CN105368752A - Bacterium AD05 which is separated from human intestinal tract and can generate anti-cancer active metabolites and application of bacterium AD05 - Google Patents
Bacterium AD05 which is separated from human intestinal tract and can generate anti-cancer active metabolites and application of bacterium AD05 Download PDFInfo
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- CN105368752A CN105368752A CN201510906899.8A CN201510906899A CN105368752A CN 105368752 A CN105368752 A CN 105368752A CN 201510906899 A CN201510906899 A CN 201510906899A CN 105368752 A CN105368752 A CN 105368752A
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Abstract
The invention discloses a bacterium AD05 which is separated from a human intestinal tract and can generate anti-cancer active metabolites and application of the bacterium AD05. Feces of healthy persons is used as a sample and is screened by the aid of first Gauserime solid culture media with potassium dichromate, so that the bacterium which can generate the anti-cancer active metabolites can be ultimately separated from the human intestinal tract and is named as AD05. The bacterium AD05 and the application have the advantages that the bacterium AD05 has the closest genetic relationship with Fimbriimonas ginsengisoli Gsoil 348 as discovered in 16S rRNA (ribosomal ribonucleic acid) comparison, and obvious anti-tumor activity of the bacterium AD05 and the metabolites of the bacterium AD05 is sufficiently proved by experiments; the bacterium is sourced from the human intestinal tract and accordingly has little or zero side effects for human bodies; a novel technical means is provided for tumor therapy, and important effects can be realized for development of biological tumor therapy.
Description
Technical field
The invention belongs to field of biological pharmacy, from people's entero-bacte, be separated to the bacterium having and can produce antitumour activity meta-bolites
Background technology
Cancer has become the disease that in world wide, situation is very serious, and cancer morbidity continues soaring, nearly cancer morbidity decades linearly ascendant trend.According to " 2012 Chinese tumour registration annual report ", China's cancer morbidity is 285.91/10 ten thousand, and city and country sickness rate is respectively 303.91/10 ten thousand and 249.98/10 ten thousand.According to " 2011 Chinese tumour registration annual report ", Cancer in China case fatality rate is 184.67/10 ten thousand.Though it should be noted that city cancer morbidity is higher than rural area, case fatality rate is lower than rural area (181.54/10 ten thousand and 196.34/10 ten thousand).According to estimates, to 2049, China's cancer morbidity may reach the level of 4,00/,100,000.The main reason that cancer morbidity raises is aging population.China aged proportion is may reach 16% after 13.6%, 20 ~ 30 years now.Therefore along with the increase of aging ratio, the high incidence of cancer and high lethality rate have all become a very severe problem, and the life and health of the mankind in serious threat.
Nearest 30 years for the research of cancer in focus on the generation of cancer, development and the reaction for medicine.Cancer is a kind of change relating to the healthy state of the dependent biological cells and tissues of many Time and place, and this change finally result in malignant tumour, and the formation of knurl body is the final biology final result of this kind of disease.Tumour cell intrudes into surrounding tissue and spreads to remote organ, which results in the high lethality rate of this kind of disease.The major obstacle of this kind of disease treatment is that the Mechanism Study for the generation of cancer is not deep enough, lacks unified theory to integrate the various diseases performance observed.Owing to cannot put disease senesis of disease in order, this causes the mortality ratio that cannot reduce disease to a great extent.Cancer is a kind of metabolism class disease to have research to think, cancer is a kind of genopathy also to have research to think, also has other a lot of research conclusions, but the conclusion of not consistent approval at present.And the Primary Care form of cancer carries out radiotherapy and chemotherapy after comprising ocal resection at present.But radiotherapy and chemotherapy all can cause damage can not kill cancer cell completely again to the normal cell of human body and tissue simultaneously.Cause that the reason of this phenomenon is mainly to lack accurate cancer cells targeting, penetration into tissue is not enough and lethal limited to cancer cells.These defects all reduce the validity for the treatment of, and meanwhile M & M increases.Especially carcinoma of the pancreas in some cases of cancer, sometimes cannot implement excision, at this moment chemotherapy becomes the therapeutic modality of standard, and therefore cancer therapy drug just becomes particularly important.
At present cancer therapy drug is mainly concentrated on to the research and development of single prescription target drug, based on this pattern, two kind anti-cancer drugs things are had to be developed, comprise tyrosine kinase inhibitor and monoclonal antibody (AnandaMChakrabarty, NunoBernardes, andArsenioMFialho, BacterialproteinsandpeptidesincancertherapyTodayandtomor row, Bioengineered2014; 5:, 234 – 242).But along with the development of this kind of medicine, the consequent is resistance and the side effect of medicine, these factors all significantly limit the continuation application of medicine.Therefore the research and development for new drug become very important.
Applying wider antitumor drug clinically at present mainly divides in order to antineoplastic alkylating agent, anti-tumor botanical and antitumor antibiotics, wherein antitumor antibiotics is a very important series antineoplastic medicament, wherein much derive from the meta-bolites of microorganism, it has antineoplastic activity, which includes the actinomycin that actinomycetes produce, anthracene nucleus antineoplastic antibiotic etc., antimicrobial treatments tumour has the history of 100 years (Endotoxin.BerryLJ (Ed) .Vol3.ElsevierScience at least, Amsterdam, pp389-448, 1985.BuschW:AusderSitzungdermedicinischenSectionvom13Nov ember1867.BerlKlinWochenschr5:137, 1868 (InGerman) .), although this is a kind of potential new therapeutic modality always, but using microbe targeting therapy on tumor still has some limitations, mainly due to its potential biological safety and other toxic actions, comprise intrinsic cytotoxin, extremely low target validity, the unstable of gene and the interaction with other treatment mode.The effect of initial discovery bacterize tumour is in 1813, find the bacteriological infection of the concurrent fusobacterium of cancer patients thus make death of neoplastic cells (VanMellaertL, Barb é SandAnn é J:Clostridiumsporesasanti-tumouragents.TrendsMicrobiol14: 190-196,2006.WeiMQ, MengeshaA, GoodDandAnn é J:Bacterialtargetedtumourtherapy-dawnofanewera.CancerLet t259:16-27,2008.).Having carried out first case German physician in 1868 utilizes bacteriological infection to carry out clinical practice (the BuschW:AusderSitzungdermedicinischenSectionvom13November 1867.BerlKlinWochenschr5:137 of Therapeutic cancer, 1868 (InGerman) .LinnebacherM, MaletzkiC, KlierUandKlarE:Bacterialimmunotherapyofgastrointestinalt umors.LangenbecksArchSurg397:557-568,2012.).After 20 years, a New York physician utilizes the pyrogen of streptococcus to treat the cancer patients that cannot perform the operation, but its curative effect does not reach the effect (ColeyWB:Thetreatmentofmalignanttumorsbyrepeatedinoculati onsoferysipelas:withareportoftenoriginalcases.AmJMedSci1 05:487-510,1893.) of cure diseases.Start to develop rapidly to this research field in 1976, occurred a series of experimental study since then.The meta-bolites that bacterium produces comprises the material of some proteins and peptides classes, by affecting the signal path of tumour cell or acting on the DNA of tumour cell thus reach antineoplastic object.Secondly, the gene due to microorganism is easy to modify, and can reach the limitation and deficiency that overcome current cancer therapy by engineered modification, strengthens the targeting of cancer therapy drug, strengthens tissue penetration thus reaches higher result for the treatment of.
Visible, utilizing bacterium to carry out Therapeutic cancer will become the breakthrough point of new drug development, the meta-bolites no matter utilizing bacterium or the genetic modification utilizing bacterium is to reach therapeutic target tropism, and utilizing bacterium to carry out Therapeutic cancer will be all very promising therapeutic modality.
Summary of the invention
The object of the present invention is to provide a kind of bacterium that can be used in Therapeutic cancer and uses thereof.
In order to achieve the above object, present invention employs following technique means:
Inventor with Healthy People ight soil for sample, screen by using the Gause I solid medium containing potassium bichromate, final separation obtains the bacterium that a strain can produce antitumour activity meta-bolites, called after AD05, through 16SrRNA comparison, bacterium AD05 of the present invention finds that itself and FimbriimonasginsengisoliGsoil348 sibship are nearest, further, also sufficient proof bacterium AD05 and meta-bolites thereof have anti-tumor activity by experiment in the present invention.
The bacterium that can produce antitumour activity meta-bolites that a strain of the present invention is separated from human intestinal, called after AD05, Classification And Nomenclature is Fimbriimonasginsengisoli, be deposited in China Committee for Culture Collection of Microorganisms's common micro-organisms center, address is in Yard 1, BeiChen xi Road, Chaoyang District, Beijing City institute of microbiology of the Chinese Academy of Sciences, its culture presevation is numbered: CGMCCNo.11486, and preservation date is on October 13rd, 2015.
Have an opsonigenous substances for antitumour activity, the bacterial secretory being numbered CGMCCNo.11486 by culture presevation produces.
Further, present invention also offers described bacterium AD05 and the purposes of meta-bolites in preparation treatment or preventing cancer medicine thereof.In one particular embodiment of the present invention, described cancer is cervical cancer, leukemia, liver cancer.
In the present invention, preferably, described opsonigenous substances is that bacterium AD05 of the present invention is inoculated in Gause I liquid nutrient medium, at 0-40 DEG C, after enlarged culturing 4-16 days, by centrifugal for the AD05 bacterium liquid after above-mentioned enlarged culturing, get supernatant liquor, obtain opsonigenous substances.
Compared to prior art, beneficial effect of the present invention is:
(1) AD05 derives from human intestinal, and source is novel, and anti-tumor activity is remarkable.
(2) because it finds at human intestinal, the side effect for human body can very little or nothing
(3) the present invention is expected to for the development of oncobiology treatment plays a significant role.
(4) it is reported first that the meta-bolites of the species belonging to this bacterium has antitumour activity.
(5) pass through the difference regulating the state of human body enteric microorganism or the ratio of quantity, thus reach the object of preventing cancer.
Accompanying drawing explanation
Fig. 1 is the result of HeLa cell after AD05 meta-bolites effect 6h;
Figure 1A is the result of HeLa cell after the effect of AD05 meta-bolites; Figure 1B is normal control cells.
Fig. 2 is the result of Leukemia cells NB4 after AD05 meta-bolites effect 6h;
Fig. 2 A is the result of NB4 cell after the effect of AD05 meta-bolites; Fig. 2 B is normal control cells.
Fig. 3 is the result of hepatocellular carcinoma H22 after AD05 meta-bolites effect 6h;
Fig. 3 A is the result of HepG2 cell after the effect of AD05 meta-bolites; Fig. 3 B is normal control cells.
Fig. 4 is the MTT result of Hela cell after the AD05 meta-bolites effect 24h of different concns;
Fig. 5 is the evolution position of AD05.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But embodiment is only exemplary, does not form any restriction to scope of the present invention.It will be understood by those skilled in the art that and can modify to the details of technical solution of the present invention and form or replace down without departing from the spirit and scope of the present invention, but these amendments and replacement all fall within the scope of protection of the present invention.
The separation andpreconcentration of embodiment 1 bacterium AD05
(1) separation and Culture of bacterium AD05
1, method
(1) with Healthy People ight soil for sample, therefrom separation and Culture bacterium.
Sampling illustrates:
We will give every ight soil supplier one sampling bag, comprise following article: 50mL centrifuge tube x1, spoon x1, PE gloves x2, paper disc x1, Informed Consent Form x1 and sampling specification sheets x1.
Operation instructions:
1) read Informed Consent Form in detail, ight soil supplier signature also fills in essential information in detail.
2) please ight soil is discharged in disposable paper disc as far as possible.
3) bring PE gloves, take ight soil centre portions with spoon, about 10g (approximately reaching the scale marks place of centrifuge tube 10mL), puts in 50mL centrifuge tube, after tightening centrifuge tube lid, puts back in valve bag.
4) whole operating process is avoided touching other uncorrelated article as far as possible.
5) because morning Monday submits sample, so collect the ight soil in morning Monday as far as possible, fresh to ensure.
6) centrifuge tube and Informed Consent Form that ight soil is housed are loaded valve bag, returned by lab assistant centralized collection.
(2) separation and Culture of AD05:
1) sample, numbering: 1,2,3,4 ...Centrifugal: 8000rpm, 30min.Collection supernatant liquor is for subsequent use.
2) sample pellet is mixed with the sand after autoclaving, natural air drying 4-16 days.
3) sample after air-dry is pulverized, 80 DEG C of xeothermic 1h of constant temperature.
4) getting the sample that 1g processes is dissolved in 10mLPBS solution, vibration 30min.
5) 30s is left standstill.
6) get supernatant and carry out 10 times, 100 times, 1000 times dilutions.
7) 10 are got
-2, 10
-3pipe 100ul is coated in (potassium bichromate on Gause I solid medium flat board respectively
+).
8) 0-40 DEG C of cultivation, single bacterium colony is chosen and mix rear covered with suitable quantity of water on slide glass, and 40 × visible mycelium spore, bacterium colony is hard, not easily picking.
11) deposit bacterium: 500ul50% glycerine+500ul bacterium liquid, after mixing, deposit bacterium for-80 DEG C.
12) inclined-plane: inoculating needle picking colony inserts slant medium repeatedly, more repeatedly rules on inclined-plane, 0-40 DEG C of cultivation, for subsequent use.
Preparation of reagents:
1) Gause I solid medium (1L): contain
Zulkovsky starch 20g/L, KNO
31g/L, K
2hPO
40.5g/L, MgSO
47H
2o0.5g/L, NaCl0.5g/L, FeSO
47H
2o (being made into mother liquor to add again) 0.01g/L, agar 20g/L, distilled water supplies 1000ml.
2) potassium bichromate concentration 50mg/L (during screening use, other need not)
Stock solution: 5g/L (matching while using, lucifuge, filtration sterilization)
If 100mL Gause I solid medium, then add 1mL potassium bichromate storage liquid (treating that substratum is not too hot to add, mixing)
3) FeSO
47H
2o mother liquor: 0.01g/mL1gFeSO
47H
2o is dissolved in 100mLH
2o, so 1000mL Gause I solid medium adds 1mL ferrous sulfate mother liquor.
4) PBS damping fluid (1L): containing KH
2pO
40.27g/L, Na
2hPO
41.42g/L, NaCl8g/L, KCl0.2g/L.
(3) for being separated the AD05 enlarged culturing obtained:
AD05 is inoculated in Gause I liquid nutrient medium enlarged culturing, culture temperature is 0-40 DEG C (such as 28 DEG C), and incubation time is 16 days.
(4) preparation of AD05 meta-bolites: by centrifugal for the AD05 bacterium liquid of above-mentioned enlarged culturing, 8000rpm, 10min, get supernatant liquor and do the experiment of follow-up inhibiting tumor cell.
(2) the anti-tumor activity analysis of bacterium AD05
(1) cultivate Hela cell, Secondary Culture and bed board, every hole 100ul, adds the meta-bolites 5ul of AD05 wherein after Hela cell attachment, then cultivates observation after six hours.Microscopic observation Hela cellular form.As shown in Figure 1, there is cavity, death in cell to result.
(2) cultivator Leukemia cells NB4, Secondary Culture and bed board, every hole 100ul, adds the meta-bolites 5ul of AD05 wherein after NB4 cell attachment, then cultivates observation after six hours.Microscopic observation NB4 cellular form.As shown in Figure 2, there is pyknosis, death in the cell adding the meta-bolites of AD05 to result.
(3) cultivator hepatocellular carcinoma H22, Secondary Culture and bed board, every hole 100ul, adds the meta-bolites 5ul of AD05 wherein after HepG2 cell attachment, then cultivates observation after six hours.Microscopic observation HepG2 cellular form.As shown in Figure 3, there is cavity in the cell adding the meta-bolites of AD05 to result.
(4) cultivate HeLa cell, Secondary Culture and bed board, every hole 100 μ l, cell density is 1x10
5/ mL, meta-bolites 2.5 μ l, 5 μ l, 10 μ l, 20 μ l, 40 μ l, the 80 μ l of AD05 bacterial strain are added wherein respectively after HeLa cell attachment, control group is Gause I liquid nutrient medium, the AD03 separately got without antitumour activity does negative control, respectively establish 6 repeating holes, then cultivate observation after 6-72 hour.Every hole adds 20 μ lMTT solution, continues to cultivate 4h.Stop cultivating, carefully suck nutrient solution in hole.Every hole adds 150 μ l dimethyl sulfoxide (DMSO), puts low-speed oscillation 10min on shaking table, crystalline material is fully dissolved.The light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument OD492nm place.As shown in Figure 4, the meta-bolites of AD05 all presents gradient for the restraining effect of HeLa cell and time and concentration to result.
(3) species identification is carried out to active bacteria:
The AD05 that can produce anti-cancer active matter carry out three roads streak culture after, post and carry out 16srRNA order-checking and qualification to Jin Wei intelligence bio tech ltd, sequencing result is as shown in SEQIDNO.1.Application MEGA Software on Drawing evolutionary tree, result as shown in Figure 5, finds that from evolutionary tree AD05 belongs to Fimbriimonasginsengisoli.
The bacterium that can produce antitumour activity meta-bolites that above-mentioned separation obtains, called after AD05, Classification And Nomenclature is Fimbriimonasginsengisoli, be deposited in China Committee for Culture Collection of Microorganisms's common micro-organisms center, address is in Yard 1, BeiChen xi Road, Chaoyang District, Beijing City institute of microbiology of the Chinese Academy of Sciences, its culture presevation is numbered: CGMCCNo.11486, and preservation date is on October 13rd, 2015.
Claims (7)
1. the bacterium that can produce antitumour activity meta-bolites that is separated from human intestinal of a strain, called after AD05, be deposited in China Committee for Culture Collection of Microorganisms's common micro-organisms center, its culture presevation is numbered: CGMCCNo.11486, and preservation date is on October 13rd, 2015.
2. there is an opsonigenous substances for antitumour activity, it is characterized in that the bacterial secretory that described meta-bolites is numbered CGMCC11486 by culture presevation produces.
3. opsonigenous substances as claimed in claim 2, bacterium AD05 according to claim 1 is it is characterized in that to be inoculated in Gause I liquid nutrient medium, at 0-40 DEG C, after enlarged culturing 4-16 days, by centrifugal for the AD05 bacterium liquid after above-mentioned enlarged culturing, get supernatant liquor, obtain opsonigenous substances.
4. the purposes of bacterium according to claim 1 in preparation treatment or preventing cancer medicine.
5. purposes as claimed in claim 4, is characterized in that described cancer is cervical cancer, leukemia, liver cancer.
6. the purposes of the meta-bolites described in Claims 2 or 3 in preparation treatment or preventing cancer medicine.
7. purposes as claimed in claim 6, is characterized in that described cancer is cervical cancer, leukemia, liver cancer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105969685A (en) * | 2016-05-12 | 2016-09-28 | 南昌大学 | Method for screening microorganisms with anticancer activity in excrement |
| CN110272855A (en) * | 2019-08-01 | 2019-09-24 | 哈尔滨天齐人类第二基因组技术开发应用科技有限责任公司 | One plant has the active bacillus CCPM7650 of powerful anticancer and its application |
| CN110295132A (en) * | 2019-08-01 | 2019-10-01 | 哈尔滨天齐人类第二基因组技术开发应用科技有限责任公司 | One plant has the active bacillus CCPM7645 of powerful anticancer and its application |
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| CN102258541A (en) * | 2011-07-08 | 2011-11-30 | 黑龙江大学 | Anti-oxidant produced by microorganisms and pharmaceutical composition thereof |
| WO2014176634A1 (en) * | 2013-05-01 | 2014-11-06 | Neoculi Pty Ltd | Methods for treating bacterial infections |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105969685A (en) * | 2016-05-12 | 2016-09-28 | 南昌大学 | Method for screening microorganisms with anticancer activity in excrement |
| CN110272855A (en) * | 2019-08-01 | 2019-09-24 | 哈尔滨天齐人类第二基因组技术开发应用科技有限责任公司 | One plant has the active bacillus CCPM7650 of powerful anticancer and its application |
| CN110295132A (en) * | 2019-08-01 | 2019-10-01 | 哈尔滨天齐人类第二基因组技术开发应用科技有限责任公司 | One plant has the active bacillus CCPM7645 of powerful anticancer and its application |
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