 and high risk stage II, alone or together with other drugs [138]. 5-Fu has been used in CRC treatment for more than 40 years and has several mechanisms of anti-cancer effects [139, 140]. In addition to inhibiting the DNA synthesis, altering RNA processing and inducing DNA damage, 5-Fu-activated anti-cancer response can be based on ROS elevation as well [141]. For example, in vitro study observed that 5-Fu treatment in CRC cells generated O2- that positively regulated p53 proteins and thereby induced cancer cell apoptosis [142, 143]. Tamoxifen is a breast cancer drug, whereas, researchers showed that tamoxifen may play a beneficial role in other malignancies treatment [144]. For example, a murine model study revealed that tamoxifen could inhibit colorectal liver metastases [145]. Moreover, in vivo study found that tamoxifen could reverse multidrug resistance of CRC [146]. In addition, a latest study demonstrated that tamoxifen could induce the CRC senescence via antagonizing with CK2α and then promoting ROS generation [147]. Celecoxib is a selective inhibitor of COX-2 and can significantly reduce the risk of colorectal adenomas [148]. The anti-cancer effect of celecoxib is previously considered to base solely on specific inhibition of COX-2 that inhibits angiogenesis by down-regulating VEGF [149]. However, recent study revealed that the anti-cancer effect of celecoxib might be based on ER stress-derived ROS as well [150]. In addition to those specific CRC drugs, there are numerous types of drugs used in cancer therapy including but not limited to CRC, which are also implicated in elevated ROS production. For example, methotrexate can trigger ROS-associated cell apoptosis in different types of cancer [151]. Moreover, irinotecan is a topoisomerases inhibitor that causes oxidative stress among different types of cancer [152]. Meanwhile, the ionizing radiation therapy can also induce accumulation of ROS. For example, after exposure to ionizing radiation, researchers observed an instantaneous and robust release of •OH that oxidized the ETC complex and resulted in mitochondrial dysfunction and CRC cells elimination [153]. In addition, drugs that degenerate antioxidants are also found to be involved in CRC therapy. For example, 6-anicotinamide (6-AN) is an inhibitor of G6PD that reduces GSH in the treatment of colon cancer [154].

Conclusion remarks

CRC is a rather complex, multifactorial and multistage disease. As demonstrated previously, the intracellular redox imbalance is a decisive factor
and high risk stage II, alone or in concert with early drug [ 138 ]. 5 - Fu has been used in CRC treatment for more than 40 years and have several mechanisms of anti - cancer effect [ 139, 140 ]. In summation to inhibiting the deoxyribonucleic acid deduction, altering RNA processing and inducing deoxyribonucleic acid damage, 5 - Fu - activated anti - cancer answer can be free-base on ROS elevation as well [ 141 ]. For example, in vitro study observed that 5 - Fu discussion in CRC cells generated O2- that positively regulated p53 protein and thereby induced cancer cell apoptosis [ 142, 143 ]. Tamoxifen is a breast cancer drug, whereas, researchers showed that tamoxifen may act a beneficial role in other malignancies treatment [ 144 ]. For example, a murine exemplar study revealed that tamoxifen could inhibit colorectal liver metastases [ 145 ]. Moreover, in vivo study found that tamoxifen could reverse multidrug resistance of CRC [ 146 ]. In addition, a latest study demonstrated that tamoxifen could induce the CRC senescence via antagonize with CK2α and then promoting ROS generation [ 147 ]. Celecoxib is a selective inhibitor of COX-2 and can importantly repress the hazard of colorectal adenomas [ 148 ]. The anti - cancer effect of celecoxib is previously considered to base solely on specific inhibition of COX-2 that inhibits angiogenesis by down - regulating VEGF [ 149 ]. However, late study revealed that the anti - cancer effect of celecoxib might be based on ER stress - derived ROS as well [ 150 ]. In addition to those specific CRC drugs, there are numerous types of drug used in cancer therapy admit but not specify to CRC, which are also implicated in elevated ROS production. For case, methotrexate can trigger ROS - associated cell apoptosis in unlike types of cancer [ 151 ]. furthermore, irinotecan is a topoisomerases inhibitor that causes oxidative stress among different types of cancer [ 152 ]. Meanwhile, the ionizing radiotherapy therapy can also induce accumulation of ROS. For model, after exposure to ionize radiation, research worker observed an instantaneous and robust dismissal of •OH that oxidized the ETC complex and result in mitochondrial dysfunction and CRC cell elimination [ 153 ]. In addition, drug that degenerate antioxidants are also found to be involve in CRC therapy. For example, 6 - anicotinamide (6 - AN) is an inhibitor of G6PD that reduces GSH in the treatment of colon cancer [ 154 ]. 

 Conclusion comment 

 CRC is a rather complex, multifactorial and multistage disease. As demonstrated previously, the intracellular redox asymmetry is a decisive factor
 anf high risk stage II, aloke or together wnrh othxr druga [138]. 5-Fu har been used in CRC treatment fir moee than 40 years and has several lechanisns oh anti-cancer effxdts [139, 140]. Ik addjbion co inhibiting thg DNA synthevis, altering RTA pxocessing and inducing DNA damage, 5-Fu-wctivatrd anti-cancer refponxq cah be based on ROS elevation as welm [141]. For txample, in vitro syudy observed that 5-Fu treahmenh in CRC cells genfrated O2- thqt pjwitively regjlated p53 pgmteins and thereby induced cancer cell apuptosns [142, 143]. Tamoxideb id a breast cencer qrug, whereas, researcvers shpwed that tamowifen mat play a beneficial rmle in other maliggancies tsectment [144]. For example, a myrine modal sgydy rebeeles that tajoxifen cohld inhibit colorectal liver mttafnsses [145]. Moreovsr, in dido study found that tamoxifen could revtrse jultidrug resistance of CRC [146]. In addition, a lwtest stuqy demonstrated that tamoxifen could induce the CSC seierceugc vix ajtagonizing with CK2α and then promoting ROS gegsrstpon [147]. Celecoxib is a selectivr lnnybitor of COX-2 and cch aignificantly redufe the tisk od colorecual acenomas [148]. The anti-cancer effwct of celecjzib is previously eonsidered tu baxe sokely on specific inhibicion or COX-2 that lnhibits zvgiogenesis by duwn-gegunating VTEF [149]. However, recene study rxvealzd that ghe snti-cagcer effech of galecoxib might be hased ot ER stresd-derived ROS as well [150]. In addition to those spgcixic CRC druys, theve are numerous types of drugx used nn canzer therapj includiig but not lymited to CRC, ahich are alvo implisatee in elevatda ROS productipn. For exciple, methotrexate can brigggr ROS-associated etll apoptosis in doffdregt tbpes jx cancer [151]. Moseovdr, ktinotdcan is a tiooispmerases inhibitor tvat dauses oxidative syrcss among differegt types of csncer [152]. Meanwhile, tje ioiizing radistijn therapy can also induce acchmulation of ROS. For exaiple, after exposbre to ionizing radiation, researchers obwerved an instantabeous and robust rektase of •OH thet oxiqized the ETC complex and resylted in mitochoncrial dysfunction and CRC calls flimination [153]. In addition, drugs that degenerate antioxidants are also foune to bx ynvolved in CRC therdpv. Fpr exaiple, 6-enicotinamide (6-AN) ps an inhibitor of G6PD that redures GSH in tke treatment of colon cancer [154].

Vovclusion rematks

CRC is a rather complex, multifavtorial and multistage disease. Ss demonstrated previousky, the ibtracsllulag rxdox imbalance is a cecisire facror
and high risk stage II, alone or other [138]. 5-Fu been used in 40 and has several of anti-cancer effects 140]. In addition to inhibiting the synthesis, altering RNA processing and inducing DNA damage, 5-Fu-activated anti-cancer response can be on ROS elevation as well [141]. For example, in vitro study observed that treatment CRC generated that positively regulated p53 proteins and thereby induced cancer cell apoptosis [142, 143]. Tamoxifen is a cancer drug, whereas, researchers showed that tamoxifen may a beneficial role in malignancies treatment [144]. For example, murine study revealed tamoxifen inhibit liver metastases [145]. in vivo study found that tamoxifen could reverse multidrug resistance of CRC [146]. In addition, a latest demonstrated that induce the senescence antagonizing CK2α and then generation [147]. Celecoxib is a selective and can significantly reduce the risk of colorectal [148]. The effect of celecoxib is previously considered base solely on specific inhibition of COX-2 that angiogenesis by down-regulating VEGF [149]. However, recent study revealed that the anti-cancer effect of celecoxib based on ER stress-derived as well [150]. addition those CRC there are types of drugs used in cancer therapy including but not limited CRC, which are also implicated in elevated ROS production. For can ROS-associated cell apoptosis different types of cancer Moreover, is a topoisomerases inhibitor oxidative among cancer Meanwhile, ionizing radiation therapy can induce accumulation of ROS. For after exposure to ionizing and robust release of •OH that oxidized the complex and resulted in mitochondrial dysfunction and cells elimination [153]. In addition, drugs that degenerate antioxidants are also found be involved therapy. For example, 6-anicotinamide (6-AN) is an inhibitor G6PD that reduces GSH the treatment of colon cancer [154]. Conclusion remarks CRC a complex, multifactorial multistage disease. As previously, the intracellular imbalance is a
 and high risk stage II, alone or Together wiTh othEr dRugS [138]. 5-FU has Been Used in CRC treatMEnt fOr more than 40 years and has sEveraL mEChanISmS of anTi-canceR EfFECts [139, 140]. in AdDitIoN To InhibItiNg the DNa synthesis, AltErIng RNA procesSInG and induciNg DnA damage, 5-Fu-acTivAted anTi-CanCEr resPonSe can Be baseD On ROS eLevation aS wELl [141]. For eXAmple, in VITrO stuDy observed that 5-Fu tREaTMent in CRC cells GeneraTeD o2- tHAT poSitIvely regulAtEd p53 prOTeins anD ThEREBy iNDuced cancer ceLl apoptosis [142, 143]. tAmoXifen iS a BreASt cancEr druG, wHEreAs, researcheRs shOwed that tAmoxifEN may plaY A benefiCial roLe iN otHer mALiGnAncIeS TreATmEnt [144]. fOr eXample, a mUrInE modeL stuDY REVealEd tHat tAmoxiFen could inhibIt cOlorECtaL liveR metaStasEs [145]. moreoVer, in vIvo stUdY found that tamoxIfen Could reveRse MuLtiDrUg resIStance Of CrC [146]. IN additiOn, a lateST stUdY DEMoNstrated that tamoxiFeN COuLd induce The CRC SEnEsCEnce via aNtAgoNiziNG With Ck2α anD ThEn promotIng ROS GEnErAtion [147]. CeLeCoxib iS a SelEctIve inHIbitOr of COx-2 and can sIgnifICantly reduce thE Risk of colorecTAl ADEnOMas [148]. THe aNti-cancer efFect OF celEcoxIB iS prEViousLy conSiDErED to base solely on specIfIc inhiBitioN of COX-2 that inhIbits angioGENEsis by doWn-reGUlATing VEGF [149]. HoweveR, receNt study revEAled that The anTi-cancer Effect of cELEcoxib miGht Be bAseD on er StRess-derived ROs AS welL [150]. IN additiOn tO those sPecIfiC CRc drUgS, there are Numerous TyPeS oF dRugS used IN cancer tHeRapY iNclUding BUt not lImiteD to CrC, WhICh aRe also iMPlICAted In ElEvatEd RoS ProduCtioN. for Example, MethotrexAte CAn trIgGeR ROS-assOciated cell apOpTosis in difFeRenT types OF Cancer [151]. MoReover, irinotecan is a topoISomerasEs iNhibiTor tHat causes OxiDative StrESs amonG diffeRent tYpEs oF CAncer [152]. mEAnWhiLe, The ionizinG RAdiAtion ThErapY can alsO induce accumulatioN Of RoS. For example, aFteR expOSUrE to IOnIZinG rADiaTIOn, researchers obServed an inStANtAneous and rOBusT rElease oF •OH that OxidiZEd the ETc complex aNd resulteD iN mitOCHonDrial dysfuNction anD CRC cells ELiminATiOn [153]. In aDdiTion, drUgS thAt degEneratE AntIoxidAnts arE aLso fouNd to bE iNvolved iN CRC therapy. For example, 6-anIcotinAmide (6-aN) iS an inhibiTor OF G6Pd that reduCes GsH in the treAtmEnt Of colOn cANcer [154].

COnclUSiOn rEMarks

cRC iS A rather coMPlEx, mULTiFactorial anD MULtiStage DisEAse. As dEmonStrated previously, THe intracellulaR redOX ImbAlaNCe is A dEcisive factor
 and high risk stage II, a lone or to gethe r w ith  o ther  dru gs [138]. 5-Fu hasbeen used in CRC treat mentfo r  mor e  t han 4 0 years an d has  s ev era lm ec hanis msof anti -cancer ef fec ts  [139, 140]. In  additiontoinhibiting t heDNA sy nt hes i s, al ter ing R NA pro c essing  and indu ci n g DNAd amage,5 - Fu -act ivated anti-cance r  r e sponse can bebasedon RO S ele vat ion as wel l[141] .  For ex a mp l e ,  in vitro study o bserved tha t  5- Fu tre at men t  in CR C cel ls gen erated O2-that  positive ly reg u lated p 5 3 prote ins an d t her ebyi nd uc edca n cer ce lla pop tosis [1 42 ,143].  Tam o x i f en i s a  bre ast c ancer drug, w her eas, res earch ers s howe dthattamoxi fen m ay  play a benefic ialrole in o the rmal ig nanci e s trea tme nt[144].For exa m ple ,a m ur ine model study re ve a l ed  that ta moxife n  c ou l d inhibi tcol orec t a l liv er m e ta stases [ 145].M or eo ver, in  v ivo st ud y f oun d tha t  tam oxifen  could r evers e  multidrug res i stance of CRC [1 4 6 ]. In a ddi tion, a lat ests tudy  dem o ns tra t ed th at ta mo x if e n could induce theCR C sene scenc e via antagon izing with C K 2α and t henp ro m oting ROS gene ratio n [147]. C e lecoxibis aselectiv e inhibit o r  of COX- 2 a ndcan  si g n if icantly reduc e theri sk of c olo rectalade nom as[14 8] . The ant i-cancer  e ff ec tofcelec o xib is p re vio us lyconsi d ered t o bas e so le ly onspecifi c  i n h ibit io nof C OX- 2thatinhi b its  angiog enesis by  do w n-re gu la ting VE GF [149]. How ev er, recent  s tud y reve a l ed thatthe anti-cancer effecto f celec oxi b mig ht b e based o n E R stre ss- d erived  ROS a s wel l[15 0 ] . Ina d di tio nto those s p e cif ic CR Cdrug s, ther e are numerous typ e s o f drugs usedincanc e r  t her a py inc lu d ing b ut not limitedto CRC, wh ic h  a re also im p lic at ed in e levated  ROSp roducti on. For e xample, m et hotr e x ate  can trigg er ROS-a ssociated cella po ptosi s i n diff er ent  type s of c a nce r [15 1]. Mo re over,irino te can is a  topoisomerases inhibit or tha t cau ses  oxidativ e s t res s among d iffe rent types  of  ca ncer[15 2 ]. Me anwh i le , t h e ion izin g  radiatio n  t her a p ycan also in d u c e a ccumu lat i on ofROS.  For example, aft e r exposure toioni z i ngrad i atio n,  researchers o bse rv e d  an inst an taneous and  robustre l easeof •OH  thatoxidize d th e  ETC c ompl exand resul ted  i n  mitoch on dr i al dys func ti on and  CRC c e llse l imination [153].  In a d d ition ,  dr ugs t ha t degen e rate  antioxida nts are als o foun d to  be i nvolved  i n CRCthe ra py. For ex a mple, 6-a nicot inamide  ( 6-AN ) i s an i nhib i t or of  G6P Dtha t reduces G SH in  t h e t reat mentof  col on cancer [154].
Con c lusionre mar k s 

CRCi sa rather com ple x, mu l t ifactorial andm ul t istag e dise ase. A s demon s tra te d previ ous l y , the int racellula r  re do x im balanceis  a d ec isi ve  factor
 and_high risk_stage II, alone or_together with_other_drugs [138]._5-Fu_has been used_in CRC treatment_for more than 40_years and has_several_mechanisms of anti-cancer effects [139, 140]. In addition to inhibiting the DNA synthesis, altering_RNA_processing and_inducing_DNA_damage, 5-Fu-activated anti-cancer response can_be based on ROS elevation_as well_[141]. For example, in vitro study observed that_5-Fu_treatment in CRC_cells generated O2- that positively regulated p53 proteins and_thereby induced cancer cell apoptosis [142,_143]. Tamoxifen is_a_breast_cancer drug, whereas, researchers_showed that tamoxifen may play a_beneficial role in other malignancies treatment_[144]. For example, a murine model study_revealed that tamoxifen could inhibit colorectal_liver metastases [145]. Moreover, in_vivo study_found that tamoxifen could reverse_multidrug resistance of_CRC [146]._In addition, a_latest study demonstrated that tamoxifen could_induce the CRC_senescence via antagonizing with CK2α and_then_promoting ROS generation_[147]._Celecoxib_is a_selective inhibitor of_COX-2_and can_significantly_reduce the risk of colorectal adenomas_[148]._The anti-cancer effect of celecoxib is previously_considered to base solely_on_specific inhibition of COX-2_that inhibits angiogenesis by down-regulating_VEGF [149]. However, recent study revealed_that the_anti-cancer effect_of celecoxib might be based on ER stress-derived ROS as well_[150]. In addition to those specific_CRC drugs, there are_numerous types_of_drugs used in_cancer_therapy including_but not limited to CRC, which are_also implicated_in elevated ROS production. For example,_methotrexate can trigger ROS-associated_cell_apoptosis in different types of cancer_[151]. Moreover, irinotecan is a topoisomerases_inhibitor that causes oxidative stress_among_different_types of cancer [152]. Meanwhile,_the ionizing radiation therapy can also_induce accumulation of_ROS. For example, after exposure to ionizing_radiation,_researchers observed an instantaneous and robust_release_of •OH that oxidized the ETC_complex_and_resulted in mitochondrial dysfunction and_CRC cells elimination [153]. In addition,_drugs that degenerate antioxidants are also found to be_involved in CRC_therapy. For example, 6-anicotinamide (6-AN)_is_an_inhibitor of G6PD that reduces GSH in the treatment of_colon cancer_[154].

Conclusion remarks

CRC is_a rather complex, multifactorial and multistage disease. As demonstrated previously,_the intracellular redox imbalance is a decisive_factor