colorectal cancer ( crc ) is the second leading cause of cancer - related deaths in the united states men and women combined ; statistical estimates for 2015 indicate ~132,700 new crc cases and 49,700 associated deaths . though several initiatives involving colon screening and therapeutic interventions have impacted the overall crc management in the developed countries of the world , clearly more efforts are still needed to overcome crc risk , to arrest the disease progression , and to reduce the mortality numbers associated with this malignancy . one such effort that has gained an appreciable momentum over the last three decades , involves the intake of non - toxic natural dietary / non - dietary agents which can be used globally , for the prevention of crc . in most cases , these agents , derived from fruits and vegetables as well as herbs and other supplements , have been shown to reduce the incidence of pre - neoplastic adenomatous polyps and/or their progression to more advanced forms of crc ( fig . , an attempt has been made to tabulate and summarize the beneficial effects of one such natural chemopreventive agent i.e. , silibinin , against crc . silibinin is a flavonolignan which is isolated from the seeds of milk thistle , silybum marianum ( fig . 2 ) ; it has a long history of human use for liver ailments , widely available as a nutraceutical supplement and now clinically used to manage hepatotoxicity in various countries including the united states . importantly , silibinin is considered as a very promising cancer chemopreventive agent based on completed studies showing its strong efficacy against various epithelial cancers ( fig . as elaborated in detail in this review , silibinin has shown significant in vitro and in vivo anti - crc efficacy in various pre - clinical models of crc . inferences from completed in depth studies investigating the cellular and biological mechanisms associated with anti - crc effects of silibinin are summarized in tables 14 , which detail the effect of silibinin on various molecules regulating cell cycle , cell survival , autophagy , apoptosis , angiogenesis , and inflammation in its efficacy against colon tumorigenesis . natural dietary agents , such as silibinin , can reduce the incidence of pre - neoplastic lesions by targeting cancer stem cells and proliferating bulk tumor cells to prevent the disease progression to more advanced forms of the malignancy . silibinin inhibits tumorigenesis , inflammatory responses , and angiogenesis involved in crc growth and progression . b : chemical structure of silibinin - the principal bioactive constituent of milk thistle extract isolated from the dried seeds of milk thistle . silibinin inhibits various signaling and regulatory pathways in its chemopreventive and therapeutic efficacy against various epithelial cancers . under in vitro cell culture conditions , silibinin has been shown to inhibit the growth and proliferation of a wide range of crc cells ( table 1 ) . mechanistic studies have attributed these inhibitory effects to cell cycle arrest as well as both caspase - dependent and -independent apoptotic pathways ( table 1 ) . an increase in cyclin - dependent kinase ( cdk ) inhibitors kip1/p27 and cip1/p21 , together with a decrease in the kinase activity of cdk2 and cdk4 in g0/g1 arrested crc cells ; while an increase in the kinase activity of cdc2/p34 molecule along with a decrease in protein expression of cell cycle regulators cdc25c , cdc2/p34 and cyclin b1 by silibinin in g2 m arrested crc cells have been reported ( table 1 ) . furthermore , a decrease in the hyperphosphorylation of retinoblastoma ( rb ) by silibinin has also been reported as one of the mechanisms involved in the early cell cycle arrest induced by silibinin in crc cells ; though total rb levels are unaffected , a decrease in the protein expression levels of cyclin -d1 , -d3 , -a and -b1 and cdk-1 , -2 , -4 , and -6 by silibinin has been reported . the in vitro effects of silibinin alone or in combination with other molecules are summarized in table 1 . growth inhibition : dose ( 50 - 100 g / ml ) and time ( 24 - 72h ) dependent . g2/m cell cycle arrest ( higher dose : 100 g / ml ) . no apoptosis at lower doses . apoptotic death ( ~ 15% ) after 48 hours with 100 g / ml dose . annexin v staining for apoptosis , caspase activity assay , and cytochrome c localization analysis . mrna and protein levels of kip / p27 and cip/ p21  protein levels of cdc25c , cdc2/p34 , and cyclin b1  kinase activity of cdc2/p34  caspase independent apoptosis . inhibitory effects of silibinin ( 100 mol / l dose ) on -catenin mediated signaling . 2010 inhibitory effects of silibinin ( 1 - 100 mol / l dose ) on cdk4 signaling pathway . mtt cell viability assays . protein levels of cdk-4 , and cyclin d1  hyper phosphorylation of retinoblastoma  dose and time dependent growth inhibition . apoptosis of ht29 cells via egr - l - mediated nsaid - activated gene-1 ( nag-1 ) up - regulation ( silibinin : 50 - 100 mol / l dose ) . ectopic expression of egr-1 significantly upregulates nag-1 promoter activity and nag-1 protein expression in a dose - dependent manner . ic50 in fet and geo lines is 75 g / ml and 40 g / ml for hct116 cells at 72 hours . growth inhibitory effects more due to inhibition of cell cycle regulatory molecules than due to apoptosis . protein levels of kip / p27 and cip / p21  protein levels of cyclin bl / dl and cdk-2  no effect on cox-2 levels . dose ( 50 - 200 mol / l ) and time ( 24 - 72 hours ) dependent growth inhibition . g1 cell cycle arrest ( lower / higher doses ) as well as g2 m arrest with 200 mol / l . protein levels of cleaved caspase -3 and -9 , and cleaved parp  protein levels of kip / p27 and cip / p21  protein levels of cyclin- d1/-d3/-a/-b1 and cdk-1/-2/-4/-6  hyper phosphorylation of retinoblastoma  
  anti - angiogenic effect . inhibits the chemotaxis migration of endothelial cells ea.hy.926 towards crc cells ( ic50 : 0.66 mol / l dose ) . inhibits ea.hy.926 capillary formation ( ic50 : 2.6 mol / l dose ) .  vascular density index in the choriallontoic membrane assay by 20 mol / l dose . transwell migration and matrigel based capillary tube formation assay . mrna levels of vegfr - l(flt - l )   vegf secretion by lovo cells ( ic50 : 131.7 mol / l dose ) . 2003/2005 invasiveness of crc cells  il-6 induced proliferation and invasion of lovo cells  [ h ] thymidine incorporation assay . mmp-2 promoter activity via attenuation of ap-1 binding activity . cell growth inhibition by 50 - 200 mol / l dose after 24 - 72 hours . nuclear and cytoplasmic -catenin levels  expression of -catenin regulator cdk-8  -catenin - dependent tcf-4 transcriptional activity  expression of -catenin transcriptional targets : c - myc and cyclin d1  anti - inflammatory effect ( 50 - 100 nuclear levels of p65 and p50  ib protein levels  phospho- ib levels  nfb transcriptional activity  300 mol mrna and protein levels of death receptors dr4/-5  both intrinsic and extrinsic apoptotic pathways involved . / l dose synergizes with hd ac inhibitors : ( saha and trichostatin a ) to cause cellular death . pi3k - akt - mtor pathway  and erk1/2 pathway  no inhibitory effect on normal human colon ncm 460 cells . events associated with autophagy  long term exposure causes autophagic cell death ( 100 mol / l dose ) while higher doses (  200 mol / l dose ) cause apoptosis . metabolomics study utilizing 13c , 1h , 3ip based nmr spectroscopy . early on reactive oxygen species generation . pi3k - akt - mtor pathway  and erk1/2 pathway  interference in mitochondrial metabolism , phopspholipid and protein synthesis , and glucose uptake . abbreviations : crc , colorectal cancer ; facs ; fluorescence- activated cell sorting ; mtt , 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2h - tetrazolium bromide ; rt - pcr , reverse transcription polymerase chain reaction ; tcf-4 , t - cell factor-4 ; trail , tnf - related apoptosis - inducing ligand ; hdac , histone deacetylase ; dnmt , dna methyltransferase ; saha , suberoylanilide hydroxamic acid ; igf-1 , insulin - like growth factor-1 ; egf , epidermal growth factor ; emsa , electrophoretic mobility shift assay ; nmr , nuclear magnetic resonance . other in depth studies have shown that at physiologically relevant dose ( 100 mol / l ) , silibinin causes oxidative stress in crc cells , which triggers an apoptotic response , and is followed by a chain of events involving strong inhibition of the pi3k - akt - mtor pathway , activation of the erk1/2 pathway , rough endoplasmic reticulum stress ( er ) , and suppression of protein translation , which results in autophagy - mediated programmed cell death type ii . high - resolution nuclear magnetic resonance spectroscopy ( h , c , p - nmr ) studies have further confirmed that silibinin interferes with essential mitochondrial metabolic pathways , and the events associated with both phospholipid as well as protein synthesis . furthermore , silibinin has also been found to interfere with the glucose uptake in these cells ; overall , these events result in energy restriction in crc cells and their severe and irreparable injury by silibinin . studies have also shown that significant apoptotic death of crc cells occurs when high silibinin doses are used , which suggests that silibinin harbors the potential to induce both apoptotic and autophagy associated programmed cell death in crc cells . with regards to silibinin efficacy against crc stem cells ( csc ) , silibinin has also been shown to interfere with the kinetics of csc pool generation , which in turn , decreases the self - renewal and rectifies the aberrant differentiation of the csc . these results are detailed in table 2 ; the potential of silibinin to target csc is being extensively investigated by our group ( table 2 ) . our in vitro studies showed that silibinin strongly decreases the percentage of colonosphere formation ( a stem cell characteristic ) of crc cells and that this effect on csc is mediated via blocking of interleukin ( il)-4/6 signaling in crc cell lines . silibinin also caused a strong decrease in il-4/6 induced activation of stat-3 and nf - kb transcriptional activity , which was associated with decreased mrna / protein levels of various csc regulatory molecules , and csc - associated markers and transcription factors ( table 2 ) . we also found that silibinin significantly reduces the booster signals of macrophages towards csc , resulting in decreased colonosphere numbers under both normoxic and hypoxic conditions ( agarwal & colleagues 2015 , unpublished data , table 2 ) . these results are highly significant , given the fact that silibinin has shown efficacy against both csc and bulk cancer cells , and that csc are now primarily recognized as the essential factors contributing to initiation / progression as well as the relapse of crc . csc from primary crc isolated from human tumor with duke c3 crc stage , and ht-29 cells . more differentiated clones  pp2a - akt - mtor pathway  
  25 - 100 mol / l dose used . csc : cd44 epcam cells  number and size of coionospheres  il4 and il6 mediated effects on csc  il4 and il6 induced effects on nfb and stat-3  mrna and protein levels of lgr5 , ascl2 , cd44 , cd133 , oct 4 , nanog . msi-1 , bmi-1 , and hes-1  symmetric self - renewal of csc  more differentiated clones  booster signals of macrophages ( u937 and thp-1 ) towards colon csc  resulting in decreased coionosphere numbers under both normoxic and hypoxic conditions . csc : cd44 epcam cells  macrophage mediated effects on csc  silibinin modifies the cytokine profile of macrophage conditioned media . agarwal & colleagues 2015 : tumorigenic potential of csc ( cd44epcam crc cells )  csc self - renewal in serial transplantation studies  inhibitory effects on both csc and bulk daughter cells . s.c cell injections of sorted csc ( cd44epcam ) ht-29 cells mixed with matrigel ( 1:1 ) in flank of nod / scid male mice . after 24 hours of cell injections ; oral gavage with silibinin ( 200 mg / kg ) in cmc vehicle every day for ~40 days . diffusion weighted mri , dce - mri , and fdg - pet ; facs , confocal microscopy , and paired cell analysis . tumor cellularity , vascularity , glycolytic activity  tumor growth in serial transplantation studies  symmetric self - renewal of csc  asymmetric self - renewal of csc  shifts the cell division to symmetric proliferation resulting in generation of two daughter cells  transforms / differentiates cd44 population into a cd44- phenotype . agarwal & colleagues 2015a : abbreviations : crc , colorectal cancer ; csc , colorectal cancer stem cells ; facs ; fluorescence- activated cell sorting ; rt - pcr , reverse transcription polymerase chain reaction ; rtpcr , real -time rt - pcr ; emsa , electrophoretic mobility shift assay ; mri , magnetic resonance imaging ; dce - mri , dynamic contrast enhanced - mri ; 18fdg - pet , 18fluorine-2-deoxy - glucose ( fdg ) positron emission tomography . notably , several in vitro mechanistic studies have used high doses of silibinin ( 300 mol / l ) ; the clinical relevance of such high doses warrants caution ; this is founded on the results of several preclinical as well as clinical trial studies that underline limiting the silibinin concentration to ~100 mol / l dose in in vitro studies based on silibinin concentrations achievable in mouse plasma and colon tissues of crc patients . specifically , the results of the clinical trial data showed that silibinin feeding in the form of 720 mg / day ( formulated with phosphatidylcholine ) as  silipide capsules for 7 days to crc patients leads to high bioavailability of silibinin in colonic tissue ( 121 nmol / g of silibinin traced in colonic tissue which is equivalent to 121 mol / l silibinin concentration ) . using azoxymethane ( aom ) and 1,2-dimethylhydrazine ( dmh ) as potential carcinogens to induce sporadic crc in rodent models , various research groups have demonstrated the potential of silibinin to decrease the number of carcinogen - induced aberrant crypt foci ( acf ) , crypt multiplicity as well as colonic tumors in these colon tumorigenesis animal models ( table 3 ) . to determine the stage specific efficacy of silibinin feeding , different silibinin feeding protocols based on whether silibinin feeding started before the carcinogen exposure ( pre - initiation phase ) , during the carcinogen exposure ( initiation phase ) , after the carcinogen exposure ( post - initiation phase ) , or through the entire period of the study ( pre-/-post initiation phase ) were carried out ; though all silibinin feeding protocols showed efficacy against crc growth and progression , the percentage of crc inhibition was stronger in the animals on the pre-/-post - initiation protocol . silibinin has also shown significant efficacy against spontaneous intestinal tumorigenesis in apc mice model ( table 3 ) . both short and long term intervention studies with silibinin have confirmed that total intestinal polyps are significantly reduced in number and size by silibinin feeding . while a decrease in proliferation index and an increase in apoptotic index were observed in the polyps of silibinin treated mice , furthermore , our lab has also used a colitis - related aom / dss - induced colon tumorigenesis model to assess the role of inflammatory conditions on colon csc generation and expansion , and their modulation by silibinin . our results have indicated the protective effect of oral silibinin feeding in this model as evidenced by the absence of large macroadenomas ( > 2 - 3 mm ) in the colon . this effect was accompanied by minimal colonic inflammation ( decrease in recruitment of inflammatory cells ) ; tissue analysis indicated a decrease in the expression of pro - inflammatory cytokines , and associated transcription factors : stat-3 and nf - kb levels in the colonic tissues ( table 3 ) . a decrease in transformed stem cell population ( for csc pool expansion ) was also identified ( dual staining for bmi-1 and cd44 ) in the colonic tissues . silibinin feeding has also shown significant preventive and/or therapeutic efficacy against human crc xenograft tumors in athymic nude mice ( table 4 ) . these studies indicate that not only has silibinin an inhibitory effect on tumor growth , but this inhibitory effect is sustained even after silibinin withdrawal ; furthermore , silibinin has also shown significant efficacy against established xenograft tumors . dose dependent decrease in azoxymethane ( aom)-induced pre - neoplastic aberrant crypt ( acf ) formation and crypt multiplicity . inhibition more pronounced when silibinin given prior to initiation and continued till study end ( pre-/-post initiation protocol ) . silibinin feeding protocols : pre - initiation ; post - initiation ; and pre-/-post initiation . pcna positive cells  apoptotic cells  ; cleaved parp  cyclin dl , cox-2 , and inos  velmurugan et al . inhibition more pronounced when silibinin given prior to initiation and continued till study end ( pre-/-post initiation protocol ) . oral gavage with silibinin ( 250 - 750 mg / kg ) in cmc vehicle for 5 days a week . pcna positive cells  apoptotic cells  , cleaved ( caspase-3 and parp ) and p21  cyclin dl , cox-2 , vegf , and inos  nuclear and cytoplasmic -catenin  key molecules of igf-1 axis : phospho ( igf-1 r , akt and gsk-3 )  ravichandran et al . oral gavage with silibinin ( 300 mg / kg ) in cmc vehicle every day . silibinin feeding protocol : start one week after last aom ( post - initiation ) . protein levels of bcl-2  and bax levels  mrna levels of inflammatory markers : mmp-7 , ell- , and tnf  protein levels of mmp-7  inhibits 1 , 2-dimethylhydrazine ( dmh)-induced colonic pre - neoplastic changes . acf formation , dysplastic acf , and tumor incidence  restores the levels of gsh - dependent enzymes . lipid peroxidation in colonic tissues  and enzymic anti - oxidants  male albino wistar rats . oral gavage with silibinin ( 50 mg / kg ) in cmc vehicle every day . silibinin feeding protocols : initiation ; post - initiation ; pre-/-post initiation ( entire period ) . fecal biotransforming microbial enzymes  colonic and fecal -glucuronidase  mucosal and fecal activities of -glucosidase and -galactosidase  nitroreductase and sulphatase  -catenin , pcna , agyrophillic nucleolar organizing regions , and cyclin dl  prevents suppression of cdx2 mrna and protein levels . 2009/2010a/2010b/2012/2014 intestinal adenoma numbers  unformulated silibinin more effective than silibinin - phospholipid complex preparation ( * silipide ) . oral gavage with silibinin ( 250 - 750 mg / kg ) in cmc vehicle for 5 days a week . pcna positive cells  -catenin , cyclin dl , c - myc , phospho ( akt and gsk-3 ) , cox-2 , and inos , levels  nitrotyrosine and nitrite levels  rajamanickam et al . 2009 decrease in total number of intestinal polyps in proximal ( 27%  ) , middle ( 34%  ) , and distal regions ( 49%  ) . decrease in polyp numbers in size range > 2 - 3 mm ( 92%  ) . anti - proliferative , pro - apoptotic , anti inflammatory , and anti - angiogenic effects ( normal crypt - villus region unaffected ) . oral gavage with silibinin ( 750 mg / kg ) in cmc vehicle for 5 days a week . pcna positive cells  apoptotic cells  , cleaved ( caspase-3 and parp )  immunoreactivity of hif - l , vegf , enos , and nestin  inhibitory effects on -catenin mediated signaling . nuclear -catenin , cyclin dl , cox-2 , and pge2 levels  modulates cytokine profile in intestinal polyps . mice sacrificed after 3 months of silibinin feeding ki67 positive cells  incidence of high grade dysplasia and intramuscular carcinoma  mice with prolapsed rectum  inflammatory cells / markers and associated transcription factors  male balb / c mice . 2% dss in drinking water for 7 days . oral gavage siliphos ( * silibinin - phyto - some preparation-600mg / kg in cmc vehicle every day : pre-/-post initiation ) . mast cells , macrophages , nfb , stat-3 , cox-2 , il-6 , and il-4  colon csc markers / regulatory factors / transcription factors  cd44 cells  and bmi-1+/cd44 + dual stained cells  nuclear ( sox2 , nanog , and oct 3/4 )  agarwal & colleagues 2015b : abbreviations : aom , azoxymethane ; acf , aberrant crypt foci ; dmh , 1 , 2- dimethylhydrazine ; cmc , carboxymethyl cellulose ; dss , dextran sodium sulphate ; csc , colorectal cancer stem cells * siliphos or silibinin - phytosome ( from indena , italy ) that contains silibinin and phosphatidylcholine in 1:2 ratio . * silipide ( from indena , italy ) that contains silibinin and phosphatidylcholine in 1:1 ratio . tumor volume ( 48%  ) and tumor weight ( 42%  ) decreased by silibinin . * silibinin - phytosome showed more significant inhibitory effect due to better bioavailability . s.c cell injections of 4  10 ht-29 cells mixed with matrigel ( 1:1 ) in right flank of athymic balb / c nu / nu male mice . after 5 days of implantation oral gavage with silibinin or * silibinin - phytosome ( sp ) combination in cmc vehicle , 5 days a week for 32 days . daily dose : silibinin ( 200 mg / kg ) ; silibinin - phytosome ( 300 - 600 mg / kg)-which is equivalent to 100 - 200 mg / kg silibinin . pcna positive cells  cyclin dl and phospho ( erk1/2 and akt )  cox-2 , hif - l , inos , and nos3  inhibits tumor growth and cell proliferation . tumor volume ( 34% - 46%  ) and tumor weight ( 38% - 49%  ) decreased by 100 and 200 mg / kg silibinin , respectively . s.c cell injections of 5  10 lovo cells mixed with matrigel ( 1:1 ) in right flank of athymic balb / c nu / nu male mice . after 24 h of cell injections ; oral gavage with silibinin in cmc vehicle , 5 days a week for 6 weeks . pcna positive cells  kip / p27 protein levels  no effect on protein levels of cdk 's , cyclins , and cip / p21 . phosphorylation of rb at ser 795 , ser 807/811 sites and total rb levels  inhibits tumor growth and cell proliferation but induces apoptosis . tumor volume ( 26% - 46%  ) and tumor weight ( 29% - 52%  ) decreased by 100 and 200 mg / kg silibinin , respectively . s.c cell injections of 5  10 sw480 cells mixed with matrigel ( 1:1 ) in right flank of athymic balb / c nu / nu male mice . after 24 h of cell injections ; oral gavage with silibinin in cmc vehicle , 5 days a week for 6 weeks . expression of -catenin signaling associated molecules : c - myc , cyclin dl , and cdk8  protocol i : even after silibinin withdrawal , a decrease in tumor volume sustains . s.c cell injections of 5  10 sw480 cells mixed with matrigel ( 1:1 ) in right flank of athymic balb / c nu / nu male mice . protocol i : silibinin fed to growing tumors , after 24 h cell injections for 28 days ; after 28 days silibinin stopped but tumor study continued for more 21 days . protocol ii : 25 days past cell injections , silibinin fed to mice with established tumors , and tumor study continued for 16 more days in presence of silibinin . pcna positive cells  expression of p - catenin and phospho- gsk-3 , cyclin dl , c - myc , and survivin  vegf , inos , and cd31  velmurugan et al . crc cells from primary tumors in spheroid culture ( or ht-29 cells ) with and without silibinin treatment ( 5 g / ml ) for 15 days . 10 to 2  10 spheroid culture enriched cells were silibinin treated prior to injections . s.c cell injections of 5  10 cells done and tumor growth monitored for 6 weeks to 6 months . in vitro effect on cancer stem cells in spheroid culture inhibits tumorigenicity and tumor growth under in vivo conditions . archived tumor tissues from lovo and sw480 xenografts used total p65 immunoreactivity score  nfb transcriptional activity  levels of nfb regulated molecules : cyclin dl , bcl-2 , vegf , mmp-9 , and inos  induction of starvation induced autophagy . immunoreactivity score of sqstm1  sqstm1 protein expression in tumor lysates . [ sqstm1 is selective substrate of autophagy and its protein levels are decreased during starvation induced autophagy ] . abbreviations : crc , colorectal cancer ; cmc , carboxymethyl cellulose ; rb , retinoblastoma . * silibinin - phytosome ( from indena , italy ) that contains silibinin and phosphatidylcholine in 1:2 ratio . the summarized studies in four tables provide adequate evidence highlighting the potential of silibinin intake to significantly impact crc growth and progression . these results also indicate silibinin potential to interfere with csc pool expansion via targeting both csc , bulk daughter cells and their inflammatory niche , as well as associated signals involved with the survival and multiplication of colon csc pool ( fig . 4 ) ; the various mechanisms involved in these inhibitory effects are : a ) silibinin causes cell cycle arrest resulting in decreased proliferation , and induces multiple programmed cell death mechanisms ; b ) silibinin interferes with cellular metabolism to induce energy restriction like conditions ; and c ) silibinin inhibits various signaling and regulatory pathways involved in tumorigenesis , inflammatory responses , and angiogenesis . the inflammatory milieu of the colorectal cancer stem cells ( csc ) niche is an important growth regulator for both csc and progenitor cell population . silibinin has the potential to target colon csc self - renewal and aberrant differentiation , and associated inflammatory niche during crc inhibition . given that silibinin has the potential to target the csc or the  tumor initiating cells  , it can be beneficial for use in the early stages of crc development , as well as in later stages in cancer treatment to eradicate the csc pool and bulk tumor cells to prevent cancer relapse ( fig . given the fact that silibinin consumption is exceptionally safe and that it has high bioavailability in colonic tissue of crc patients , the efficacy evaluation of silibinin in clinical trials is advocated , both as a crc preventive agent and as an adjunct therapy for its clinical use in crc cases which are incurable by current therapeutic modalities . novel preventive and therapeutic strategies are needed to reduce csc number , target their self - renewal capacity or rectify their aberrant differentiation , or interfere with the pro - tumorigenic signals arising in the colon  niche
abstractglobally , the risk of colorectal cancer ( crc ) as well as the incidence of mortality associated with crc is increasing . 
 thus , it is imperative that we look at alternative approaches involving intake of non - toxic natural dietary / non - dietary agents , for the prevention of crc . the ultimate goal of this approach is to reduce the incidence of pre - neoplastic adenomatous polyps and prevent their progression to more advanced forms of crc , and use these natural agents as a safe intervention strategy during the clinical course of this deadly malignancy . over the years 
 , pre - clinical studies have shown that silibinin ( a flavonolignan isolated from the seeds of milk thistle , silybum marianum ) has strong preventive and therapeutic efficacy against various epithelial cancers , including crc . 
 the focus of the present review is to provide a comprehensive tabular summary , categorically for an easy accessibility and referencing , pertaining to the efficacy and associated mechanisms of silibinin against crc growth and progression .