Ptn Role Medicin Mushrms Breast Cancer

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  • 1. [nternt/ionul.lournu/ of'Mtrlitina/ Mushroon:, Vol. 7, pp. 1'+1-155 (2005) Potential Role of Medicinal Mushrooms in Breast Cancer Treatment: Current Knowledge and Future Perspectives Roumyana D. Petroa,a,l'2 Solomon P Wasser,l JamalA. Mahajna,2 Caetomir M. Denchew,3 €l Eeiatar Ne,uo| llnstitute of Evolution, tJniversirv of Haifa, Mount Carmel, Haifa,Israel;2N'{igal-Galilee Technologv Center, South Industrial Zone,Kiryat Shmona,Israel;3Instirute of Botany, Bulgarian Academy of Sciences, Sofia, Bulgaria *Address all correspondence to Sokrmon P.W'.rsser, Institute oiEl'olution, LJniversin'of IIaifa, XIount Cartnel, Ilaifa -11905, Israt-'l; sprvasser@re-search.haif a.ac.i1 ARSTRACT Brcast cancer has bccomc thc most common invirsive fbrrn of f-ernalc c2rnccr in the lirst tew decndes. Statistics shor,v that the r:rte ofnern4r'diagnosed cascs ofbreast czincer is rising even'vear dcpcnding on agc, rrrcc, heredin', and cthnicit'ri Thc National Cirncer Institute oiUS and rnainl't'the I)ir.ision of Cancer Control and Population Sciences (DCCPS) promotc and conduct rese arch that also idcntifies the econonic, soci:rl, cuirural, psvchological, behavioriil, and bioiogical mcchanisms that are pote ntial rcrrsons for brcast cancer developrnent. Adr.anccd breast canccrs do not respond'lvell to the rapr., and their gene expression arouses uncontroiled growth. Although estroeen-reccptor (ER)-positive bre:rst canccrs re spond to hormonal therapr.., thc trcatrncnt of ER-negativc cancers is more cornplicatcd bccausc of their abiliw fbr developing rcsistance to dmgs. Lack o1-rnolecular targcts in cstrogcn rcccptor-negatir.-e brcast cancer is a major therapeutic hurdlc. It has bccr.r knor'vn that NF-rcB is significantlv impr)rt:tnt ir] the proccsses of inflammation, cell survival, transfbrmation, and oncogcnesis, as well as in the etiologv of brcast cance r. A theorv exists, according to which E,R-ncgative breast clncer ce1ls dcpcnd on NF-rB fbr abcrrant celi prolifbration and sirnr,rltancou-slv avoid apoptosis, sugeesting that NF-rB can bc used as a potenti:1l rnolecuiar targct in breast cancer tre2ltment. Studics on new anticancer treatments and othcr medicinal substances from mushrooms hrrve been significnntlv expandcd in the last lcrv verrs. f l-ris is mainlr. bccausc they contain bioactive polymers such as polysaccharides and polvsaccharide/protein cornplexes, secondary metabolitcs, and enzymes isolated from fruit bodics, mvcclia, and culture broth. Thcrc arc clata shovl'ing the potential activin. of rncdicinal mushrooms in breast cancer trcatmcnt. Gdna- t{ernm /ucidun has show-n thc most significant ir.rhibitorv ellect on NF-rB activitv in highlv invasir.e brcast cancer cells. Other medicin';r-l mushrooms that ha','c aiso been repoltcd to producc biologicallr' actlve substanccs, havc bccn tcstecl in in. tiro or in vitro, irnd har.c dcmonstrilte d breirst cancer inhibiton activirv- are,4garicus bisporus,A. hrc.si/ien:is,7i'ametes tersico/or, Gry'b/a.lrondo.sa, Inonottts obliquus, Lentinus edades, Leucoagaricu.r antericanus, P/eurotus o-ttreatL/-t, Spara.t-si-r .risfa, et.. KllY WORDS: mcdicinnl mushrooms, breast canccr, nuciear factor kapp:r B (Nli-xB), poh'saccharidcs, poivsaccharide/protein complexcs, sccondarl' rnctabolites ABBREVIATIONS AHCC: acti.c Akt: serirre/the rionine kinase ; AP-1: activator protein-1; 840: FI[,A hu- hexose correlirted compound; rnan leukoo'te antigcn n'pc; CAPE: call-eic acid phencthvl cstcr; CDzl0L: CD-40 ligand;DCCPS: Division of Cancer Control and Population Sciences; dnlKKB-mut: dominant-negirtive IkkB mutant; EGF: epidermal gr-owth factor; IAP: 1521-9.r37l05 $35.0t) rO 2005 by Begell I louse.Inc. 141 Electronic Data Center, http://edata-center.com Downloaded 2008-5-6 from lP 24.89.172.2 by Begell House
  • 2. R. l). PETROVT Fl'I'Al-. imrnunostrppressir.c acidic protcin; IGF-1: insulin-likc growth factor-1; ER: cstrogerr rcccptor; Fas-L: Fhs ligand; HDP: host def-ensc potentiators; IkR: inhibitory protcins kappa B; IKK: IkB kinase comlcx; I[,-1: interleukin-1; LM fractions: low-molccuiar-rveight fractions; LPS: lipopoh.saccharide; MEKK3: rnito€ien-zlcti.ated Protcin kin:rsc/extracellultr signal-regulated kinase kinase 3; NF-kB: nuclear factor kappa B; NK cells: natural kil1cr cells; PR: progestcrone re- ccptor; RIP2: receptor interacting protein 2; SDF-1a: stromal derived factor-1cx; TM: tetrathiomolr'bdate; TNF-tr: turnor-necrosis factor-cr; uPA: urokinase-n'Pe plasminoqen lctiviltor INTRODUCTION qrcat importance to find and applv ncw and more precisc drugs for treatmcnt. [n order to treat various rvpes of cancer, surgical Nowadays, considcrable attcntion has been ope ration, radiothcrapv, and che mothcrapr- (admin- fbcuscd on thc cfl-ectivencss of l-rcrbal medicincs istration of anticanccr agents) arc gencrallv used. bccause thcv havc cnormous popr,rlariw as self-- Horvever, their side eff'ccts cause scriolls damagc medication products. N{anv herbs and natural and sullering to patients. As an alternative to these products, including mushrooms, arc available on trcatmcnt methods, immunothcrapv is now gaining thc u'orld market and appear to have potcntial in more attention than ever. Immunothcrapv substan- thc trcatment of proeressivc cancers. Studies on the tinlly reduccs the sufi-crirrgs of side c.lTects and thc medicativc activiqv of mushrooms have alre adv been inherent pain of cancer and hclps to ovcrcome the carried out, not onlv because oftheir traditional use canccr growth, even in its last stagc, bv promotin€i in folk medicine for centuries, but also because thev the power ofimmunityrvith rvhich thc human bodv havc shorvn significant activirv as immunomodula- is originally equippcd. tors and dietary supplements (Wasser, 2002). Thc I)espitc thc observed succcss of most chemothcr- cclmpounds thev possess havc bccn classificd as host apeutic regimcs, ccllular adaptations havc enabled dcfense potentiators (HDPs), rvhich can havc im- tumor cclls to evade manl of the chcmothcrapeutic mune svstcm enhanccmcnt properties. That is one drugs. One of thcsc ccllular chemorcsistancc factors ofthe reasons thcv are currcntlv used as adjuncts to is the transcription factor NF-rB. It is a dimeric cancer trcatment in Far East countries. trar.rscription factor tl-rat belongs to thc RcVNF- Thc benefits of mushroom compounds on dif: rB familv of transcriprtion factors (Nakshatri et al., ferent clinical conditions hat'c attracted the interest 1997; Palrl, 1999; Zandi and Karin, 1999; Karin of the scicntific communiw in thc last decadc in an and Ben-Neriah,2000; Karin ct aI.,2002). NF-rB attcmpt to understand thc molecular mechanisms complex is maintainecl in the cytoplasm in an inec- responsible fbr thcir action (Hobbs, 1995). Several tivc fbrm by the lkB protein.'1}e major activator classes of mushroom compounds such as proteins, of NF-rcB is known to be thc IkB kinasc complex polysaccharides, lipopolvsaccharidcs, and glucopro- (IKK) (Zandi and Karin, 1999), suggesting that telns have been classified as moleculcs that have the IKK complcx can servc as a potential targct for potent effects on the immune svstem. The,v mav inhihition of NF-rcB rctivin. rcstorc and augment immunologicai respronscs of Several enzvmes have alrerrdv bcen reportcd host imrliune elTcctor cells, but thev havc no direct as indircct activators of NF-liB. For cxample, cytotoxic ei1-cct on tumors (Rorvan et al.,2003). N{EKK3 is overexprcsscd ir-r brcast canccr cells Immunoccuticals isolated from more than 30 and leads to activation of NF-rB, resulting in mtishroom spccics have dcmonstratcd antitumor rcsistance to chcmotherapeutic agents (Samanta activity in animal trcatments. Horvever, onlv a felv et al., 20011). Anothcr cflzvnle, Akt, is also kno'rvn havc bcen testcd for antic'f,ncer potcntiel in humans to induce the transcription function of NF'-tcB (W:rsser and Weis, 1999c).The few that have been b'r.'stimulating its RclA/p65 subunit (N{adrid et tested are B-n-glucans or B-n-glucans linked to al.,2001). Becausc of tl-rc spccificity and molccu- proteins. N4oreover, thc latter hal'e shown llreater lar mechanisms of these processes that must bc immunopotentiation activify than the free glucans ovcrcome and rcgulated, it becomcs a matter of (Sakaeami and Aoki, 1991; Kidd,2000). 142 lnternationa! Journal of Medicinal Mushrooms Eleclronic Data Center, http://edata-center.com Downloaded 2008-5-6 from lP 24.89.172.2 by Begell House
  • 3. MED I CINAI, NIUSI IROOM S IN B RI,]AST CANC }.)R TRF]ATM ENT 'fhcrc are numcrous clinical studies proving the tumor actir,'ify and mechanism of action in breast cancer irrhibitory ellccts of Lentinus edarles (I)crk.) canccr cells are compiled. Rcsults of cxperimental Singcr (Furue ct a1., 1981; Taguchi et al., 1985; tcsts and clinical treatments are also summarized. N4atsucrka ct aI., 1997), Gry'bla Jianrla.vz (Dicks. : Morcover, somc of thc main therapcutic targets uscd Fr. ) Grar' (Nanba, 19 97 a,b), S ch izop hy / ltt m c0 tn nt u n e in clinical trials today, as lvcll as some novcl thera- Fi. : Fr. (Fugimoto and Furuc, 1984; Furne, 1985; pcutic agents successfully appiicd in brcast cilnccr Kimura et al.,1994), Gartodernta lucidtrm (W.Curtis tre?rtmcnt, are dcscribed. : Fr.) Llovd (Jong and Birmingham,1992; Gao ct 'a,1.,2002), Tran'tetes tersicolor (L. : Fr.) Llovd (l,iu and Zhou, 1993; Nakazato et ai., 1994; Kidd,2000), BREAST CANCER Inonotus obliqutts (Pers. : Fr.) Pilit (Mizuno et al., 1999), and Phellinus /inteus (Berk. ct N'I.A. Curtis) Progesterone Receptor (PR) Teng (Ikckawa et a1., 1968; Kim et a1., 1996; Han ct al., 1999; Mizuno,2000), ctc. Progestcrone is a steroid hormone that regr.rlates a Othcr mushroom compounds of therapcutic great number of processes in di1l-erent tissues. Its intcrcst arc the secondarv mctabolitcs as lectins, biological action is mcdiated bv the Progesterollc lactoncs, terpenoids, alkaloids, antibiotics, and metal rcceptor, lr..hich is presented bv tr,vo isoforms, PR- A chclating agcnts, which arc also important for the and PR-R.l1ley are distinguished br.'the additional immune function of thc organism (Wasscr and amino acid stretch in thc N tcrminus of PR-B. Botir Wcis, 1999c). Mushrooms also contain a number of of them contain DNA and ligand binding domains enzymes such as laccase, superoxide dismutasc, glu- lvith activation functions. PR-A is neccssarv lbr the cose oxidase, and pcroxidase. It has bccn shown that progcsterone-dependent rcproductive responscs re- enzymc thcrapv plavs an important rolc in czlncer quired for f'emaic fcrtilitr., whercas PR-B is requircd trcatmcnt, prevcnting oxidatir,r stress and inhibiting for normal proliferativc rcsponscs in the mammarv cell growth (Ossowski arrd L,rpcz. 1q96). gland. PRs rcsulirtc a grcat numbcr of gcncs, inclucl- The rapid expansion ofour knowledgc concern- ing those involvcd in breast cancer developmcnt. inq the processes of cell difrercntiation, ccll cvcle, It has bccn clemonstrated that PR-A and PR-R apopttrc i s, a nqi ogcn esis. rLrm oroqe n csi s. mctlstasi s, express difrercnt subsets of genes involved in par- and signal transduction control l'ravc unveiled an ticular functional pathways (Richer ct al.,2002; Li abundancc of specific molecular targets for can- and O'NIallq,;2003).In breast cancer cells, although ccr therap)., including a varictv of small-molcculc somc gcnes arc regulatcd through both PR isolorms, compounds that inhibit or stimulatc these molccu- most gencs arc uniqucly regulated through PR-B. lar targets (Zaidman ct al.,2005). Somc mushroom PR can be activated not onlv by progesteronc, low-molecuiar-wcight substances harc already bccn but also b-v some kinases and growth thctors (Zhang recorded to possess anticancer actir.ifii For instancc, et aL.,1991). Proscsteronc sienaling is often intcr- the caft'eic acid phenethyi ester (CAPtr), which twined r'vith other hormones. For cxamplc, estrogen specificallv inhibits DNA binding of NF-rcB and can induce expression of PR; thus, manv of thc ef- has shown some promising results in human breast fccts attributed to progestcrone are dcpcndent on canccr X4CF-7 cells, w:rs found to be produced bv estrogcns. Hormone-induced prevcntion of breast Agaricus bisporus (J.E. Langc) Imbach, Lentitttts canccr involvcs combination of cstrogen and pro- edades, and Phel/inus linteus (N'Iattlla ct a1., 2001; gesteronc (Ilcdina et rr1.,2001). Nakamura et al., 2003). 'lhese reports provcd that such substances could bc used as molccular targcts in rnalignant cells in ordcr to treat breast cancer. Estrogen Receptor (ER) In the present article, available data on medicinal mushroom polysaccharides, polvsaccharide/pcpticle Estroge ns play a critical role in the growth, dcvelop- complexcs, sccondarv metabolitcs, and their anti- ment, and maintenance of a diversc range of tissues, Volume 7, lssues 1&2, 2005 Electronic Data Center, http:l/edata-center.com Downloaded 2008-5-6 from lP 24.89.172.2 by Begell House
  • 4. R. D. PFITRO!'A ET rl -ll.rcsc including nrArnrnary elands. h<lrmones excrt shown to producc higl]er responsc ratcs and to their physiolosicai el{ccts via the estrogcn receptot postponc discase progression to a greater cxtcnt rvhich fu nctions as a ligand-actir.'ated transcriptior-ra1 comparcd to tamoxil-en (Wolft, 2002). regulator. ER is a mcmbcr of a large fhmil-v of nuclear Numerous natural cndocrine disrupters, such as receptor transcription factors and consists of two phyto-estrogens (a group of estrogenic compounds isofbrms, ERrx and ERB, rvhich have cqual functions produccd bv plants), are also capable of binding tcr in some tissues. but dil1'crcnt in others. ER has a ER, which rnay :ri1'cct l'ruman health. For cxamplc, charactcristic modular stmctural organization with Genistcin, an isoflar,'onoid phvto-cstrogen found in distinct domains associatcd with transirctivation, high quantitics in soya beans and sov products, is DNA binding, and hormone binding (White and known to bind to ER, cvcn to its twc'r isoforms, ERcl Parker, 1998). Hormonc bindins to thc ER ligand and ER$ (Kuipcr ct aL,1997). binding domain induces a conlbrmational change in tirc receptor,r'vhich initiates a series of e."'ents that culminate in the activation or rcprcssion of respon- NUCLEAR FACTOR KAPPA B (NF-rcB) sive gencs (Tsai and O'N'Iallev, 1994). Nuclear recep- tors, such as liR, are also capable of rcgulating thc In inflammatory diseases and many citncers the level transcription of gcne s that lrrck hormonc rcsponsive of active NF-rB is rathcr elevated. NF-rcB is of clcme nts bv modulating thc activifi' of othcr tran- significant importancc in the processcs ofinflamma- scription factors, such as NF-rcB and AP-1, which tion, cell sun ival, transfbrmation, and oncogene sis. scrvc as critical targcts fc.rl many signaling pathwavs Morcover, therc arc strong suggestions that NF-rB requlatins cell diftcrentiation, proiiferation, and plavs an important role in thc ctiolosv of breast transfbrrnation. That is wl-rv ER is irn important cancer. Elcvatcd NF-rcB DNA-binding activin' is pharmaceutical target for hormone replaccmcnt in detcctcd in both mammarv carcinoma cell lines and menopirusal wome n and for chemothcrapcutic drugs primirrv l-ruman breast cancer tissucs (Cao and Karin, against ccrtain rcprrrdrrctivc c'Jnccrs. 2003). NF-rcB is also responsible fbr tumor metas- It is known that some growth factors, ncurotrans* tasis in other organs. N{ctsstasis is a nonrandom mittcrs,:rnd other hormone s can modulatc thc actir'- llroccss, and each cancer tvpc hirs its own preferred itv of steroid hormone receptors (Power et al., 1991). sites of- mctastasis. For cxample, breast canccr cclls Thus, any alternation in the rcceptor activi6'and preferentizLllv mctastasizc to the lr'mph nodcs, lungs, €{cnc cxprcssion, which arc involvecl in ccll prolif- li.,.cr, and bone (l-iotta, 2001). Hclbig et al. (2003) eration, is de te rmined not onlv bv hormone signals, demonstratcd that NF-rcB directl_y rcguiatcs ti-re ex- but also b-v changes in other signaling pathways that pression of thc chemokine reccptor CXCR4,which takc place in brcast canccr progression. appcars to be critical fbr thc motilitv of cancer cclls Tamoxifen is a common anti-cstrogenic drug in responsc to the SDF-1,a in aitro. that inhibits thc binding of estrogen to ER. Un- fortunatel-r', breast cancer adjuvant therapv rvith tamoxifcn is not alwavs successful. Most paticnts NF-rcB activators n'ith advanced discasc dcvclop resistance to all fbrrns of endocrine therapv (l,ykkcsfcldt, 1996). Numerous The IKK complcx has been identified as a major studics fbcused on the control of thc antagonistic activator of NF-rcB (Zandi and Karin, L999).In and agonistic effccts of anti-estrogcns on tumor response to a rrarictv of stimuli, such as TNF- gror'vth (Osborne et aI.,2003). It has been known tx, CD40L, IL-1, and LPS, thc IKK complex is that tamoxif-cn has both antagonistic and aeonistic activated and phosphorylates the IkB inhibit,rrl propcrties-i.c., it inhibits growth in brcast tissuc proteins, resulting in thcir degradation and nuclcar but stimulatcs the proliferation ofthc endometrium. translocirtion of NF-rB, whcrc transcriptional E,ndocrinc therapies that lack cstrollen aeollistic acti.ation ol targct gcnes begins (Karin and Ben- propcrties, such as aromatic inhibitors, havc been Neriah, 2000). Thus, IKK can servc as a potcntial 144 International Journal of Medicinal Mushrooms Electronic Data Center, http://edata-center.com Downloaded 2008-5-6 fromlP 24.89.172.2 by Begell House
  • 5. NIED IC I N, L NIUS I I RO O Nl S I r.- Il REA ST CAN C I'l R T REATNI ItNT targct for inhibition of NF-rcB activit'. fherc arc It,-1B.Thc IKK complex is thc ccntral do"vnstream a varietv of targct gcncs rcgulated bv NF-rB suclr mediator of caspase -1-induced NF-xB activation, as immunoregulatory and inflammatory genes, which is also RIP-2 dependcnt. However, thc nnti-apoptotic gencs, gcncs that positivclv rcgrrlate proteolltic activity of thc enzyme is not important ccll prolif-cration, and genes that cncode ncgativc fbr that proccss (Lamkanfi ct a1.,2004). rcgulations of NF-rB (Pahl, 1999; Karin et a1., Biswas et al. (2000) recorded that thc cpidermal 2002). When NF-rcB dimcrs are uncouplcd from growth factor (EGF) fhmilv of receptors is over- thcir normal mode of regulation, thev can causc produced in ER-negative brcast cancer cclls and tumorolfenesis through ser,rcral mechanisms, such on low-level production of ER-positir''c cells, thus as promotion of cell proliferation, inhibition o1- suggesting that FIGF is a major Eirowth-stimulat- apoptosis, and incrcasing tumor mctastasis ancl ing fictor for ER-ncgatlve cells. Thc basal level of angiogcncsis (Karin et aL.,2002). actir.e NF'-rB in ER-negativc brcast cancer cclls is Progression of thc mammary carcinoma cell line clcvatcd bv trGFR and inhibited b1' anti-trGFR fu'I22-F5 from an estrosen rcccptor ER-positivc antibodr,', thus qualifying EGFR as a NF-xB acti- to an ER-ncp;ative rvas fbund to be accompanicd vation factor. bv constitutive activation of NF-tcB (Nakshatri et al., 1997).Incrcascd IKK activitv was shorvn br' Romicu-N{ourez et a1. (2001) in transformcd brcast NF-rB inhibitors cancer cell lines, and thc inhibition of IKK activin decreased NF-rB activity in tr.imor cell lines.Thus, The low-molccular-weight compound Go6976 is thc IKK complex is a potential targct fbr controlling klorvn to be an NF-rB inhibitor, blocking its EGF- NF-rcB activation and its functions. Samanta et irl. induccd activation and also causing 2lpoptotic death, (2004) cstablished that anothcr cnzvmc, lIEKK3, predominantlv in ER-neqative ce11s. Thus, Go6976 also has an elcvatcd cxprcssion in brcast cancer and sirnilar NF--rB inhibitors r.r.erc shown 2rs po- ccl1s. T}-rcir studv indicated dircct participation of tentiallv nor,cl low-moleculzrr-r.vcight ther:rpeutic N'tFlKK3 in the activation of NF-rcB, rcsultins in agents for trcatment of ER-negative breast canccr increascd cxpression of cell sunival lictors and re- patients. Go6976 r,vas shown not onlv to inhibit tu- sistance to chemotherapcutic agents, thus suggest- mor grorvth, but also to cause the ftlil-grown tumors ing functional coopcration betw.een N{EKK3 and in micc CSN'II-O cclls to regress, thr.rs confirminq othcr signaling molecules activatcd bv thc cytokines. the previouslv reported inhibitory etl-ect of Go6976 Indeed, such a molcculc, downstream of the il,-1 on NF-xB (Biswirs et a1., 2001). In a later stud1., and'I'NF signaling pathwa1., is Akt, which is also Biswas et al. (2003) tcstcd trvo inhibitors of NF-tcB rcported to participate in t1-rc actir.ation of NF-rcB. activation: Go697 6 and dnlKKB-mut. Thesc agcnts Akt uses IKK to stimulatc the transactivation po- modificd the expression ofgenes relatcd to apoptosis tcntial of the ReWp65 subunit of NF-rcB. Akt and specifically produced a high rate ofapoptosis of can also use thc protein kinasc p3B, but thc iattcr the cancer ccl1s. Results showcd that treatment of requircs coactivators to stimulate NF--rB (N{adrid animals with Go6976 caused essentiallv completc et a1., 2001; Dugourd ct a1., 2003). Thus, N'IEKK3 fumor rcsression. Also, dnlKKB-mut-cxprcssing and Akt mav also servc as therapcutic targets to cclls did not fbrm rumors. control cancer cell rcsistancc to cl'tokinc- or drug- In an in titro studv irnother chemical compound, induccd aDoDtosis. TNI, rvas demonstr2lted to have an tinticancer e lfect Recently, it has bcen reported that caspase-1,, indc- suppressing NF-rcB,leading to global inhibition of pendendv of its enz.vmc activitr'', can activatc NF-rcB, NF-rB-mediatcd transcription of pro-angioecnic suggcsting that the enzyme is inr,'olved in additional and promctastatic gcnes. Moreol'cr, the results pro-inflarnmatory pathways.Thus, 1. F'-rB activatior-r showcd that TNI specificallv targcts NF-rIJ actir,'- is a novel function of caspase-1, in contrast to thc ity of cancer cclls rvithin thc tumor mass (Pan ct induction of apoptosis and thc maturation of pr,.'r- al..2003). Volume 7, lssues 1&2,2OO5 145 Efectronic Data Center, http://edata-center.com Downloaded 2008-5-6 from lP 24.89.172.2 by Begell House
  • 6. R. I). PETROVA F]T AL Another potcnt inhibitor of NF-rB activiw is demonstrated eillcacv against spccilic rvpes ot can- CAPE,u4rich specificall-v inhibits DNA binding of ccr, as in monotherapy, the overwhclming successes NF-r<B but not other transcription factors (Natara- havc occurred when thcv werc tcsted to function jan et al., 1996).Watabe et al. (2004) reportcd results togethcr with proren and accepted che motherapcu- of tcsting CAPE in human brcast canccr NICF-7 tic agents. Hor,vcvcr, somc low-molccular-weight ceils. This sfudv demonstrated that CAPtr not onlv mushroom substanccs with fungal orisin havc also inhibited NF'-rcB activitv, but also activate d the Fas been rcported to be active in cancer trcatment. derrth receptor in r Fas-r--indcpendent manner. A11 compounds that are not involvcd in the N'Ioreovcr, CAPE inducecl Ba-x exprcssion, caspasc ccntral metabolic processcs of the organism, such activation, DNA fragmentation, and apoptosis not as thc generation of encr!$ the formation of thc onlv in breast canccr, but also in othcr various cancer building blocks of proteins, nucleic acids, and cell ccll lincs. Re sults showcd that cance r cclls with high membrancs, are known as secondary metabolites. basal NF-rcil activifv are morc scnsitivc to NF-rB Sccondar-v metabolites arc found among fungi and inhibition bv CAPE rhan are normal cells. Tl-ris plants and include compounds such as antibiotics raiscs thc possibility that canccr-ce11-spcci{ic drugs (c.g., pcnicillin, streptomvcin), dves (e.g., indigo), could be dq'cloped if NF-rcB-spccific inhibitors flavoring and odor compounds (e.g., menthol and wcrc available for humans. limonenc), and er.'en substances such as ta-xol (fbr treatment of ovarian canccr) and cyclosporin A (an immunosuppressant uscd to prcvcnt transplant rc- MUSHROOMS AND BREAST CANCER jection). Somc of the poisonous substanccs made bv funsi, such as alpha-amanitin and pl-ralloidin liom Because a great number of polysaccharidcs and tl-re death cap mushrooms, muscarinc from the flv polvsaccharide proteins isolated from mcdicinal agaric, orellaninc lrom the faisc chanterelle, and mushrooms havc shown significant anticanccr activ- lvscrgic acid from crgot of n'e, havc bccn purifiecl, ifi'. manv studie s have been conductcd to prclve thcir and scientific and mcdical uses havc bcen found as -Ihcsc potentirl effect in the treatment of diffcrcnt fipcs of :r result. substances also rclate to secondarv cancers. Nllushroom immunoccuticals act mainlv by mctabolites. elevating the host irnmune system. This process in- Several tungi rverc fbund to produce a range cludes activation of dcndritic cells, NK cclls,T cells, of antibiotics, producecl undcr spccific conditions. macrophagcs, and production of o,tokines (Halpcrn For instance, fungi such as T-richodernra, Penici//iunt, and N{illcr, 2002). Several fungal products, mainlv a.nd Aspergi//tLs producc :r diverse rangc of arrtibiot- polvsaccharidcs and cspeciallv B-glucans, were ics. Secondarl' rnetabolitcs such as penicillic acid, developed rvith clinical and commercial purposcs: rvhich is an antibacterial, aflatoxins that are mam- lcntinan, isolatcd from Lentinus edodes (Chihara et maliar.r toxic, and trichodermin that mav have broad al., 1,97 0);schizopvllan, from S c h izoplty I lu m c07nn1u ne antilungal activiru- were isolated from these tungi. (Komatsu et al., 7969); D-fraction, liom Grifola Somc of tl-rese fungal compounds disrupt DNA and frontlosa (Hishida ct 41., 1988); kestin (PSK), from protein svnthesis, others disrupt ribosomal activiw Trametes tcrsicolor (Sakagami and Takeda, 7993); or tl-re cytoskeleton, making them extrcrncl-v broad PSP also lrom Z verticolor (Yang, 7999); AHCC; and general toxirrs. 'Ihe ecologicai significance of and manv othcrs. most sccondarv mctabolites is still unccrtain, but These natural proclucts becamc popular in medici- thcrc is no doubt that thcv have a function in thc nal practice mainly bccausc of the biologically activc biochemical pathrvays of thcir prroducers as well as compounds tircy possess, which arc supposed to be fbr the iliferent properties of the latter. The recent relatccl to the naturc of tumor-specificity. Some of progress made in fermcntation, isolation, and struc- thcm havc alrcady been reported to possess antican- turc clucidation tcchnologies has madc investie:rting cer activitv in breast cancer modcls. While therc arc into the secondarv mctabolism of Basidiomvcetes cxamples in which mushroom polvsaccharides have secm ."vorthwhile. 146 lnternational Journal of Medicinal Mushrooms Efectronic Data Center, http://edata-center.com Downloaded 2008-5-6 from lP 24.89.172.2 by Begell House
  • 7. NI I,] D I CINAL I,'1 U S T{ RO ONl S I N B REASI' CANC I.] R T REAT NI I,]NT Mushrooms: Bioactive Compounds and rcfusing chcmotherapv. D-fraction plus tablets of Products Used in Breast Cancer Treatment dried crude extract of GriJbla Jiondosa wcrc used. Dosagcs varied depending on the paticnt, D-frac- Lentinan is a high-molccular-rveight polysacci-raridc tion doses ranging frorn 35 to 100 mg pcr dav with B-(1+3)-o-glucosc triple helix structure and and crudc mushroom cxtract ranging lrom 4 to 6 B-(1, 6)-o-glucopvranoside sidc chains (Aoki, 1984; grams. Svmptomatic improvemcnts or rcgrcssion Hobbs, 1995).lt was isolated from Lentinus edodes, were claimcd for approxim atelv 73o/o of the paticnts a wcll-knor'vn medicinal mushroom that has antitLt- rvith breast cancer. mor, immunon-roclulating, antiviral, antibactcrial, an- PSK is a unique protein-bound polysaccharide, tiparasitic, cardiovascular, and l.repatoprotcctive elTects which has grcat potential as an adjuvant canccr ther- (Wasser and Wcis, 1997). Rcsults of son'rc clinical apv agcnt, with positive results sccn in the adiuvant applications of lcntinan have pror.en prolorrgation of treatment of gastric, csophageal, colorcctal, breast, lifc span of the patients with advanced and recurrent and lurrg canccrs (Frsher and Yang, 2002). Sugirna- stomach, colorcctai, and breast canccr with fbw toxic chi et al. (1984) publishccl results from a long-tcrrn sidc ctTccts (Taguchi. 1 983; Chiharr, 1 992). immunotherapvwith PSK in coniunction with che - Scveral major substirnccs rvith potcnt im- motl-rerapv to brcast cancer patients anci shorved that munomodulating action sucir as pclh'saccharides, the survival ratc after recurrcncc was significantlr' protcins, and tritcrpenoicls l-ravc bccn isolatcd from extended bv the immunochernotherap'ri G a n derrna / uci d u m. Thc pharmacological activities of o Toi and Hottori (1992), in a much lnrgcr trial this medicinal mushroom are attributed primarilv to (914 paticnts) using in-depth analvsis, implied triterpenoids and polvsacciraricles (Wasser and Wcis, that PSK significantlv extendcd survival in ER- 1999b). it has been known that the highly metastrtic ncgativc, Stage IiA patierlts without lvmph node canccr cells arc characterized bv constitr-itivc acti'J- irrvoivemcnt. In 1995, lino et al. publishcd rcsults tion of transcription factors AP-1 and NF-rcB. Bv from a trial on breast cirnccr patie nts with vascular using commcrciallv availablc dictarv supp.rlements in invasion. Ilascd on thc knorvlcdgc that 840 antigcn thc form of spores (GS) and fruiting bodics (GFB), status irad bce n linkcd to the possibilitv of sun ival Sliva ct aI. (2002,2003) showcd that G. lucidum r,vith breast cancer, the rescarchcrs comparcd thcir inhibits constitutivclv activc AP-1 and NF-rB B40-positive paticnts trcated with PSK to the 840- in highlv invasive breast and prostatc canccr cells. negative ones.The studv yiclded the finding that thc Furthermore, both GS and GF'ts downregulatcd thc 840-positir.'c patients, who wcrc trcated rvith PSK in cxprcssion of uPA and its rcccptor uIAR as wcll as addition to chemothcrapv, had 100% survival :ifter sccrction of uPA, resulting in the inhibition of ceil 10 vears; horvevcr, thc B40-negativc patients had motilitv. An alcohol cxtract t'tf G. luridum inhibitcd approximatclv 5070 sunival (Yokoe et aI., 1'997). prolifcration of breast ciurccr cells by uprcgulating PSP also showed high antitumor activirv: but not thc cell-cvclc inhibitor p2lNVaf-l and bv do'"vn- in breast cancer p:rtienrs.'Ihe Phase I trial providcd regulatinu cvclin l)1.Thc:Llcohol extract also induced PSP at doses up to 6 grams per dav fbr 1 month to apoptosis of breast cancer cells, r'rdich was mcdiated 16 healthy persons and five breast canccr patients. through the uprcgulation of expression of proapop- Appetitc incre ased in a majorirv of the subjccts, but totic B'ax protein (Hu ct 'a|.,2002). no evidencc rv,rs fcrund for seriotts advcrsc cfiects Thc maitake D-fiaction was tested and shon'ed (Xu,1993). significant symptomatic iinprovements in a number Thc AHCC, whosc active component is an of clir-rical trials in breast, prostatc, lung, liver, and oligoznharidc, is obtaincd from several medicinal gastric canccrs in thc US andJapan, most ofwhich mushrooms culrured in liquid mcdium. Ilatsushita werc at an carly ciinical stagc (phase lilI) (Smith ct al. (1998) carricd out a studv on combinetion ct al.,2002). Nanba (1995) published some results thcrapv of AHCC plus UFT (tcgafur and uracil from a studv on 165 paticnts with various tvpes of in raticr 4:1) for in aizto treatmcnt of rat mammarv cancer, manv of them in advanccd stages and some atlenocarcinoma. Thcir results showcd that the Volume 7, lssues 1&2,2OO5 147 Electronic Data Center, http://edata-center.com Downloaded 2008-5-6 ftom lP 24.89.172.2 by Begell House
  • 8. R. I). I'F]TRO1 ET II,. combination of AHCC and UFT brought eood Aromatase, a crtochrome P450 enzvme cont- effects, not only on primary tumor growth, but also plex, conr.crts ar-rdrogens to estrogcns. Aromatase on reducing metastasis. rt oitro exPcriments shorved expression occurs in breast tumors and plavs a more that AHCC irctivated the NK cells in addition to the dominant role in rumor prolifcration tl'ran circulat- ilctivatior-l of macrophages.'lhese effccts resulted in ing cstradiol (Tekmal ct aL.,1'996; Brodic ct aJ.,1997; restoring or irctivating thc host immunc systcm, thus Yue et al.,1998). Some tests ofthe aromatasc activitr' sugee sting that AHCC ma-v be a good candidate for inhihition wcrc mrdc bv Grubc ct al. (2001) usirrg n biological response modifier. extracts from different mushrooms. Sienificant anti- Talorctc ct al. (2002) cxposed thc human breast aromatase ell-ects we re demonstrated bv Auricu/aria canccr linc MCIrT to an aqueous, hot watcr extract spp.,Agoricus bisporus (crimini, white button mr.Lsh- {romAgoricus brasiliensis S. Wasser et al., to a natural room, baby button mushroom, and stuffins mush- cstrogcn (E2, 17-B-estradiol), to a proren xenocs- room), A. hrasiliensis, Pleurotu-r ostreatus, Plettrottts trogen (NP,p-nonvlphenol), and to combinations sy:tp., Lentinu.r edodes, and Cantharel/zs spp. Horvct'cr, of these compounds r'vith or lvithout the mushroom the stulling mushroom showe d thc most potcnt but extract to determine their proliferative efrect ot-t do s e- dep end ent i nl-ribi torv elli:ct, which was dctcr- NIICF-7 cells. Resuits showcd no significant ilift-er- minccl in MCFTaro cclls culturcd in thc prcsence or ence in ccll proliferation bct'vcen ceils incubated absencc of testostcrone.With the increase of mush- wrth Agarictl-r cxtract and the control. Moreovcr, room cxtract concentration, there '"vas a proportionirl no significant dillercncc in prolifcrativc activitv of decrease in the tcstosteronc-dcpendcnt arotnatasc cells incubatcd u,'ith NP plus E2 was noted. Wcak activity. In thc presence ofthe highcst concentration cstrogcns, such as NP, can compcte r,vith 17-B-cs- of mushroorn extract (10 pL), the aromatase xcti'- tradiol lbr cstrosen rcceptors but do not ciicit the itv was inhibited to thc degrcc of the initial ler.cls same pleiotropic responsc. Rcsults also showcd no of cultivation (presence or absence of testostcronc). detectablc c-,izzz mRNA signal from anv of the This suggested that testostcronc mav compete u'ith trcatmcnts arrd thc controi. The c-iun mRNA rvas some putative components of mushroom extracts, stronglv exprcssed on11, i1-v the prresence of EGF and producing a protective efrect. An aromatase inhibit- iGF-1 (Philips ct al., 1993). An aqucous extract of ing compound was also isolatcd from LeLrcoagarirtr.s this fungus induccd c-iun protcin exprcssion and arneritanus (Peck) Vcllinga (Kim ct al., 2000), sue- enhanced the prolifcration in N'ICF7 cclls in the gesting that the specics might possiblv be uscd in prcs€ncc of nonl'lphenol, which mav be duc to thc the trcatment of breast canccr (Tablc 1). involvement of the AP-1 gene rcgulatorv comprlex (il'alo rete ct aL., 200 2) . N cve rth clc s s, N{ izuno (2 002 ) dcscribcd the casc ofa breast canccr patient whose Mushrooms: Secondary Metabolites tumol 7 lcars aficr thc operation, sprcad to thc lungs. Alier 3 months of administration of Agari- Lorcnzen and Anke (1998) preciselv described thc rus brasiliensfu extract, the patient was completclr' origin, structurc, and activitv t>f low-molecular- recovered from the canccr. wcight mushroom mctabolites. As an outcome of In a clinical trial, powcler of Sparassis crispa (YuI- their rcsults, many mushroom specics could bc usecl fen : Fr.) Fr. (300 mg/day)r,vas given orally to several as anticanccr therapcutics. Numcrous tritcrpenoids cancer paticnts (lung, stomach, colon, breast, orariatl, such as ganoderic acid, lucidcnic acid, ganodermic uterine, prostate, pancreas, and liver) after onc course acids, ganodcrenic acids, lucidonc, ganodcral, and of lvmphocvte transfer immunothcrapt', and most of ganodcrols have been isolated from the mvcelia them showed significant improveme nt. Morcor,'cr, the and fiuiting bodv of Ganoderna lucidum and have rcsults showed a complete rcsponse in breast cancer dcmonstratcd antitumor and immunomodulating paticnts with aclvanced canccr. Thcse flcts stronglv activitv (Wasscr and Wcis, 1999a). suggest that S. crispa ts a good soLlrce for cancer im- A scrccning of 500 strains of llilsidiomvcetcs, munotherapv (Ohno et a1.,2003) ('lhble 1). Ascomvcctcs, and anamorphic fungi carricd out 148 lnternational Journal o{ Medicinal Mushrooms Electronic Data Center, http://edata-center.com Downloaded 2008-5-6 tromlP 24.89.172.2 by Begell House
  • 9. N{I.]I)ICINAI, NTUST{ROONIS IN I]REAST CANCT.]RTREATN1 ENT bv trrkel et al. (1996), resulting in thc isolation of (Ebina and Fujimiya,1998).A. brasiliensis has pro- panepoxidone f ronr cultures of thc basidioml'cete grcssivelv becn propagatcd in the outdoors in manv Lentinus crinitus (L. : Ilr.) Fr. Paneporydone was tropical areas, but its harvesting car-r be affcctcd bv shorvn to interfcrc with thc NF-rB mccliated sig- clirnatic conditions, and thus structural analysis of nal transduction in COS-7 and HeLa 53 ccl1s bv lorv-molecular-weight molccules with bkrlogicnl ac- inhibiting thc phosphorylation ofIkB and, thercforc, tivitv is very important in thc dcsigning oi possible sequestering the NF-rB complex in irn inactive form sr,'nthctic analogues of natural products (fuimiva in the cvtoplasm.'lhc samc cell lines with a high af- ct a1.,1,999). finigv binding site fbr the transcription lactor AP-1 Two active substanccs, an alphatic compclund revcaled no inhibition of AP-1 DNA binding bv irnd phe nol, from thc mvcelium of Cordyccps ophio' panepoxidonc, indicating prcfcrcntial targct r,vitl-rin .qlossoidrs (Ehrh. : Fr.) Link, were isolated. Both of thc NF-rcB activatin€i pathwa-v. Pancpoxidonc, izo- ihcm shorued cstrogenic activities and arc supposcd panepoxidonc, and several rclated dcrivates werc to be important fcrr avoiding some side eifccts of rcported also as sccondarv metabolites from Panus carcinogencsis (Kawagishi ct al., 2004). conchattts (Bull. : Fr.) Fr. a.nd Penici//ium tttricae (Sch- The cal{cic acid phcncthyl ester (CAPE), which guchi and Gauchcq 1979; Shotwcll et al.,2000). spccificallv inhibits DNA binding of NF-rcB and Kahlos et al. (1987) pr-iblishcd data on some triter- shor'ved some promising results in human breast pcnoids isolated from Irtonotus abliqutt-r, cspccialll' cancer NICF-7 cclls, was purified from culture inotodiol, wl-rich had a significant ilnticrincer effect mvcelia o{ Phellirtu.r lintetrs, showing f, grctt poten- against Walker 256 carcinosarcoma and I'ICF-7 hu- tial anticancer activitv of this medicinal mushroom man mammarv adenclcarcinoma. Rccentlv, a ncw (Nakarnnra et al.,2003). CaIl-cic acid has also been triterpene from this mushroom was isolated, and its found in thc fiuit bodics of Agaricus bisportrs and anticancer propcrties are worth future invcstigations Lentinus edodes ('Nlattila ct al., 2001) (Table 1). (Shin et al..2000). Sornc fermentation products from Pleurotus ostreatus (Jacq. : Fr.) P. Kumm. were tested in bio- CONCLUSIONS AND FUTURE assavs and showcd thcir rlliri'a activin' eqainst PERSPECTIVES threc rodcnt tumor systcms: sarcoma, Inammarv adenocarcinoma 755, and lcukemia L1210 (Jong All investigations on the bretrst cancer cell lincs and Donovick, 1989). Yassin ct al. (2003) also re- carricd out up to date showcd that NF-rcB plays cordcd irrhibition of proliferation and diil-erentia- a maior rolc in the proccsses of tumorogenesis. It tion of K562 human leukcmia cel1s due to somc is clear that NF--rB activation is associatcd rvith low-molccular-wcight sr-rbstanccs from mushroom promotion of ccll grolvth in mammarv tumors and crude extracts. inhibition of NF-xB and provides irn elTectivc wav Fujimiva et al. (1999) described thc tumoricidal fbr treating brcast cancer. Distinct modcs of NF'-rcB activity of L14 fiactions derivcd from Agarirtrs activation bv IKK complcx,IKKu, and IKKB also brasiliettsis and studied thcir action n in oitro and susgest that selcctive inhibitors lor IKK would have irt tiao systems showing a markcd incrcase in IAP more specific inhibitory effccts on NF-rcB activitr' lcvels in the serum of mice rccciving thcse frac- (Cao and Karin,2003). Activated NF-rcB is such a tions and dcmonstrating thc possible activation of targct, the removal of which (b-v an inhibitor) can granulocytes. Results indicated tl-rat LM fractions reverse the specific anti-ilpoptosis of cance r cel1s.The havc not onlv a dircct tumoricidal action but also low-molecular-rveight compound ()o697 6, which immunopotcntiating activitv. An acid- treated ( irm - selectivclv kills cancer cells in culture and mice, is the monium-oxalatc soluble) fraction from A. brasiliensis first potcntiallv applicable chcmotherapeutic agent has a unique mode of action in that it has both a that restores apoptosis bv blocking thc activation direct cl'totoxic action on tumor cclls and indircct of NF-xB. Pro-apoptotic thcrapl'is rtovcl, dilTering immunopotentiating action on tumor-bcaring mice from classic therapcutics directcd against cc11 prolif- Volume 7, lssues 1&2, 2005 149 Electronic Data Center, http://edata-center.com Downloaded 2008-5-6 from lP 24.89.172.2 by Begell House
  • 10. R. r). PI-TTROV, Fll'Ar_. TABLE 1. Medicinal Mushrooms Demonstrating Antibreast Cancer or NFrcB Inhibition Activity in Animals and Humans Biological Effect Suppression of aromatase activity A:; r'.r t " b, " t;l;;;; i b i; i co iayr" pt o pn"gt ori.,ari{""Jioe Two active compounds showing estrogenic Kawagishi et al., 2004 qqy-T,v Tr a m ete s versico/or-i n ed i b I e PSK showed positive r.rrltr r.* in;Jw;i."-l F',th"r *d Y*9, iOOl', treatment ot breast cancer lmmunotherapy with PSK in conjunction with Sugimachi et al., 1984 chemotherapy signifi cantly extended survival rate PSK significantly extended survival in ER- Toi and Holtori, 1992 negative, Stage llA patients PSK in addition to chemotherapv leads to 100 lino et al., 1995; ,!et!9!!gfry9l_ Yokoe et il 1997 G anode r m a /ucidum-inedible I lnhibition of AP-1 and NF-rB Sliva et a1.,2002,2003 Gl cell cycle arrest Hu et al., 2002 Grifola frondosa-edible I D-fraction leads to symptomatic improvements Nanba, 1995 or reoression of the breasr cancer D-fraction showed significant symptomatic Smith et a|.,2002 improvements in the patients at an early clinical I stage of cancer (phase l/ll) i lnonotus obliquus -inedible I lnotodiol has a significant anticancer effect on Kahlos et al.,1987 MCF-7 human mammary adenocarcinoma i Lentinus edodes-edible i Lentinan prolongs the life span of the patients i Taguchi, 1983 with advanced and recurrent breast cancer I Chihara. 1 992 Suppression of aromatase activity i Grube et al., 2001 CAPE, an inhibitor of NF-rB binding to DNA, i Mattila et al., 2001 was isolated from fruit bodies I Lentinus crinitus Panepoxydone interferes with the NF-rB i Erkel et al., 1996 -edible mediated signal by inhibiting phosphorylation itiurougurirrt u-.ii."nrs-edibl" Suppression of aromatase activity Kim et al., 2000; Pan; ffi;iltl;'' I F*"po-iJon" und ,.opu."po*id,rne shouued-Sh"t*"ll ;;;f , 2000 I 7tnar.,, t,,t.,;;Jibi; {i#!;}5#F,rn*,, o* uinains-rF*B ,1h ;J- --l"n*;Jilil;--l 2oo3 lPl"*otu, ortr"utir-.*aiol"-'' --- l in *riu.iiuit/"9e'.,rt -a"nt r*;;;tt aoenocarcinoma 755 19Bt lsp-",'L;Lp,-.d',br. i8l;P;"### l with advanced cancer * Cordyceps ophioglossoides belongs to Clavicipitaceae (Ascomycetes). 150 lnternational Journal of Medicina! Mushrooms Electronic Data Center, http://edata-center.com Downloaded 2008-5-6 from lP 24.89.172.2 by Begell House
  • 11. N,I E D I C I N A I - N{ U S I I RO O N{ S I N B R Fl; S T C A N C I'l R T RF],'T N{ Fl. r- T crntion (Biswas et al.,2003). On thc other l-rand, the arrd efi'cctivelv inhibitcd using such kinds of mo- larowledge of thc spccific components of otokine lccular targcts. netr,vorks and signaling pathwavs and their rolc in Bccause of this ncccssiq','nve have alrcady started thc rcgulatic'rn oi immunc responscs is important a screening of75 strains of67 species, kept in thc in dcsigning stratcgics to augment thcsc rcsponses Culture Collcction of the Institute of Er.'olution, (7.aidman ct al., 2005). l,Iniversity of Hirif:r (f{AI). The list was based Searchins for neu'and eft-ective but natural com- mainlv on the literaturc data on the reportcd ac- por-rnds with NF-rB inhibitorv ellcct is worthr'vhilc. tivc compounds in medicinal mushrooms that have For manvvcars, phrtoestrogens havc bcen the object alre adv shorvn, or arc supposecl to shor,v, activin'in of scicntific investigations becausc of their beneficial hum:rn hreast canccr. Tl-re list was madc in order elfcct on human hcalth. Phytoestrogens, such as qeni- to includc spccies bclongine to different taxo- stein, wcre tcstecl iir oitro itt hum:rn breirst canccr nomical and ccological groups, such ns members models and shorved a high ir-rhibiton' activin' on of-Ascomr.'cctcs-e.g., Morche//a esculenta (L. : Fr.) cell proiiferation, althougl-r this was dependcnt on Pcrs., M. cra.rsipes (Vcnt. : Fr.) Pers., and Cordyceps the phytoestrosen conce lrtration (This et al.,2001). sinensis (Berk.) Sacc.-and manv Basidiomvcetes. Similar nirtural compounds have bccn fbund in The lattcr gror-rp inclutles membcrs of Agaricaccac, mcdicinal mushrooms. lJnfbrtunatell', onlr' a small Bolbitiace ae, Coprinace ae, Ganodcrmataceae, N'Icr- number of rnedicinal mushrooms havc bccn invcs- ipiliaceac, Plcurotirceae, Plutcaccac, Polyporaccac, tigated and reported to possess anti-breast-cancer Strophariaccae, etc. Somc of them, such as Lentinus activitl', and further inr.'cstigaticlns should be focused edodes, [,episttt nuda (Bull.: Fr.) Cooke, and Ple uro- on their potenti?11 '.rntitumor eflect on brcast canccr tus 0streatus, arc cdiblc; and others, such as -Frt7d-t do'elopmcnt. Onlv 13 species of Basidiomvcetes and Jbmentdrius (1,. : Fr.)JJ. Kickr., Famitopsis pirticola onc of Ascom,cctcs have been reportcd to possess (Sw. : Fr.) P. Karst., and Gloeopht,llum ubietittum active compounds with anticanccr potential in iz (Bu11. : Fr.) P. Karst., arc inedible. X'Iorcover, there .rtiz,o and in t'itro brcast canccr models. arc nlso some poisonous species, such as Amtnita More attcntion must be paid to thc isolation ntuscariu (1,. : Fr.) Hook. and Omphalotus olearius testing of mushroom sccondarv n-ictabolitcs irs ar-rd (DC. : Fr.) Singcr. Our aim is to isolatc some bio- potcntial inhibitors of NF-rB, IKK, NltEKK3, and active low-molecular-weight compounds from thc Akt as main thcrapeutic tirrgets in brcast cancer. mt'celia and culture broth in ordcr to investigatc Thus, it wili be possible to detcrmine r'r'hether NF- their potential NF-rB inhibitorv effcct in human rB activitv in brcast canccr cel1s can bc spccificallv bre,rst clnccr eell linc'. REFERENCES Biswas D. K., Martitt K.J., McAlister C., Cruz A. P., Graner E., Dai S., and Pardee A. B. 2003. Aoki T. 1984. Lentinan. In :I mmu nc Nlodulirtion tscnts Apoptosis caused bv chcmothcrirpeutic inhibi- and Their Nlcchar.risms, ltnichel R. L. and Chireis tion of nuclclr fzrctor-kB activation. Cancer Ru, N[. A., cds., [ntntwtol Stud,25, pp.62-77. 63,290-295. Biswas D. K., Cruz A. P., Gansberger E., and Pardee A. Brodie A., Qring L., and NakamuraJ. 1997. Arornatase B. 2000. Epi deln-ra1 grouth firctor-induccd nu clear in tl-rc normal brctrst and brcast cancer. J Steroid factor kR activation: a maior path'iav of celi-cyclc Biochern LIol Ilio/, 6t,281-286. progression in cstrogcn-receptor ncgative breast Cao Y. and Karin N{.2003. N}--kB in r.t.rammary plland canccr cclls. Med Sci ( PNAS), 97(15), 8512-8547. devclopr.ncnt and breast c'tnccr.J Mumnt Gland IJio/ Biswas D. K., Dai S. C., Cruz A., Weiser 8., Graner Neop[ 8(2), 215t23. E., and Pardee A. B. 2001. 'fhc nuclear firctor Chihara G.1992. Rcccnt progress in immunopharma- kB (NF-kIl): A potential thcrapeutic targct lbr cokrgl and therapeutic cffccts of polvsaccharidcs. estro€ien rcccptor ncgatil'e breast cancers. Md ki I)et, Biol Stand, 77, 191-197. ( PNAS ). 98, 10386-1 039 i. Chihara G., Hamuro J., Maeda Y. Y., Arai Y., and Volume 7, lssues 1&2,2OO5 151 Electronic Data Center, http://edatacenter.com Downloaded 2008-5-6 ftom lP 24.89.172.2 by Begell House
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