Rahemi, Samaneh

Simorgh Research Repository

aaL)/s))rf ,Qtt{-<,:,;1 olS,-1,.11.t,#l* ,#3# 4:,iJ .r,irl ,r*,1'..r.JtS etL *E "l*t+:;13'.ccrj-l .,.- .rlg t* P.r*,1+-# J BCRP JRAKI ;t* ;l-t^ .r* tlnrl ct' r.;4AQ LrttJ*., JJl* 6Je ri: ;a ,-rKSi.;i g ou-1',J3,. 65143;ll t,u "^lJ CL""' tL" "Jj6)ti ,*,.,.- ;iS.l :t^l,ol; lll,..ldl.L ,r4lll c,; .Xrll,r,l, ;S.r :rgl .r. o .rtL.l\Y1V-\Y1l :(J+-.S"r JL-tudvyj,sJr[6(UKerrnan University Of Medical SciencesFacualy of MedicineIn Partial Fulfilknent of the Requirements for the Degree(MSC)Title:Relationship betrn'een IRAKI, BCRP and P-gp gene expression and drugsensitivity to Methotrexate and Topotecan in four breast cancer cell lines(in vitro assay)BySamaneh RahemiSupervisor:Dr. Hossein FallahAdvisor:Dr. Noralddin NematollahiYear:2017ri(:':r;v lJ/tilyto-/r,r$" dI atx,L;l -L-l "j'-s.l,, il _-<a. j!,,) -..+ .;rl .',;1 -:J ,,r -L,- tp ;"_)*_L; .rh-_ ,lt,-:A.Ji.-at .1-.i .s[,,#E ,]S r .r,-ori: c*91-6o #l .sl os-ip ;9":1 Gss C-l;l otl**l Ll .;-l .r1;*, - - -d--*." Jl; J'*i rL;- r, .r,-,.,.b i.9'.lo,J\--^rK. J,tu<" ;t *i- .rr5 e )f ;U'c-.-; ,J;ti; :--ar-19 .sl";t*t aS c*l os ;ai-; ,j;8 * i,.>,"..o .,--IATP (ABC) c-iJ a, a;ul9 .51-o c---::4-Jtt";--l;1.!*o .ijiL .,. Lir GLy.jQ+;: '-c,l; tutb L (\IRAKs) \ #l*-' .-;-ul3; 91y 9 c,L-S 9; 9;, .51-r9;ir di ...r"L^- alx* I P-gp ,BCRP , IRAK1 Ot* Olr" ,s*. L i . _-,IRAK1/4 o-r-51\a (pg/pl) c-lj;Gic.oL-Siy. t ol6;xi.ill>*.5[,o c^Llc r;:l.l ei9r; :'.*+ .5La --llo ,,-S iJRAK1/4 o-r;5;lqd (pg/pl) ;-tj ;ti-c s okyy.'-cl-a.. .5r.o - ^-,BT-549 ,BT-20-,MCF-7 JrL'.5Lr orl .5e.2 2, IRAKll4 "rrg )V (pglpl) c.l3 c^tl,c ,WST-I ;>c,- S.;, o"lt )1o:li;l [ .r(!,r1;- .!ti ,+ aV-i &: C) ;r.ji t, J+ 3L .-..sL" ;j ,jl-? j-q^a .rrf ,lf ,r-rx:,,r V /7AAD- j*^(.;f ! ,"Jr- ,y_1 ,sr*i -(.i; . .- -.n ,-t,tt Real-Time PCR j9) U P-,ep ,BCFjp 6-t-;5)t{d ;1 6'-;3.:tF ,r" J/- ".r rt+,t r" rr IC5s ,*ot5 c-.c! IRAKI o.r;5.s- :',a,J.F 'k 9BT-54991VICF-7 Jr.-.gLr o:r,r):-y'f {..,Kly s -61,Jy- u,-, : - -l! J/-- .5Lo o:1 arL VY n,".-t?,il .-r,_.:f oroL,l-. MB-468 Jrl" or, ,.: IC5o -.*.:J .: ,-'p; ) c-u.rl" Ji- .r{f,;-l c,-cL. u;-:; ,9L a,. ,:t*S 9y y- Lsk y..p cjb;.,': " Lr- . rBT- .5Lo J*" .rt" o)t ,.S9sIRAK c<o'Xl,"t *V ,S or.ia) JLi aS :x.:rS 7A-\Do:ulf;\." rb ;1 ; RT-qPCR Orjl e-L::.s!.r.tL, rtr MCI--7 e \IB--:. . :,r-" ,;al_l VY 9 Yf ,\Y .5ta1L; ,,) .rL-t uA:- J|- o),r ,rQ? ,: 1, IRAK 9 ABCB , - --i9- .r"i eb |'g" t+rt; ,il .i_ e".p ABCG3 -,l,r,g9 JJi.rL-" Jr- c-r:-t;;u { 9 r1l,: ,r*< jL;r.r,-lrL<;Lr-: ,r^..i ,,51"s,"r: .: -- ;.4,r- ,b 4q ,J-ii*b P-gp .9lr:,*9- al ;Lr: ,.^*; .9io9;i; e9 .+ { 4+;- 1 -, - _-.tI lnterleukin Receptcrr,{s soc i i,.ted K irra se.*.rB r-r=gi=* *l,r-- .;..--+. u&-,5 c-.-E \ yy -;gs\:.a';:i j,- :'i ,." I-R-{K-l ;>l:,,1 e -r-,.. ') .irr .:' -61-o :*:-<-q: ji ;i;r -r^ a;.o- Al r; a-<..r.;;L ,r,L,,-. ,--"; ],* +;*;3orb turL ;;*>i _.1- .: -"iol-< , -_-_t)'::.=-l-",,- ;_'il ;^q-t jLrl .r-+ g,1.,1 ;l-r.rl: ! ,J: ;t*l J;g-t Jfu\KI..:r5 c.:li:rl )g gi .;: -,.rKZy *>L3,;gn,;1:- ;lty ,u'-9sb ulb:ljl9 Jt.AbstractBackground and objectives: Breast cancer is the most common type of cancer amongwomen. Chemotherapy is one of the main methods of breast cancer treatrnent, but this methodis increasingly affected due to drug resistance and the lack of resistance predictive factors.One of the most important mechanisms of drug resistance in cancer is the activation of ATP-binding cassette transporters (ABC). One of the newly discovered factors associated with drugresistance in cancer cells is Interleukin Receptor Associated Kinase 1 (IRAKs). The aim ofthis study was to investigate the relationship between IRAK1 expression amount, BCRP, P-gpand sensitivity to the methotrexate and topotecan drugs.Materials and methods: At various concentrations of topotecan and methotrexate, constantconcentration (lpglpl) of IRAKI/4 inhibitor, mixed various concentrations of topotecan andconstant concenffation (lpg/pl) of IRAK1/4 inhibitor, mixed various concentrations ofmethotrexate and constant concentration (lpg/pl) of IRAK1/4 inhibitors on MCF-7, BT-20,BT-549, MB-468 cell lines, the cell viability was examined by the trypan blue exclusion tes!metabolic activity using colorimetric assay WST-I, and cell apoptosis by staining them withAnnexin-V/7AAD. The expression of IRAKI, BCRP, P-GP genes was also assessed by Real-Time PCR method.Results: IRAK1 inhibitor decreased ICso is the four cell lines. The least inhibitory effect onincreased drug sensitivity of methotrexate and topotecan was observed in the MCF-7 and BT-549 cell lines, respectively; and the most inhibitory effect in reducing the IC50 was observedin the MB-468 cell line. The 72-hour incubation of cell lines with IRAK inhibitors andtopotecan and methotrexate drugs significantly increased the annexin-V and annexin-Y/7AAD positive cells, suggesting an apoptotic effect of IRAK on the BT-20, BT-549, MB-468 and MCF-7 cell lines of breast cancer. RT-qPCR test results indicated that IRAKinhibitor reduced the gene expression of ABCB1 and IRAK in four breast cancer cell lines at12,24 and72 h time intervals, but had no effect on the expression of ABCG2 at any time.Conclusion: Most chemotherapy drugs have a low therapeutic efficacy and rarely distinguishbetween normal and malignant cells, a problem often reinforced by the onset of inevitableresistance and relapse of the disease. Given the wide range of chemotherapy drugs that have aP-gp substrate, it appears that selecting IRAK-I as a therapeutic target can be an effectivedrug selection with cancer cell selection properties to reduce drug resistance to chemotherapyagents. In this case, specific IRAK inhibitors can be used in combination with commonchemotherapy drugs to increase drug sensitivity and reduce the risk of tumor reclurence.Keywords: Drug Resistance, Breast Cancer, Methotrexate, TopotecanIohy' GriJ pr.b!:in3otiSi.its (sl*s$s*.a;ol'*n,-:tl lrL+-:l ..,,^-*J, " ilr--o a-i .=iJLJ,sal-igat +;*;..1 sj3z;Jl: .r-o*'t; dta*{ rSLt }-*; a,l; .1[-1" +.'-1i: ---Olby,,," Jgl*, oo) Ci-r jc qJl--Sgrgi g sL-4i9,n sgL*g.;tc a-f r+rt* Jt.;"+ gV6a;gy,filf,BCRP,lRAKI:jl J<.j:.g!;31:irLa i*6tael)r*\tqY/Yif ?r"t;*igJ j-q;11/f'6*:tar:'ril'lvltro'.-,r1*;t'-^(Aofctg;ib fU S fU i/.A+JgYs g{r.2 ;5-c 5$T,-.r1,7 (J3l) L;oll -:E-l:.-ilt$1:r)L:,a1-l :[:-l :-.5Ct c"^J it'-"rJl.lp.l*, ifo,"StiT ?L+e-f iS*rt La.f)ii;s-c iglsT url.ryE--"*i .5s9F, OcY ;fc r+Lt .lU-:. 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بررسی ارتباط بین میزان بیان BCRP , IRAK1 و گلیکوپروتئین P با میزان حساسیت به داروهای متوترکسات و توپوتکان در چند رده سلولی سرطان پستان

http://eprints.kmu.ac.ir/28578/1/6634.pdf

بررسی ارتباط بین میزان بیان BCRP , IRAK1 و گلیکوپروتئین P با میزان حساسیت به داروهای متوترکسات و توپوتکان در چند رده سلولی سرطان پستان

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