关于安卓健的学术论文安卓健对乳腺癌细胞的诱导作用.docx

关于安卓健的学术论文安卓健对乳腺癌细胞的诱导作用.docx

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关于安卓健的学术论文安卓健对乳腺癌细胞的诱导作用

论文标题：

安卓健对乳腺癌细胞的诱导作用

论文摘要：

乳腺癌是全世界最流行的妇科癌症，同时乳腺癌也是全球第二大（除肺癌）造成妇女死亡的癌症。

本研究，我们通过老鼠实验证实萃取自牛樟芝的环乙烯酮化合物—安卓健对乳腺癌细胞具有明显的抑制其成长，促使其凋亡的作用。

我们将80只雌性大白鼠分为五组，分别为AC低剂量组（喂食0.25g牛樟芝菌丝体每千克体重）、AC高剂量组（喂食0.5g牛樟芝菌丝体每千克体重）、安卓健低剂量组（喂食15mg安卓健每千克体重）、安卓健高剂量组（喂食30mg安安卓健每千克体重）、紫杉醇组（喂食5mg紫杉醇每千克体重）。

实验结果显示，无论是牛樟芝组、安卓健组还是紫杉醇组，小于10mm的乳腺肿瘤均显著地缩小。

但是，大于10mm的乳腺肿瘤只在安卓健组观察到显著缩小。

同时发现，高剂量的牛樟芝组比低剂量的牛樟芝组，乳腺肿瘤的缩小程度更显著，并且在高剂量的牛樟芝组，小于10mm的乳腺肿瘤在17周内没有出现复发现象。

英文版本论文全文如下：

Name：

Antrodiacamphorateextractanditspurifiedcompound-Antroquinonolorally

treatsN-methyl-N-nitrosourea-inducedbreastcancer

Summary:

Antrodiacamphoratepossessesanti-breastcanceractivity

TheGoldenBiotechnologyCorp..camphoratainitiatedbythecompany,manyexpertsinvolvedinthestudythemechanismforthetreatmentofbreastcancer

Relatedresearch.StudieshaveshownthatA.camphoratawithanti-canceractivity.

Li-HsuenChen1,Wei-ChihYang1,Gain-HeFang1,Mao-TienKuo2,Wu-CheWen2,PeiniChen3,Ching-FengWeng1*1

DepartmentofLifeScienceandtheInstituteofBiotechnology,National

Dong–HwaUniversity,Hualien974,Taiwan.

2

GoldenBiotechnologyCorp.,DanshueiTownship,TaipeiCounty251,Taiwan.

3

DepartmentofRadiology,TaipeiVeteransGeneralHospital,Taipei112,

Taiwan.

*Towhomcorrespondenceandreprintrequestsshouldbemade

Runningtitle:

Antrodiacamphoratepossessesanti-breastcanceractivity

____________________________________________________________

*Correspondingauthor.Tel.:

+88638633637;fax:

+88638630255.

E-mailaddress:

cfweng@mail.ndhu.edu.tw（Ching-FengWeng）.

Abstract

Breastcanceristhemostprevalentcancerinwomenworldwide,excluding

non-melanomaskincancer,andisthesecondleadingcauseofcancerdeathsin

women（followinglungcancer）.Inthisstudy,Antrodiacamphoratemyceliumwith

mediumextract（AC）anditspurifiedcompound-Antroquinonolwereappliedtotreat

insitubreastcancerinanN-methyl-N-nitrosourea（MNU）-inducedratmodelto

evaluatethetherapeuticpotentialofA.camphorate.EightyfemaleSprague-Dawley

rats（21daysold）werefedadlibitumwithstandardratchowandwereinjected

intraperitoneallythreetimeswith25mgMNU/kgBwt.Ratswerepalpatedevery

weektocheckthesizeofthetumorsandthetumordimensionsweremeasuredusinga

caliper.Breastcancerratsweredividedintothreegroups.Fourgroupswereorally

treatedwith

（1）low（0.25g/kgBwt）and

（2）high（0.5g/kgBwt）dosesofAC;（3）low

（15mg/kgBwt）and（4）high（30mg/kgBwt）dosesofAntroquinonolfor5weeks,

whiletheothergroupwasgiven5mgPaclitaxel/kgBwtintraperitoneallyfivetimes.

Theresultsshowedthatratbreasttumorssmallerthan10mmweremarkedly

diminishedinthePaclitaxel-,Antroquinonol-andAC-treatedgroups,however,

tumorslargerthan10mmwerenotreducedamongthePaclitaxelandACgroups.

Examinationsofthetumorssmallerthan10mmshowedthatthehighdoseACgroup

hadmoretumorshrinkagecomparedtothelowdosegroup.Moreover,lessthan10

mmindimensionafterhighdoseACtreatmentexhibitednorecurrencewithin17

weeks.Inconclusion,Antrodiacamphorateanditspurifiedcompound-Antroquinonol

possessesanti-tumoractivityfortreatingtheearlystagesofbreastcancer.

Keywords:

Antrodiacamphorate,Antroquinonol,Paclitaxel,N-methyl-N-nitrosourea,

insitubreastcancer

Introduction

EdiblemushroomsincludingGanodermalucidum（Reishi）,Lentinula.edodes

（shiitake）,Antrodiacamphorate（niu-chang-chih,Chang-chih）havebeenwidelyused

asamedicinalfungus.G.lucidumhasalsobeenusedtosuppresscelladhesionand

cellmigrationofhighlyinvasivebreastandprostatecancercells,suggestingits

potencytoreducetumorinvasiveness（reviewedinThyagarajanetal.,2007）.

Recently,onereportdemonstratedthatcombinationsofgreenteawithG.lucidum

extractsshowpotentialforthesuppressionofgrowthandinvasivenessofmetastatic

breastcancer（MDA-MB-231）cells（Thyagarajanetal.,2007）.Moreover,structurally

relatedlanostane-typetriterpenes,includingganodericacidA,FandH（GA-A,GA-F,

GA-H）,havebeenidentifiedinanorientalmedicinalmushroomG.lucidum.GA-A

andGA-Hexerttheirbiologicaleffectsthroughinhibitionofthetranscriptionfactors

AP-1andNF-ĸB,resultinginthedown-regulationofexpressionofCdk4and

suppressionofsecretionofuPA,respectively（Jiangetal.,2008）.Lentinulaedodes

（shiitake）aqueousextractshavedemonstrateddirectinhibitionoftheproliferationof

humanbreastcancercellsinvitroandimmuno-stimulatorypropertiesintermsof

mitogenicandco-mitogenicactivityinvitro（Israilidesetal.,2008）.

A.camphorata,oneoftheextensivelyusedmedicinalmushrooms,iswellknown

inTaiwanasatraditionalChinesemedicineandhasrecentlybeenidentifiedas

belongingtothenewgenusoftheAntrodiaspecies（Taiwanofungus）.Itsfruitingbody

hasbeenutilizedintraditionalChinesemedicineforthetreatmentoffoodanddrug

intoxication,diarrhea,abdominalpain,hypertension,skinitches,livercancer,

anti-inflammatory,anti-oxidation,inducedvasorelaxation,decreasedhepatitisBvirus,

andhypotriglyceride（reviewedinSuketal.,2008）.However,theA.camphorata

fruitingbodiesareveryrareandexpensive,andlittlehasbeenreportedaboutits

biologicalactivity,especiallyintreatingthebreastcancer.Breastcanceristhemost

prevalentcancerinwomenworldwide,excludingnon-melanomaskincancer,andis

thesecondleadingcauseofcancerdeathinwomen（followinglungcancer）.Breast

cancerremainsaglobalpublichealthproblemwithsome1.1millionwomennewly

diagnosedwithbreastcancerin2002（Ferlayetal.,2002）,withapproximately

185,000newcasesandover40,000deathsestimatedintheUSAin

2008（Jemaletal.,2008）.Therefore,developingasuitableanimalmodelfortesting

theanti-breastcancerpotencyofA.camphoratabecomesahighpriority.

N-methyl-N-nitrosourea（MNU）isanalkylatingagentthatmethylatesDNAbasesat

nucleophilicsites（generatingN7andN3alkylpurines）.Theprimarymutageniclesion

isO6methylguanine.MNU-inducedmammarytumorigenesisinratsisoneofthe

mostbroadlyusedrodentmammarytumorigenesismodelsforstudyinghumanbreast

cancer（Russoetal.,1990;Gould,1995;Nandietal.,1995）.MNU-inducedrat

mammarytumorigenesisandhumanbreastcancerdevelopmentsharemany

similaritiesinhormonedependency,pathogenesis,histologicalclassification,and

immunocytochemicalmarkers.Basedonthesesimilarities,MNU-inducedrat

mammarytumorigenesisappearstobeausefulexperimentalmodelforthestudyof

humanbreastcancerdevelopment（Thordarsonetal.,2001）.Antroquinonol

（1）,an

ubiquinonederivative,isisolatedfromthesolid-statefermentedmyceliumofA.

camphorate,aparasiticfungusindigenoustoTaiwan.Thestructureofcompound1is

elucidatedbytheanalysisoftheirspectroscopicdata.Itcontainsanti-tumoractivity

（Leeetal.,2007）.Recently,A.camphorateextracthasbeenprovenforthetreatment

ofsystemiclupuserythematosus（SLE）inSLE-proneNZB/WF1mice（Changetal.,

2008）.Theaimofthisstudywastoproducebreastcancerinratstoevaluatethe

anti-tumoractivityofA.camphorateextractanditspurifiedcompound-

Antroquinonolfortreatinginsitubreastcancer.

Materialsandmethods

Chemicals

N-methyl-N-nitrosourea（MNU,N4766）andPaclitaxel（Taxol

TM

T7191）were

purchasedfromSigma-aldrich（St.Louis,CA,USA）.ThepureAntroquinonol

compoundandA.camphorataextract（ACE）wereobtainedfromGolden

BiotechnologyCompany,Taiwan.

PreparationofA.camphorataextract

TheA.camphorata（strainno.486bp）usedinthisstudywasauthenticatedbyDr

TzeanShang-Shong,DepartmentofPlantPathologyandMicrobiology,National

TaiwanUniversity,Taiwan.ThemyceliaofA.camphoratawereculturedin1000mL

ofgrowthmediumcontaining0.1gNaCl,10gpeptone,2gyeastextract,10gagar

and10gcerealmixture（rice,wheatorcorn）,pH7.5at25

o

Cfor12–14weeks.After

cultivation,500goflyophilizedA.camphoratamyceliumwasextractedwith2500

mLofn-hexanefor6h.Then-hexanefraction,definedasA.camphorateextract

（GD-66,productnameandGD-AIDT7,batchname）,wasconcentratedto20–30mL

viavacuumevaporation.A.camphorateextracthasbeenapprovedasahealthfoodby

TaiwanFDA（HealthyFoodNo.A00124）.ThepurifiedprocedureofAntroquinonol

wasdescribedinourpreviousstudy（Leeetal.,2007）.Briefly,Antroquinonolwas

purifiedfromA.camphorateextractbysilicagelchromatography（column=45cm,5

cmi.d.）（ASTMsilicagel,MerckCo.,Germany）andelutedwithn-hexane:

ethyl

acetate（10:

3v/v）.Theresultingeluatewasfurthersubjectedtosizeexclusion

chromatographyusingSephadexLH20column（70cmlong,5cmi.d.）（ABgel,GE

HealthcareBio-Science,USA）.Theantroquinonol（98%purity）waselutedwith95%

ethanol;theA.camphorateextractfractionwasdeterminedtohave0.01%

antroquinonol.

Animalsandtreatments

Twenty-one-day-oldfemaleSprague-Dawleyratswereobtainedfromthe

BioLASCOTaiwanCo.,Ltd（Taipei,Taiwan）andwerekeptina

temperature-controlledenvironment（23

o

C）with70%relativehumidityundera12-h

light/darkcycle.Theanimalexperimentswereperformedaccordingtothe‘‘Guidefor

theCareandUseofLaboratoryAnimals’’ofNationalDong-HwaUniversity.Rats

werefedstandardratchow（LabDietTM-500lRodentDiet;TestDiet,Richmond,IN,

USA）.Afteroneweekadaptation,allratsre