of edible mushrooms that detect all contain ergosterol peroxide (table 1).This result supports edible mushroom useful to cancer patient from active substance basis.
The present invention discloses first the amount that ergosterol peroxide can enter by increasing paclitaxel cell and has strengthened the inhibitory action to cancer cell multiplication.The consumption of paclitaxel be can significantly reduce with ergosterol peroxide coupling, thereby toxic and side effects and the expense of paclitaxel reduced, and likely effective to drug resistance JEG-3.The coupling of paclitaxel-ergosterol peroxide can become new departure for the treatment of cancer.The Mycophytas such as edible mushroom contribute to cancer patient's treatment.
The above is preferably detailed description of the invention of the present invention, and protection scope of the present invention is not limited to this.Any those of ordinary skill in the art are in content disclosed by the invention, and the technical scheme that can obviously obtain by simple change or equivalent replacement all falls within the scope of protection of the present invention.
Claims (5)
1. suppress a compositions for Hela cancer cell multiplication, it is characterized in that said composition is made up of ergosterol peroxide and paclitaxel.
2. compositions described in claim 1, it is characterized in that ergosterol peroxide and paclitaxel have the effect of the collaborative Hela of inhibition cancer cell multiplication, particularly ergosterol peroxide: the concentration of paclitaxel is within the scope of 6.25-12.5 μ g/ml:0.025-0.1 μ g/ml, and two material synergism are remarkable.
3. compositions described in claim 1, is characterized in that said composition is greater than the restraint to normal cell proliferation to the restraint of cancer cell multiplication, and in principle and normal cell, SOD expression is higher, and effectively metabolism ergosterol peroxide is relevant.
4. compositions described in claim 1, is characterized in that the ability that ergosterol peroxide can increase paclitaxel and enters cancerous cell.
5. compositions described in claim 1, its feature can significantly reduce the consumption of paclitaxel in said composition, and reduction expense and toxic and side effects also may be to there being the JEG-3 of the anti-paclitaxel property of medicine effective.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108707180A (en) * | 2018-08-08 | 2018-10-26 | 齐齐哈尔医学院 | 3 beta-hydroxy -5 α, 8 α-peroxide androstane -6- alkene -17- (isatin substitution) hydazone derivatives and preparation and application |
| WO2020163626A1 (en) | 2019-02-07 | 2020-08-13 | Universidad Central Del Caribe | Biologically active ganoderma lucidum compounds and synthesis of anticancer derivatives; ergosterol peroxide probes for cellular localization |
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| WO2008140203A1 (en) * | 2007-05-15 | 2008-11-20 | Korea Research Institute Of Chemical Technology | Phospholipid nanospheres for solubilization of diterpenoid alkaloid and preparation |
| CN102764263A (en) * | 2012-07-06 | 2012-11-07 | 广东粤微食用菌技术有限公司 | Application of 5alpha-8alpha-ergosterol peroxide-6,22(E)-diene-3beta-alcohol to preparation of anti-tumor drug |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101012268A (en) * | 2005-12-09 | 2007-08-08 | 包海鹰 | Fasciation naematoloma ligarine extraction, preparing method thereof and use in preparing pharmaceutical for treating tumour |
| WO2008140203A1 (en) * | 2007-05-15 | 2008-11-20 | Korea Research Institute Of Chemical Technology | Phospholipid nanospheres for solubilization of diterpenoid alkaloid and preparation |
| CN102764263A (en) * | 2012-07-06 | 2012-11-07 | 广东粤微食用菌技术有限公司 | Application of 5alpha-8alpha-ergosterol peroxide-6,22(E)-diene-3beta-alcohol to preparation of anti-tumor drug |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108707180A (en) * | 2018-08-08 | 2018-10-26 | 齐齐哈尔医学院 | 3 beta-hydroxy -5 α, 8 α-peroxide androstane -6- alkene -17- (isatin substitution) hydazone derivatives and preparation and application |
| WO2020163626A1 (en) | 2019-02-07 | 2020-08-13 | Universidad Central Del Caribe | Biologically active ganoderma lucidum compounds and synthesis of anticancer derivatives; ergosterol peroxide probes for cellular localization |
| EP3920948A4 (en) * | 2019-02-07 | 2022-08-03 | Universidad Central del Caribe | Biologically active ganoderma lucidum compounds and synthesis of anticancer derivatives; ergosterol peroxide probes for cellular localization |
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