Kutsanya Nekenza: Maitiro Ema Molechi Uye Chikumbiro Chekushandisa

Alessio Nencioni, Irene Caffa, Salvatore Cortellino uye Valter D. Longo

Abstract | Kukanganisa kwemasero emukenza kuva nehuwandu hwekudzivirira uye kuvimba kwavo pane metabolites chaiyo inotarisa zviratidzo zvekenza. Kutsanya kana kutsanya-kutevedzera kudya (FMDs) kunounza kuchinja kukuru mukukura kwezvinhu uye mumatanho emetabolite, zvichiita mamiriro ezvinhu anokwanisa kuderedza kukwanisa kwekenza masero kugadzirisa uye kupona uye nokudaro kuvandudza migumisiro yerapa remishonga. Mukuwedzera, kutsanya kana maMFM zvinowedzera kupikisa chemotherapy muzvakanaka asi kwete maitiro emukenza uye kukurudzira kugadziriswa mumagadzirirwo akadai, izvo zvingabatsira kudzivirira zvinogona kuipa uye zvingangove zvinopisa mungozi yemigumisiro yemishonga. Nekutsanya hazviregi kurambidzwa nevarwere, zvose mhuka uye zvidzidzo zvekurapa zvinoratidza kuti maitiro e-low-calorie FMDs anokwanisika uye akachengeteka zvachose. Mitezo yakawanda yekliniki inoongorora kukosha kwekutsanya kana maMFM pamigumisiro-inoshandiswa yakaipisisa uye pamigumisiro inobudirira iri kuenderera mberi. Tinokurudzira kuti kusanganiswa kweMFMs ne chemotherapy, immunotherapy kana mamwe marapirwo kunomirira nzira inogona kuvimbisa yekuwedzera kurapwa kwehutano, kudzivirira kushandiswa kwekudzivirira uye kuderedza madhara.

Zvokudya uye mararamiro ane chokuita nehupenyu ndizvo zvinokonzera kuisa njodzi yekuva nekenza, nemamwe magomarara ari kunyanya kutsamira pakudya pane mamwe1�9. Zvinopesana nemafungiro aya, kuneta kunofungidzirwa kukanganisa kwe14% kusvika ku20% yevose vanofa nekenza muUnited States7, zvichiita kuti tive nemirayiridzo pamusoro pekudya zvinovaka muviri uye kuita basa rekuita kuti kuderedze njodzi yekuvandudza cancer6. Uye zvakare, zvichipiwa kuwedzera kwecancer maseru, asi kwete eakajairika matishu, kusateerera anti-kukura zviratidzo (nekuda kweoncogenic mutations) 10 uye kutadza kwavo kunyatsoenderana nemamiriro ekutsanya11,12, pane kuwedzera kufarira mune mukana wekuti zvimwe zvinodyiwa zvine macalorie zvinogona zvakare kuve chikamu chakakosha chekudzivirira gomarara uye, pamwe, yekurapa kenza senzira yekuwedzera kushanda uye kushivirira kwevamiririri veacancer.

Kunyange zvazvo mumakore gumi adarika takaziva kuchinja kusati kwamboitika uye kufambira mberi kunoshamisa mukurapa kwekenza14,15, pane chimwe chinhu chinokosha chinodiwa kuti chibudirire uye, zvichida, nzira dzokurapa nokuti matumbo asi zvakare, uye sezvakakosha, nekuda kwekugadzirisa migumisiro yemigumisiro yekenza15,16. Nyaya yehutano-zviitiko zvinokuvadza zvinoitika (TEAEs) chimwe chezvipingamupinyi zvinokosha mukurapa incology15,16. Ichokwadi, varwere vazhinji vane kenza vane ruzivo uye / kana kwenguva yakareba migumisiro yekenza mishonga, iyo inogona kudikanwa muchipatara uye kurapwa kwechisimba (zvakadai semishonga inorwisa mabhakitiriya, haematopoietic kukura zvinhu uye kuwedzerwa ropa) uye zvakanyanya kuchinja unhu hwavo hwehupenyu (somuenzaniso, chemotherapyinduced peripheral neuropathy) 16. Nokudaro, nzira dzakagadzikana dzekuchera hutsinye hunofanirwa uye dzinofungidzirwa kuva nehutano hwakakura, hupfumi uye hupfumi huwandu hweXXUMUM.

Kutsanya kunoita kuti masero ane utano agone kupindira zvishoma nezvishoma uye yakachengetedzwa mamiriro ezvinhu anovadzivirira pakushorwa kunotapira kunobva pamishonga yekurwisa mishonga panguva yekukurudzira mhando dzakasiyana dzemasero ekenza kune idzirapeutics11,12,17. Uku kuwanikwa kunoreva kuti kupindira kwekudya kumwe chete kunogona kubatsira kutarisa zvakasiyana uye zvakaenzana zvinokosha zvekenza itachiona.

Muchikamu chino cheMagariro, tinokurukura maitiro ezvokudya nekutsanya kana kutsanya-kutevedzera kudya (FMDs) kune maEAE asina kunaka asiwo kudzivirira uye kubata chirwere. Isu tinofananidzawo mavhareji emayero aya eXXUMUMX uye yakabudiswa uye inoenderera mberi zvidzidzo zvekliniki umo kutsanya kana maMMM ave achishandiswa kuvarwere vane kenza.

Systemic & Cellular Kutsanya Kupindura

Kutsanya kunotungamirira kuchinjairo mumabasa emaitiro akawanda emagetsi anoshamwaridzana nechinoshandiswa mune imwe nzira inokwanisa kuunza simba uye metabolites vachishandisa kabhoni zvinowanzobudiswa zvikuru kubva pachimiro chechidimbu uye muchidimbu kubva mumasumbu. Kuchinja kwemazinga ekufambisa mahomoni uye metabolites kunoshandura pakuderedza kushandiswa kwesero uye basa remagetsi hwemazuva ose masero uye pakupedzisira unozvidzivirira kubva chemotherapeutic kutukwa11,12. Kanzerini masero, nokusateerera mirairo yekurwisana inokurudzirwa nemararamiro aya ekushaya nzara, inogona kuva nemhinduro yakasiyana yemasero ezvakanaka uye saka inokurudzirwa chemotherapy uye mamwe mishonga yekenza.

Kugadzirisa Kwazvo Kuzvinyima

Mhinduro yekutsanya yakarongedzwa muchidimbu nematanda ekupararira kweglucose, insulini, glucagon, kukura hormone (GH), IGF1, glucocorticoids uye adrenaline. Munguva yepakutanga post-absorptive phase, iyo inowanzoita 6 24hours, insulin mazinga anotanga kudonha, uye mazinga eglucagon anomuka, achikurudzira kuparara kwezvitoro zveropa glycogen (izvo zvakaneta mushure memaawa makumi maviri nemana) nekusunungurwa kweshuga kwesimba.

Glucagon uye yakaderera masosi e insulin zvakare inokonzeresa kuparara kwe triglycerides (ayo anonyanya kuchengetwa muadipose tishu) mu glycerol uye yemahara fatty acids. Panguva yekutsanya, akawanda matishu anoshandisa mafuta acids esimba, nepo uropi huchivimba neshuga uye nemitumbi yemaketone inogadzirwa nema hepatocyte (ketone miviri inogona kugadzirwa kubva kuacetyl-CoA inogadzirwa kubva kumafuta acid? -Xidation kana kubva ku ketogenic amino acids). Muchikamu che ketogenic chekutsanya, miviri ye ketone inosvika mukati me millimolar renji, kazhinji kutanga mushure memazuva maviri ne2 kubva pakutanga kwekutsanya. Pamwe pamwe nemafuta-anotorwa glycerol uye amino acids, ketone miviri mafuta gluconeogenesis, iyo inochengeta mazinga eglucose pakufungidzira ingangoita 3mM (4mg pa dl), iyo inonyanya kushandiswa nehuropi.

Glucocorticoids uye adrenaline inobatsirawo kutungamira kushandiswa kwemagetsi ku kutsanya, kubatsira kuchengeta shuga yehutachiona uye kukurudzira lipolysis20,21. Zvinonzwisisika, kunyange zvazvo kutsanya kunogona kuwedzera zvishoma nekanguva kuwedzera GH mazinga (kuwedzera gluconeogenesis uye lipolysis uye kuderedza piripheral glucose uptake), kutsanya kunoderedza IGF1 mazinga. Mukuwedzera, pasi pekutsanya, IGF1 basa rezvakaberekwa rinodzivirirwa muchikamu nekuwedzera kwemazinga e insulini-kufanana nekukura kunosunga mapuroteni 1 (IGFBP1), iyo inosungiridza kupararira IGF1 uye inodzivirira kusangana kwaro neinoenderana nesero surface receptor22.

Pakupedzisira, kutsanya kunoderedza maitiro ekupararira leptin, hormone yakawanda yakaitwa neadidicytes inodzivisa nzara, ichiwedzera huwandu hweadiponectin, iyo inowedzera fatty acid breakdown23,24. Nokudaro, pakugumisa, zviratidzo zvemammalian zvinogadziriswa nekutsanya zvikamu zvakaderera zveglucose uye insulin, yakakwirira ye glucagon uye miviri ye ketone, mazinga akadai eGF1 uye leptin uye yakakwirira mazinga adiponectin.

Mhinduro yeChechi KuKutsanya

Mhinduro yemasero ane hutano pakutsanya ndeyekushanduka-shanduka uye inopa kuchengetedzwa kwemasero, uye zvirinani muzvipenyu zvemuenzaniso, yakaratidzirwa kuwedzera hupenyu hwehupenyu uye healthspan12,22,25-31. Iyo IGF1 chiratidzo kukwira chiyi chinhu chiratidzo nzira inobatanidzwa mukugadzirisa mhedzisiro yekutsanya padanho remaseru. Pasi pechikafu chakajairika, protein kudyiwa uye kuwedzerwa mazinga eamino acids kuwedzera IGF1 mazinga uye kukurudzira AKT uye mTOR chiitiko, zvichidaro kuwedzera mapuroteni synthesis. Zvichienderana, panguva yekutsanya, IGF1 mazinga uye kudzika kwekuratidzira kuderera, kudzikisira AKT-mediated inhibition yemammalian FOXO zvinyorwa zvinyorwa uye kubvumira izvi zvinyorwa zvinyorwa kuti zvishandure magene, zvichikonzera kumisikidzwa kwema enzymes senge haem oxygenase 1 (HO1), superoxide dismutase ( SOD) uye catalase ine antioxidant zviitiko uye zvinodzivirira32. High glucose mazinga anomutsa protein kinase A (PKA) chiratidzo, iyo inorayira zvinoshandisa tenzi simba remagetsi AMP-activated protein kinase (AMPK) 35, iyo inobvisawo kutaura kwekushungurudzika kwepfungwa kushandiswa kwekutanga kukura kweproteinini 1 (EGR1) (Msn2 uye / kana Msn4 muviriswa) 26,36 .

Kutsanya uye kukonzeresa glucose kudzora kunodzivisa chiitiko chePKA, kuwedzera chiitiko che AMPK uye kumisikidza EGR1 uye nekudaro kuzadzisa maseru-ekudzivirira mhedzisiro, kusanganisira iwo ari mu myocardium22,25,26. Chekupedzisira, kutsanya uye maMFM (ona pazasi pekuumbwa kwavo) zvakare vane mukana wekusimudzira maitiro ekuvandudza (Bhokisi 1) nema mamolekemu maitiro, mamwe acho akaverengerwa mukenza, senge kuwedzera autophagy kana induction ye sirtuin chiitiko22,37-49 .

Zvokudya Zvokudya MuMagetsi eC Cancer

Idzo nzira dzekudya dzinoenderana nekutsanya kwakaferefetwa zvakanyanya mu oncology, zvese zvakanyanyisa uye zvekurapa, zvinosanganisira kutsanya kwemvura (kurega kubva pane zvese zvekudya nezvinwiwa kunze kwemvura) uye maMFM11,12,17,25,26,50-60 (Tafura 1). Yekutanga kiriniki dhata inoratidza kuti kutsanya kweinenge makumi mana nemasere maawa kungangodiwa kuti uwane zvinonzwisisika zvemakiriniki mune oncology, sekudzivirira chemotherapy-inokonzeresa kukuvara kweDNA kumatishu ane hutano nekubatsira kuchengetedza murwere hupenyu hwehupenyu panguva yechemotherapy52,53,61.

Nekudaro, varwere vazhinji vanoramba kana kuve nematambudziko ekupedzisa kutsanya kwemvura, uye njodzi dzinogona kuvepo dzekuwedzera kwekoriori uye kushomeka kwemicronutrient kunoenderana nazvo kunonetsa kutsigira. MaMFM ari ekurapa akagadzirwa madhayeti ehurongwa akadzika kwazvo mumacalorie (ndokuti, anowanzo pakati pe300 ne1,100kcal pazuva), mashuga nemapuroteni anodzokorodza mazhinji emhedzisiro yekutsanya kwemvura-chete asi nekuteerera kuri nani kwevarwere uye kudzikisira njodzi yehutano22,61,62, 3. Munguva yeFMD, varwere vanowanzo gashira huwandu hwemvura husina kuganhurirwa, zvidiki, zvakaenzana zvemuto muto, masobho, majusi, nzungu mabara, uye tii yemakwenzi, pamwe nekuwedzera kwemicronutrients. Mune kiriniki yekudzidza ye5 pamwedzi kutenderera kweiyo 1-zuva FMD mune yakajairika nyaya, chikafu chakabvumidzwa zvakanaka uye chakadzikiswa trunk uye akazara muviri mafuta, kuwedzerwa kweropa uye IGF62 mazinga3. Munguva yakapfuura uye inoenderera oncological kiriniki miedzo, kutsanya kana maMFM akawanzo kupihwa kwega kwega mavhiki e4, semuenzaniso, mukubatana nemakemikari regimens, uye nguva yavo yakatangira pakati pe1 ne5 mazuva52,53,58,61,63-68 . Zvakakosha, hapana zviitiko zvakakomba zvakashata (chikamu G3 kana pamusoro, zvinoenderana neCommin Terminology Criteria yeZviitiko Zvakaipa) zvakataurwa mune izvi zvidzidzo52,53,58,61.

Ketogenic Diets

Ketogenic dhayeti (KDs) madhayeti ezvokudya ane zvakajairika koriori, mafuta ane mafuta uye akadzika-macarhydrate zvemukati69,70. Mune yechinyakare KD, chiyero pakati pehuremu hwemafuta uye huremu hwakabatana hwehydrohydrate uye mapuroteni ndi4: 1. Nezve izvo, maMFM zvakare ari ketogenic nekuti iwo ane mafuta-ane zvemukati uye anokwanisa kukwidziridza kwakakura kukwirisa (? 0.5mmol per litre) mumatanho ekutenderera ketone miviri. Muvanhu, KD inogona zvakare kudzikisa IGF1 uye insulin mazinga (neanopfuura makumi maviri kubva muzana kubva pamatanho ekutanga), kunyange hazvo mhedzisiro iyi ichikanganiswa nematanho uye mhando dzemacarhydrate uye mapuroteni mune chikafu20. KDs inogona kudzikisa huwandu hweropa, asi ivo vanowanzo gara mukati meyakajairika renji (ndokuti,> 71mmol pa litita) 4.4.

Sezvineiwo, maKD anogona kuve anoshanda mukudzivirira kuwedzera kweshuga uye insulin inowanzoitika mukupindura PI3K inhibitors, iyo yakataurwa kudzikamisa kushanda kwayo72. Pachinyakare, maKD ave achishandiswa pakurapa pfari inokanganisa, kunyanya muvana69. Mune mbeva mhando, KDs inokonzeresa anticancer mhedzisiro, kunyanya mu glioblastoma70,72-86. Zvidzidzo zvekiriniki zvinoratidza kuti maKD anogona kunge asina basa rakakura rekurapa kana richishandiswa sevashandisi vasina kuroorwa mune varwere vane gomarara uye zvinoratidza kuti mabhenefiti ezvekudya izvi anofanirwa kutsvakwa pamwe chete nedzimwe nzira, senge chemotherapy, radiotherapy, antiangiogenic kurapwa, PI3K inhibitors uye FMDs72,73.

KDs dzakanzi dzive neuroprotective mhedzisiro mune yekumusoro tsinga uye mune hippocampus87,88. Nekudaro, zvinoramba zvichisimbiswa kuti KDs zvakare ine proregenerative mhedzisiro yakafanana nekutsanya kana maMFM (Bhokisi 1) uye kuti KDs zvakare inogona kushandiswa kudzivirira zvipenyu zvipenyu kubva kune huturu hwechemotherapy. Zvinonzwisisika, izvo zvinogadziriswazve mhedzisiro yekutsanya kana maMFM anoita kunge akawedzeredzwa neshanduko kubva kunenzara-mhinduro modhi, iyo inosanganisira kuparara kwemaseru maseru uye kufa kwemasero mazhinji, uye nguva yekudzoreredza, umo masero nematukisi zvinoitika kuvakazve22. Nekuti maKD haamanikidze kupinda mune nzara modhi, usasimudzire kuparara kukuru kwezvinhu zvemukati mezvitunha uye zvinyama uye hazvisanganise nguva yekumisikidza, hazvigone kukonzeresa rudzi rwekugadziriswazve kunoonekwa panguva yekudzoreredza kweMFM.

Calorie Restriction

Nepo chisingaperi macalorie anodzivisa (CR) uye kudya kunoshomeka mune chaiwo amino acids zvakasiyana zvakanyanya kubva nguva nenguva yekutsanya, ivo vanogovana nekutsanya uye maMFMs zvakanyanya kana zvishoma kusarudza kusarudza muhutano, uye vane anticancer mhedzisiro 81,89 112. CR inowanzo sanganisira chisingaperi 20-30% kudzikira kwesimba rekudya kubva pane yakajairwa koriori yekudyira iyo inobvumidza munhu kuti achengetedze yakajairwa113,114. Izvo zvinoshanda kwazvo mukuderedza zvemwoyo njodzi mungozi uye kenza zviitiko mune zvemuenzaniso zvisikwa, kusanganisira primates108,109,114.

Nekudaro, CR inogona kukonzera mhedzisiro, senge shanduko muchitarisiko chemuviri, kuwedzera kutonhora kwekunzwa, kuderedzwa kwesimba, kutadza kuenda kumwedzi, kushaya mbereko, kurasikirwa kwe libido, osteoporosis, inononoka ronda kupora, kudya kudya, kutsamwa, uye kushushikana. Mune varwere vane gomarara, pane kunetseka kwakanyanya uko kunogona kuwedzera kushaya chikafu zvinovaka muviri uye kuti zvinokonzeresa kurasikirwa kwakanyanya kwemuviri wakaonda18,113-116. CR inoderedza kutsanya kweropa glucose mazinga, asi ivo vanogara mukati meyakajairika renji114. Muvanhu, CR isingaperi haibate mazinga eGF1 kunze kwekunge mapuroteni ane mwero akaiswawo117.

Zvidzidzo zvinoratidza kuti nekuderedza mTORC1 kuonekwa muPaneth masero, CR inogadzira stem cell function uye kuti inodzivirira kuchengetedzwa kwemakumbo emasero kubva kuDNA damage118,119, asi hazvizivikanwe kana zvinowanzogadziriswa mune dzimwe nhengo zvinoshandiswa naRC. Nokudaro, iyo inowanikwa dare inoratidza kuti kutsanya uye maMFM zvinoumba chimiro chemagetsi, regenerative uye chekuchengetedza icho chakasiyana uye zvichida zvakanyanya kupfuura icho chakaitwa neKD kana CR.

Kutsanya & maMFM Mune Therapy: Mhedzisiro pane mahormone uye metabolite mazinga

Zvizhinji zvekuchinja kwemazinga ekupararira mahomoni uye metabolites ayo anowanzoonekwa pakupindura kutsanya ane simba rekushandisa zvinopisa zvinokonzera (kureva, kuderedzwa kwehutachiona, IGF1, insulini uye leptin uye kuwedzera mazinga e adiponectin) 23,120,121 uye / kana kuti kuchengetedza utachiona hwakanaka kubva pamigumisiro (kureva, kuderedza mazinga eGF1 uye glucose). Nokuti ketone miviri inogona kukanganisa histone deacetylases (HDACs), kuwedzera kwekutsanya-kuwedzerwa kwemitumbi yeketone kunogona kubatsira kuderera kwechirwere kukura uye kukurudzira kuparadzaniswa kuburikidza nemagadzirirwo epigenetic122.

Nekudaro, iyo ketone muviri acetoacetate yakaratidzirwa kumhanyisa, panzvimbo yekuderedza, kukura kwemamwe mamota, senge melanomas ine mutated BRAF123. Iko kushandurwa uko kune hwakasimba humbowo hwechikamu mune zvinobatsira mhedzisiro yekutsanya uye maMFM kurwisa kenza ndiko kuderedzwa mumatanho eGF1 uye glucose. Padanho rema molecular, kutsanya kana iyo FMD inoderedza mascacellular ekuisa chiratidzo macascades anosanganisira IGF1R AKT mTOR S6K uye cAMP PKA siginecha, inowedzera autophagy, inobatsira maseru akajairika kutsungirira kusagadzikana uye inosimudzira hutachiona hwehutachiona25,29,56,124

Kusiyanisa Kushungurudzika Kushungurudzika: Kuwedzerwa Chemotherapy Kutambura

Mamwe mbiriso incogene nyanzvi, dzakadai saRas uye Sch9 (nyanzvi yezvemagariro emamamalia S6K), inokwanisa kuderedza kusagadzikana kwepfungwa mumararamiro emuenzaniso27,28. Mukuwedzera, kushanduka kunoita kuti IGF1R, RAS, PI3KCA kana AKT, kana kuti iyo isingashandisi PTEN, iripo muzhinji hwevanhu vane kanzura10. Pamwe chete, izvi zvakakonzera kufungidzira kuti nzara yaizokonzera zvinopesana nekenza zvichienderana nemasero ezvakanaka maererano nekwanisi yavo yekudzivirira masero epfungwa, kusanganisira chemotherapeutics. Mune mamwe mazwi, nzara inogona kutungamirira zvakasiyana kushungurudzika kushorwa (DSR) pakati pezvakagara uye kenza masero.

Zvinoenderana neiyo DSR hypothesis, maseru akajairwa anopindura nzara nekudzora kuwanda kwakabatana uye ribosome biogenesis uye / kana magineti egungano, izvo zvinomanikidza maseru kuti apinde munzira yekuzvigadzirisa uye anovadzivirira kubva mukukuvara kunokonzerwa nekemotherapy, radiotherapy uye mamwe maronda ane chepfu. Kupesana, mumasero ekenza, iyi yekuzvigadzirisa modhi inodzivirirwa kuburikidza neoncogenic shanduko, iyo inokonzeresa kuita inhibition yekumanikidza kupindura nzira12 (Fig. 1). Zvinopindirana neiyo DSR modhi, nzara-yenguva pfupi nzara kana kubviswa kweproto-oncogene homologues (kureva, Sch9 kana maviri Sch9 uye Ras2) kuwedzera kuchengetedzwa kweSaccharomyces cerevisiae kurwisa oxidative kushungurudzika kana chemotherapy mishonga kusvika ku-100 puro kana ichienzaniswa nemasero masero anotaura nezvekushanda kwecogene ishamwari Ras2val19.

Mitsara yakafanana yakawanikwa mumasero emammalia: kuvharwa kwepasi-glucose media yakachengetedzwa mutsara weglia glia masero pakusvibiswa nehydrogen peroxide kana cyclophosphamide (a prooxidant chemotherapeutic) asi haana kudzivirira mapundu, ronda uye vanhu glioma uye neuroblastoma yerineni mitsetse. Zvinopesana nemashoko aya, a 2-zuva kutsanya zvakajeka kupona kwemakonzo aibatwa nehopeside yepamusoro yakaenzaniswa nemakwenzi asina kutsanya uye akawedzera kupona kweeuroblastoma allograftbearing manyowa akaenzaniswa newasingafungi maronda-ane mice12.

Zvidzidzo zvakatevera zvakawana kuti kuderedzwa kweGF1 kusaina mukupindura kutsanya kunodzivirira kwekutanga glia uye mauroni, asi kwete glioma uye maseru euroblastoma, kubva kucyclophosphamide uye kubva kune pro-oxidative macomputer uye inodzivirira mbeva embryonic fibroblast kubva doxorubicin29. Chiropa IGF1-inoshomeka (LID) mbeva, mhuka dzinochinja muviri dzine mamiriro echiropa Igf1 jeni kubviswa iyo inoratidza 70hibit80% kudzikira mukutenderera kweiyo IGF1 mazinga (mazinga akafanana neaya akawanikwa nekutsanya kwemaawa 72 mumakonzo) 29,125, aidzivirirwa matatu kubva mana emakemotherapy madhiragi akaedzwa, kusanganisira doxorubicin.

Histology zvidzidzo zvakaratidza zviratidzo zve doxorubicin-inosimudzira moyo myopathy mune chete doxorubicin-inorapwa mbeva dzekudzora asi kwete muLID mbeva. Mukuyedza mhuka dzine melanoma-dzinotakura dzakarapwa ne doxorubicin, hapana mutsauko maererano nekufambira mberi kwechirwere pakati pehutongi nembeva dzeLID zvakaonekwa, zvichiratidza kuti maseru egomarara haana kudzivirirwa kubva kumakemotherapy nemazinga akaderedzwa eGG1. Asi, zvakare, mbeva dzinotakura tumarara makonzo akaratidzira mukana unoshamisa wekupona uchienzaniswa nemhuka dzinodzora nekuda kwekugona kwavo kumira doxorubicin toxicity29. Nekudaro, zvakazara, mhedzisiro iyi yakasimbisa kuti IGF1 kudzikisira chinhu chakakosha nzira yekutsanya kunowedzera chemotherapy kushivirira.

Zvose dexamethasone uye mTOR inhibitor zvinowanzoshandiswa mukurapa kenza, zvichida nekuda kwekushanda kwavo se-anti-emetics uye anti-allergics (ndiko kuti, corticosteroids) kana kuti nokuda kwavo antitumour dzimba (kureva, corticosteroids uye mTOR inhibitors). Zvisinei, chimwe chezvakakosha uye nguva dzose maitiro emigumisiro emigumisiro ndeye hyperglycaemia. Zvinoenderana nepfungwa yekuti yakawedzera glucose cAMP PKA chiratidzo kunoderedza kusagadzikana nehupfukidzi hwemakemikarirapeutic mishonga12,26,126, zvose dexamethasone uye rapamycin inowedzera toxicity ye doxorubicin mu mouse cardiomyocytes uye mice26. Zvinonakidza kuti zvaikwanisika kudzosera utsvina hwakadaro kuburikidza nekuderedza kupararira kwemazinga emushuga kuburikidza nekutsanya kana kuti injulin injections26.

Aya mapindiro anoderedza chiitiko chePKA nepo ichiwedzera chiitiko cheAMPK uye nekudaro ichigadzirisa EGR1, zvichiratidza kuti cAMP PKA chiratidzo chinoratidzira iyo yekutsanya-inosimudzira DSR kuburikidza neEG1 (ref. 26). EGR1 inosimudzirawo kutaura kweyepiooprotective peptides, senge atrial natriuretic peptide (ANP) uye iyo B-mhando natriuretic peptide (BNP) mune yemoyo tishu, iyo inobatsira mukushora doxorubicin. Zvakare, kutsanya uye / kana FMD inogona kuchengetedza mbeva kubva ku doxorubicin-inokonzeresa chirwere chemoyo nekuwedzera autophagy, iyo inogona kusimudzira hutano hwemagetsi kuburikidza nekuderedza inoshanda yeoksijeni marudzi (ROS) kugadzirwa kuburikidza nekubviswa kweanoshaya mitochondria uye nekubvisa zvine chepfu zvikamu.

Kunze kwekudzora chemotherapy inokonzeresa huturu mumasero uye kuwedzera kupona kwemakemikari anorapwa nemakemikari, maitiro ekutsanya anokonzeresa mwongo wemapfupa uye kudzivirira kudzvinyirirwa kunokonzerwa necyclophosphamide mune PKA-inoenderana uye IGF1-nzira ine hukama25. Nekudaro, kumanikidza kwekufanobata mhedzisiro kunoratidza kugona kwekutsanya uye maMMMs kuwedzera chemotherapy kushivirira uye kudzivirira makuru mhedzisiro. Nekuti yekutanga kiriniki dhata inokweretesa rutsigiro kune izvi zvingave, izvi zvekumberi zvidzidzo zvinowaka chikonzero chakasimba chekutarisa maMMM mune akaomeswa emakiriniki miedzo neTEAEs sekutanga kwekupedzisira nzvimbo.

Kusiyanisa Kushungurudzika Sensitization: Kuwedzera Kufa kweCells Cells

Kana ikashandiswa yoga, nzira dzakawanda dzekudya, kusanganisira kudya uye maMFM, dzine zvishoma zvinokonzerwa nekenza kufambira mberi. Maererano nekusiyanisa kushungurudzika kwechisimba (DSS) pfungwa, kusanganisa kwekutsanya kana maMMM ane chirwere chechipiri kunowedzera kuvimbisa11,12. Iyi pfungwa inofungidzira kuti, nepo kenza yemasikirini inokwanisa kugadzirisa kusvika pakukanganiswa kweokisijeni uye kuwandisa kwezvibereko, mhando dzakawanda dzemasero ekenza hazvigone kuita shanduko dzinogona kubvumira kupona muzvakakwana-zvisingakoshi uye zvakashata zvinokonzerwa nekubatana kwekutsanya uye chemotherapy , Semuyenzaniso. Kuongorora kwepakutanga mukenza webonde, maranoma uye glioma masero akawana kuwedzera kunoshamisa kwekutaura kwemajeni anowedzera-kufanana kana kuti ribosome biogenesis uye magemu emagungano mukupindura kutsanya11,12. Kuchinja kwakadaro kwaifambidzana neAxpected AKT uye S6K kushandiswa, ruzivo rwekuita ROS uye DNA kukanganisa uye kukurudzira kusvika kune DNA-zvinodhaka zvinodhaka (via DSS) 11.

Tinofunga nezvekusaita kwakadaro kusina kukodzera kwemasero emukenza kumamiriro akashandurwa kusanganisira kuderedza kweGIF1 uye mazinga eaglucose anokonzerwa nekutsanya kana maMMM sechinhu chikuru chinoita kuti antitumour zvimiro zveaya mapindiro ezvekudya uye kugona kwavo kugona kupatsanura mhedzisiro yemishonga yekurapa nekenza pane zvakajairika maringe nemaseru akaipa11,12 (Fig. 1). Zvinoenderana neiyo DSS hypothesis, nguva nenguva yekutsanya kana maMFM akakwana kudzora kukura kwemarudzi mazhinji tumarara masero, kubva kune yakasimba tumarara maseru maseru kusvika kune lymphoid leukemia maseru, mune mbeva uye, zvakanyanya kukosha, kukurudzira maseru ekenza kune chemotherapeutics, radiotherapy uye tyrosine kinase inhibitors (TKIs) 11,17,22,25,50,54-57,59,60,124,127,128, XNUMX.

Nokuderedza kuwanikwa kweglucose uye kuwedzera mafuta asidi? -Oidation, kutsanya kana maMFM anogona kusimudzira switch kubva kuaerobic glycolysis (Warburg mhedzisiro) kune mitochondrial oxidative phosphorylation mumasero ekenza, izvo zvinodikanwa mukuchengetedza cancer maseru kukura munzvimbo ine huturu-isina hurombo 50 (Mufananidzo 2). Iyi switch inotungamira mukuwedzera ROS kugadzirwa11 semhedzisiro yekuwedzera mitochondrial yekufema chiitiko uye inogona zvakare kusanganisira kudzikiswa kwemaseru redox kugona nekuda kwekudzikira kwe glutathione synthesis kubva kune glycolysis uye iyo pentose phosphate nzira50. Iyo yakasanganiswa mhedzisiro yeROS yekuwedzera uye yakadzora antioxidant dziviriro inowedzera kushushikana kweiyo oxidative mumasero ekenza uye inowedzera chiitiko chechemotherapeutics. Zvinonzwisisika, nekuti chiitiko chepamusoro cheglycolytic chinoratidzirwa neakakwira-lactate kugadzirwa kunofungidzira kwehasha uye metastatic propensity mumhando dzinoverengeka dzekenza129, iyo inopesana neWarburg mhedzisiro yekutsanya kana FMD ine mukana wekunyanya kushanda pakurwisa cancer uye ine metastatic cancer.

Kunze kwekuchinja kwemasabetism, kutsanya kana maMMM anoita zvimwe zvigadzidzo zvinogona kukurudzira DSS mumasero ekenza yepancreatic. Kutsanya kunowedzera mazwi ekutaura kuenzana nucleoside mutakuri 1 (ENT1), mutakuri wegemcitabine kuyambuka membrane yeplasma, zvichitungamira mukuvandudza chiitiko cheichi chinodhaka128. Mumasero ekenza yemazamu, kutsanya kunokonzeresa SUMO2-mediated uye / kana SUMO3-yakagadziriswa modhiyo yeREV1, DNA polymerase uye p53-inosunga protein127. Iko kushandurwa kunodzora kugona kweREV1 kutadzisa p53, zvichitungamira mukuwedzera p53-yakagadziriswa kunyorwa kwema pro-apoptotic majini uye, pakupedzisira, kune cancer cancer demise (Fig. 2). Kutsanya kunowedzerawo kugona kweanowanzo kupihwa maTKI kumisa cancer cancer kukura uye / kana kufa nekusimbisa MAPK kuisa chiratidzo inhibition uye, nekudaro, kuvharidzira E2F kudhindisa chinhu-inoenderana geni kutaura asiwo nekuderedza glucose kutora 17,54.

Pakupedzisira, kutsanya kunogona kukonzera reptor leptin uye pasi kwayo chiratidzo kuburikidza neprotein PR / SET dura 1 (PRDM1) uye nekudaro inodzivisa kutanga uye kudzosera kufambira mberi kweB cell uye T cell acute lymphoblastic leukemia (ALL), asi kwete yechirungu chechimiro leukemia (AML) 55. Sezvineiwo, ongororo yakazvimiririra yakaratidza kuti B maseru epamberi anoratidza mamiriro ekurambidzwa kusingaperi muglucose nemagetsi zvinopihwa nezvakanyorwa zvinhu PAX5 uye IKZF1 (ref. 130). Shanduko mumageneti anonongedza aya mapuroteni, ayo aripo anopfuura makumi masere muzana ezviitiko zvepamberi-B maseru ZVESE, zvakaratidzwa kuwedzera kutora kweglucose uye mazinga eATP. Nekudaro, kugadzirisazve PAX80 uye IKZF5 mu preB-ese maseru kwakatungamira kune dambudziko remagetsi uye kufa kwesero. Kutorwa pamwechete pamwe nekudzidza kwakapfuura, iri basa rinoratidza kuti VOSE vanogona kutarisisa kunovaka muviri uye simba rekumanikidzwa rinoiswa nekutsanya, pamwe zvichimiririra mukiriniki akanaka kukwikwidza kuyedza kushanda kwekutsanya kana FMD.

Sezvineiwo, zvingangoita kuti mazhinji maseru emukenza maseru, anosanganisira AML29, anogona kuwana kushora nekudzivirira iyo metabolic shanduko inoiswa nekutsanya kana maMFM, mukana uyo unowedzerwa nekuwedzera kwehutachiona hwehutachiona hunoratidzira vazhinji kanzira129. Nekudaro, chinangwa chakakura chenguva yemberi iri padyo ichave yekuziva mhando dzekenza dzinonyanya kubatwa neaya madhimoni edhayeti kuburikidza nema biomarkers. Kune rimwe divi, kana zvabatanidzwa nemushonga wakajairika, kutsanya kana maMMM hazviwanzo kukonzera kuwanikwa kwekurwisa mukenza mbeva modhi, uye kuramba kwekutsanya kwakabatana nekemotherapy zvakare hakuwanzo muzvidzidzo mu vitro, ichiratidza kukosha kwekuziva marapirwo ayo, kana ichibatanidzwa neFMDs, zvinoguma zvine simba zvine chekuita nekenza maseru ane huturu hushoma kune akajairwa maseru uye matissue11,17,50,55 57,59,124.

Antitumour Immunity Kuvandudzwa nekutsanya kana FMD

Dzakaitika pfupi yapfuura zvinoratidza kuti kutsanya kana maMFM pachavo, uye kusvika pamwero mukuru kana uchibatanidzwa nekemotherapy, kunokonzera kuwedzera kwevatachiona ve lymphoid uye kukurudzira tumarara immune immune kuburikidza nenzira dzakasiyana25,56,60,124. FMD yakadzora kutaura kwe HO1, puroteni inopa chengetedzo kubva kukuvara kweiyo oxidative uye apoptosis, mumasero ekenza mu vivo asi yakasimudza HO1 kutaura mumaseru akajairwa124,131. HO1 kudzikisira mumasero emukenza inopindirana neFMD-inosimudzira chemosensitization nekuwedzera CD8 + bundu-rinopinda mukati lymphocyte-inoenderana cytotoxicity, iyo inogona kuve inofambiswa ne kudzikisira kwekutonga T masero124 (Fig. 2). Chimwe chidzidzo, chakasimbisa kugona kwekutsanya kana maMFM uye CR mimetics yekuvandudza anticancer immunosurveillance, zvinoreva kuti anticancer mhedzisiro yekutsanya kana maMFM anogona kushanda kune autophagy inokwanisa, asi kwete yekuzvimba-isina kukwana, kanzira56. Chekupedzisira, ongororo ichangoburwa yekutsanya-kwemazuva-kutsanya kwemavhiki maviri mune mbeva kenza yemakonzo modhi yakaratidza kuti, nekumisikidza autophagy mumasero ekenza, kutsanya kunodzora kutaura kweCD2 uye nekudaro kunodzora kugadzirwa kwemunosuppressive adenosine nekenza maseru73. Pakupedzisira, CD60 kudzora kwepasi kuburikidza nekutsanya kwakaratidzwa kudzivirira macrophage switch kune M73 immunosuppressive phenotype (Fig. 2). Pahwaro hwezvidzidzo izvi, zvinokatyamadza kufungidzira kuti maMFM anogona kunyanyobatsira pachinzvimbo kana mukubatana ne immune checkpoint inhibitors2, majekiseni emukenza kana zvimwe zvinodhaka zvinokurumidza antitumour kudzivirira, kusanganisira mamwe maitiro echemirochemrapeutics133.

Anticancer Zvokudya muMouse Models

Pakazara, mhedzisiro yezvidzidzo zvemberi zvekutsanya kana maMMM mune mhando dzemukenza yemhuka, kusanganisira mamodheru ekenza yemastastatic (Tafura 2), inoratidza kuti kutsanya kwenguva nenguva kana maMMMs anowana mhedzisiro yeanticancer anticancer mhedzisiro uye inogona kuita chiitiko chemhemotherapeutics uye maTKI apo uchipa simba rekudzivirira uye rekuvandudza. mune dzakawanda nhengo22,25. Kuzadzikisa mhedzisiro yakafanana pasina kutsanya uye / kana maMMM zvaizoda kutanga kuzivikanwa uyezve kushandiswa kwemazhinji anoshanda, anodhura uye anowanzo kuve nemishonga ine chepfu uye angangove asina mukana wekudzivirira hutano hwakanaka hwemasero. Zvinokosha kuti mune zvidzidzo zviviri zvinotsanya pamwe chete nemakemikari zvakaratidza kuti ndiko chete kupindira kunokwanisa kuzadzikisa bundu rakazara kana kupona kwenguva refu muchikamu chakaenzana chemhuka dzakarapwa11,59

Chronic KDs inoratidzawo a tumarara kukura-kunonoka kushanda kana uchishandiswa se monotherapy, kunyanya mukenza kenza mbeva mhando 77,78,80 82,84,134. Gliomas mumakonzo akachengetedzwa pane isingagumi KD akaderedza kutaura kweiyo hypoxia marker kabhoni anhydrase 9 uye ye hypoxia-inducible factor 1?, Yakaderedza nyukireya factor-? B activation uye yakadzora vascular marker expression (ndokuti vascular endothelial kukura factor receptor 2, matrix metalloproteinase 2 uye vimentin) 86. Mune isingabvumirwe mbeva modhi yeglioma, mbeva dzakapa KD kuratidzwa kwakawedzera tumor-reactive innate uye adaptive immune mhinduro dzainyanya kupindirana neCD8 + T masero79. KDs dzakaratidzwa kuvandudza mashandiro e carboplatin, cyclophosphamide uye radiotherapy muglioma, kenza yemapapu. uye neuroblastoma mbeva mhando73-75,135. Uye zvakare, ongororo ichangoburwa inoratidza kuti KD inogona kubatsira zvakanyanya pamwe chete nePI3K inhibitors72. Nekudzivirira insulin chiratidzo, ava vanokurudzira kuparara kweglycogen muchiropa uye kudzivirira glucose kuwanikwa mumusana wemasaga, izvo zvinotungamirira kune nguva hyperglycaemia uye kune inobhadharisa insulin kuburitswa kubva mupancreas (chiitiko chinozivikanwa se insulin feedback ). Nekudaro, izvi simudza mune insulin mazinga, ayo anogona kutapurika, kunyanya kune varwere vane insulin kudzvinyirira, inogadzirisazve PI3K mTOR chiratidzo in matumbo, nokudaro nekudzivirira zvakasimba kubatsirwa kwePI3K inhibitors. A KD yakaratidzwa kuva yakabudirira zvikuru pakudzivirira insulin mhinduro mukupindura kwemishonga iyi uye kusimbisa zvakasimba basa ravo rekuita basa mumushonga. Pakupedzisira, maererano nekuongorora mune murine tumor-induced cachexia model (MAC16 tumor), KDs inogona kubatsira kudzivirira kurasikirwa kwemafuta uye kusina mafuta mumuviri muvarwere vane cancer85.

CR yakadzora tumorigenesis mune geneti mbeva kenza mamodheru, mbeva modhi ane otomatiki tumorigenesis uye carcinogen inokonzera kenza mbeva modhi, pamwe nematsoko91,92,97,98,101,102,104-106,108,109,136-138. Kupesana, chidzidzo chakawana kuti CR kubva pakati pezera repakati inowedzera chiitiko cheplasma maseru neoplasms muC57Bl / 6 mice139. Zvisinei, muchidzidzo chimwe chete, CR yakawedzera hupenyu hwakareba neinosvika gumi neshanu muzana, uye kuwedzera kwakacherechedzwa kenza chiitiko kwakakonzerwa nekuwedzera kwehurefu hwemakonzo ari kuita CR, zera iro kuora-tora mbeve dziri kupinda CR dzakafa uye chikamu che kuora-tora mbeve dziri kupinda CR dzakafa. Nokudaro, vanyori vakapedzisa kuti CR inogona kunge ichidzorera kukurudzira uye / kana kufambira mberi kwekenza yekenza lymphoid. Meta-kuenzanisa chirevo chisingakoshi CR neC intermittent CR maererano nekukwanisa kwavo kudzivirira kenza mumakiritsi yakagumisa kuti mukati reR CR inonyanya kuve muine genetically engineered mouse mararamiro, asi hazvina kubudirira mumakemikari anokonzerwa nemakwenzi maZXXMUMX. CR yakaratidzwa kunonoka tumarara kukura uye / kana kuti kuwedzera kupona kwemapundu mumarudzi akasiyana-siyana emukenza mhando, kusanganisira ovarian uye pancreatic cancer140,94 uye neuroblastoma81.

Zvinonyanya kukosha, CR yakagadzirisa basa reanticancer kurapwa mukenza yakasiyana-siyana, kusanganisira basa re antiIGF1R antibody (ganitumab) rinorwisa kenza ye prostate141, cyclophosphamide inopesana neuroblastoma masero135 uye autophagy inhibition mujenografts yeHRAS-G12Vtransformed immortal baby mouse zvipembenene epithelial cells100. Zvisinei, CR kana kuti KD yakabatana nemishonga yekurapa inoratidzika seisingabatsiri kupfuura kutsanya. Chidzidzo chekutsvaga chakawana kuti, kusiyana nekutsanya oga, CR chete haikwanise kuderedza kukura kwekuwedzera kwechidiki GL26 mouse gliomas uye kuti, zvakare, kusiyana nekutsanya kwenguva pfupi, CR haina kuwedzera cisplatin basa ne subcutaneous 4T1 muchifuva tumours51. Muchidzidzo chakafanana, kutsanya kwakaratidzawo kuti kwakabudirira zvikuru kupfuura CR uye KD pakuwedzera kubvumira kwe doxorubicin51. Kunyangwe kutsanya kana FMD, CR uye KD inogona kunge yakagadzirisa uye inogadzirisa chiratidzo nzira, kutsanya kana FMD zvinogona kunge zvinokanganisa nzira dzakadaro nenzira yakanyanyisa panguva yakaoma chikamu chekuwedzera kwemazuva mashoma.

Chikamu chekudzorera zvingadaro nyasha kugadziriswa kwe-homeostasis yemuviri wose asiwo kushandisa uye kukurudzira nzira dzinogona kukurudzira kuzivikanwa nekubviswa kwe tumarara uye kuchinjazve masero ane utano. CR uye KD inopindira inogona kugadzirisa zvishoma nezvishoma kugadzirisa-kunzwisa nzira, zvichida pasina kusvika kune zvikamu zvakakosha zvakakosha kuvandudza migumisiro yemishonga inorwisa mishonga, panguva yekuisa mutoro unorema uye kazhinji kuwedzera kurasikirwa kwemahombekombe. CR uye KD sezvokudya zvinogara zvisingagumi kune vanorwara nekenza zvakaoma kushandisa uye zvinogona kutakura ngozi dzehutano. CR ingangodaro inotungamirira mukurashikirwa kwakanyanya kwemuviri wepachionda uye kuderedza steroid hormone uye pamwe nekudzivirira muviri142. Chronic KDs inobatanidzawo zvakafanana kunyange zvisinei nemigumisiro yakaoma143. Nokudaro, nguva yekutsanya uye mafomu emagetsi anogara asingapfuuri kwemazuva 5 anoshandiswa pamwe chete nemishonga yakawanda ine mikana yakakosha yekuvandudza kurapwa kwekenza panguva yekuderedza migumisiro yaro. Zvinonzwisisika, zvichave zvakakosha kudzidza chiitiko chekubatanidzwa kwe periodic FMDs, isingaperi KDs uye maitiro ekurapa, kunyanya mukurapa kwekenza dzine utsinye seglioma.

Kutsanya uye maMFM muChancer Prevention

Zvidzidzo zveEpidemiological uye zvidzidzo mumhuka, kusanganisira monkeys108,109,144, uye vanhu vanokweretesa kune pfungwa yokuti chitubu CR uye nguva yekutsanya uye / kana FMD inogona kuva nekenza-inodzivirira migumisiro yevanhu. Kunyange zvakadaro, CR haikwanise kushandiswa muhuwandu hwevanhu zvichienderana nehutano hwekuteerera uye kune zvingave nemigumisiro115. Nokudaro, nepo humwe humwe humwe humwe hunoti humwe hutano hunofanirwa hunodiwa (kana kuti hudzivise) uyewo mararamiro ekurudziro kuderedza chirwere chekenza chinotanga kuumbwa6,8,9,15, chinangwa chazvino ndechekucherechedza uye, zvichida, kuenzanirana zvakanaka zvakarambidzwa, nguva dzemazuva ezvekudya zvekudya zvakaderera kana kwete migumisiro uye kuongorora kenza-kudziviririra kushanda muzvidzidzo zvekliniki.

Sezvakakurukurwa pekutanga, mafungiro emagetsi anokonzera kuderedzwa kweGF1 uye glucose uye kuregererwa kweGGBBP1 nemitumbi yeketone, iyo inoshanduka yakafanana neyo inokonzerwa nokutsanya pachayo uye inoshandiswa kwekutsanya mhinduro22. Apo C57Bl / 6 mice (iyo inowanzobudirira matumbo, zvikurukuru lymphomas, sezvavanenge vava nemakore) vakafambisa FMD yakadaro kwemazuva 4 kaviri pamwedzi kubva pamakore emakore uye kudyidzana kwekudya kwemaidhi munguva iyo iri pakati peMFM, maitiro emapupa akasimudzwa kubva kunenge 70% mumashonga ari kutonga kudya kune anenge 40% mumakonzo muboka reMFD (rinowanikwa 43% kuderedza) 22. Mukuwedzera, iyo FMD yakasarudzwa nemwedzi inopfuura 3 kuitika kwekufa kwevana vasina kufanana, uye nhamba yemhuka ine zvipembenene zvisingawanzoshandiswa yakanga inopfuura katatu yakakwirira muboka rekutonga kupfuura mumashamba eFMD, zvichiratidza kuti vazhinji matumbo muMFD mice dzakanga dzisinganyanyi kurwisana kana kushaya bongo.

Chimwe chekutanga chekutsanya-zuva rokutsanya, iro rakaitwa pakati pemakwikwi epakati-kati kwemwedzi ye4, rakaonawo kuti kutsanya kwakaderedza kuitika kwe lymphoma, kuitora kubva ku33% (yekudzora mice) ku 0% (mukutsanya mhuka) 145, kunyange zvazvo nekuda kwenguva pfupi yekudzidza hazvizivikanwe kana iri regimiro yekutsanya inodzivirirwa kana kungoita kunonoka tumarara kutanga. Uyezve, kushandiswa kwezuva-zuva kunotora mazuva 15 pamwedzi wekutsanya kwakakwana kwemvura-chete, asi mukuedza kweMFM kunotsanangurwa pamusoro apa makonzo akaiswa pazvokudya zvakapa zvokudya zvishomanana kwemazuva 8 chete pamwedzi. Mune vanhu, 3 maitiro eFMF-day FMD kamwechete pamwedzi yakaratidzwa kuderedza kuderera kwepamuviri uye zviratidzo zvekuputika uye IGF5 uye mazinga eglucose muzvidzidzo nezvikamu zvakakwirira zvezviratidzo izvi1, zvichiratidza kuti kushandiswa nguva nenguva kweMFD kunogona kunge zvinodzivirira zvinokonzerwa nokuora-zvakabatana kana kuputika-zvine chokuita, asiwowo dzimwe, kanzira dzevanhu, sezvakaratidzwa mice62.

Nokudaro, zviitiko zvinokuvadza zvezvidzidzo zvekudzivirira zvinosanganiswa nekliniki data pamusoro pemigumisiro yeFMD pangozi zvinhu zvinowanikwa aging-associated zvirwere, kusanganisira cancer62, kukweretesa rubatsiro mune ramangwana rezvidzidzo zveMFMs sechinhu chinogona kushandiswa kudzivirira kenza, pamwe chete nezvimwe aging-associated zvisingaperi, mumunhu.

Clinical Applicability in Oncology

Zvidzidzo zvina zvekutsanya uye maMFM muvarwere vanopinda chemotherapy vakabudiswa sezuva ranhasi52,53,58,61. Mune imwe nyaya yevarwere ve10 vanorwara nemhando dzakasiyana-siyana dzekenza, kusanganisira mazamu, prostate, ovarian, chibereko, chirwere chepapu uye oesophageal, avo vakatsanya kudya kusvika ku140hours vasati vasvika uye / kana kusvika ku56hours vachitsvaga chemotherapy, pasina migumisiro mikuru inokonzerwa nokuzvitsanya pachavo kunze kwekuzara nenzara uye kuchena kwemavara kwakaparidzwa58. Varwere ivavo (vatanhatu) vakawana chemotherapi uye vasina kushanya vakaratidza kuderedza kuderedza kuneta, kushaya simba uye kwepamusoro kwezviitiko zvinotambudza panguva yekutsanya. Mukuwedzera, kune avo varwere umo kufambira mberi kwekenza kunogona kuongororwa, kutsanya hakuna kubvumira chemotherapy-kunokonzerwa kuderedzwa mumatomu yevhesi kana mumaronda. Mune rumwe ruzivo, vakadzi vechi13 vane HER2 (inozivikanwawo seEERBB2) yakaipa, chirwere chepachipiri II / III chepachifu chebonde chinogamuchira neo-adjuvant taxotere, adriamycin uye cyclophosphamide (TAC) chemotherapy yakashandurwa kutsanya (mvura chete) 24hours vasati vatanga chemotherapy kana kuti kune chikafu maererano nemitemo yakazara52.

Kutsanya-kwenguva pfupi kwaive kwakatsungirirwa zvakanaka uye kwakadzora kudonha mune zvinoreva erythrocyte uye thrombocyte kuverenga mazuva manomwe mushure memakemikari. Sezvineiwo, muchidzidzo ichi, iwo mazinga e? -H7AX (mucherechedzo wekukuvara kweDNA) yakawedzerwa maminetsi makumi matatu mushure memakemikari mumalukocyte kubva kuvarwere vasina kutsanya asi kwete kuvarwere vaitsanya. Muchidimbu kukura kwekutsanya mune varwere vari kurapwa platinum-based chemotherapy, makumi maviri evarwere (avo vainyanya kurapwa kurapwa kweiyo urothelial, ovarian kana kenza yemazamu) vakasarudzika kutsanya kwe2, 30 kana 20hours (yakakamurwa se24hours pamberi chemhemotherapy uye 48hours mushure mekemotherapy. 72. Maitiro ekugona (anotsanangurwa sezvikamu zvitatu kana kupfuura kubva pazvitanhatu zvidzidzo muboka rega rega rinodya? 48kcal pazuva panguva yekutsanya pasina kuwandisa huturu) zvakasangana. Kutsanya kwakabatana nekutsanya vaigara vaine gorosi 2 kana kuti pasi, iyo inowanzova kuva kuneta, kuora musoro uye chizoro. Sezvakaitwa mune zvekare, kuderedza DNA kuipa (sezvakaonekwa na comet assay) mu leukocytes kubva kune avo vakatsanya kusvika 48hours (kana vachienzaniswa nevaya vaizvinyima nokuda kwe24hours chete) vanogona kuonekwawo mumuedzo uyu muduku. Mukuwedzera, chimwe chinhu chisingaiti chekuita nechepakati peklasi 3 kana gorosi 4 neutropenia kune varwere vakatsanya nokuda kwe48 ne72hours pamwe neavo vakatsanya nokuda kwe24hours chete vakanyorwa zvakare.

Munguva ichangopfuura, chirongwa chekliniki chakakonzerwa nemaitiro chakashandiswa kuongorora migumisiro yeFMD pamusoro pehupenyu hwehupenyu uye nemigumisiro yechemotherapy mune vose varwere ve34 vane kenza yemazamu kana ovarian61. I-FMD yakave ye zuva nezuva caloric kudya kwe <400kcal, kunyanya nemajusi nemabhurosi, kutanga 36-48hours isati yatanga chemotherapy uye inogara kusvika makumi maviri nemana maawa apera chemotherapy. Muchidzidzo ichi, iyo FMD yakadzivirira iyo chemotherapy inokonzeresa kudzikiswa kwehupenyu hwehupenyu uye zvakare yakaderedza kuneta. Zvakare, hapana zviitiko zvakakomba zvakashata zveFMD zvakataurwa. Mamwe akati wandei emakiriniki ekuedzwa kweMMFs akabatana nekemotherapy kana nemamwe marudzi emishonga yekurapa irikuenderera mberi kuzvipatara zveUS neEuropean, kunyanya kune varwere vanoonekwa kuti vane cancer kana yeprostate cancer24-63,65. Iyi ingangove ruoko-rwechipatara kiriniki kuongorora FMD kuchengetedzeka uye kugona kana kusarongeka makiriniki ekuongorora anotarisana nemhedzisiro yeFMD pane huturu hwechemotherapy kana pahunhu hwehupenyu hwevarwere panguva yekemotherapy pachayo. Pamwe chete, izvi zvidzidzo zvave kunyoresa pamusoro pevarwere mazana matatu, uye mhedzisiro yavo yekutanga inotarisirwa kuwanikwa mu68.

Matambudziko muThe Clinic

Kuongorora nguva yekutsanya kana yeMFDs muincology haisi yekushungurudza, kunyanya maererano nekukwanisa kuti rudzi urwu rwezvokudya zvinogona kukonzera kusadya, kudya, sarcopenia, uye cachexia mune vakafanorongerwa kana vasina kusimba varwere (semuenzaniso, varwere vanovandudza anorexia semhedzisiro yekemotherapy) 18,19. Nekudaro, hapana zviitiko zveakakomba (pamusoro pegiredhi 3) kurasikirwa uremu kana kwekushomeka kwezvakakwana zvakataurwa muzvidzidzo zvekiriniki zvekutsanya pamwe nekemotherapy yakaburitswa sezvazvino, uye avo varwere vakawana kurasikirwa nekurema panguva yekutsanya kazhinji vakadzorera huremu hwavo pamberi pe inotevera kutenderera pasina kukuvara kunoonekwa. Zvakangodaro, isu tinokurudzira kuti nguva nenguva anorexia uye hutano mamiriro ekuongorora uchishandisa nzira dzegoridhe-dzakasarudzika18,19,146 should150 inofanirwa kuve chikamu chakakosha chedzidzo idzi uye kuti chero chinotevera chinokanganisa hutano kune varwere vari kutsanya uye / kana maMFM chinogadziriswa nekukurumidza.

mhedziso

Nguva nenguva yekutsanya kana maMMM anogara achiratidza zvine simba anticancer mhedzisiro mune mbeva kenza mhando kusanganisira kugona kugona chemoradiotherapy uye TKIs uye kukonzera anticancer immune. MaMFM macircuit anokwanisika kupfuura echinyakare madhayeti ezvekudya nekuti anotendera varwere kuti vadye chikafu nguva dzese panguva yeFMD, chengetedza chikafu chinowanzoitika pakati pemakomba uye hachigumisi pakurasikirwa zvakanyanya nekurema uye pamwe zvinokanganisa masisitimu ekudzivirira uye endocrine. Sezvineiwo, seyakazvimirira marapirwo, kutsanya nguva nenguva kana maMMM macircule angangotaridza kushanda kwakaringana pamusoro pemamota akasimba. Muchokwadi, mumakonzo, kutsanya kana maMMM anokanganisa kufambira mberi kwecancer yakati wandei zvakafanana nekemotherapy, asi voga, havawanzo fananidza mhedzisiro inowanikwa pamwe chete nekenza zvinodhaka izvo zvinogona kukonzeresa kuti murarame-musina gomarara11,59. Nekudaro, isu tinokurudzira kuti iko kusanganisa kwe periodic FMD kutenderera nematanho akajairika ayo ane mukana wepamusoro wekusimudzira kupona-kusina gomarara muvarwere, sezvakakurudzirwa nemhando dzemakonzo11,59 (Fig. 3).

Iko kusanganiswa kunogona kunge kwakanyanya kune zvikonzero zvakasiyana-siyana: kutanga, kenza yemishonga uye dzimwe nzira dzokurapa zvinogona kubudirira, asi chikamu chevarwere hazvipinduri nokuti kenza yemasera inotora dzimwe nzira dzinoshandiswa mumagetsi dzinotungamirira pakupona. Aya maitiro emamwe emagetsi anoshandiswa zvakanyanya kuoma kuchengetedza pasi nekutsanya kana ma FMD nekuda kwekushayikwa kana kuchinja kweglucose, mamwe amino acids, mahomoni, uye kukura zvinhu, uyewo mune dzimwe nzira dzisingazivikanwi dzinotungamirira kusero kufa. Chechipiri, kutsanya kana maMMM anogona kudzivirira kana kuderedza kushandiswa kwekusagadzikana. Chechitatu, kutsanya kana maMMM anochengetedza masero akare uye nhengo kubva pamigumisiro inokonzerwa nemhando dzakasiyana-siyana dzekenza zvinodhaka. Pachikonzero chekutarisa uye kuchipatara uchapupu hwekugona, kuchengeteka uye kubudirira (pakuderedza IGF1, mafuta e-visceral uye mishonga yemwoyo inokonzera ngozi), FMDs inoratidzika seyakakodzera kudya nzira yekudzidza mukudzivirira kenza. Chinhu chinokosha mune ramangwana chichava chekuziva avo matumbo iyo ndiyo yakanakisisa inobvumirwa kubatsirwa nekutsanya kana maMMM. Kunyangwe mumaronda emukenza izvo zviri pachena kuti hazviregi kuteerera kana kutsvaga maMMM, zvinogona kunge zvichigoneka kuziva zvirongwa zvekudzivisa uye kupindira nemishonga inokwanisa kugadzirisa kusagadzikana. Zvimwe, kuchenjerera kunofanira kugamuchirwa nemamwe marudzi ezvokudya, kunyanya kana yakakwirira mumakirori, sezvo zvaigona kutungamirira kuwedzerwa uye kwete kuvharwa kukura yevamwe kanzira. Somuenzaniso, KD inowedzera kukura yemuenzaniso we melanoma wakashandurwa BRAF mu mice123, uye yakaudzwa zvakare kukurumidza kufambira mberi kwezvirwere mumushonga AML model72.

Uyezve, zvakakosha kushandisa maDMD nekunzwisisa nzira dzekuita, kubva pakuita kwavo kana kushandiswa zvisina kururama zvinogona kuunza zvakaipa zvakaipa. Semuenzaniso, apo makonzo akazvinyima uye achibatwa nekemikari yakasimba vasati vashandura, izvi zvakaguma nekukura kwemafi anogara muropa, koni uye rectum kana ichienzaniswa neasina kutsanya151,152. Kunyange zvazvo nzira dzakabatanidzwa mune izvi zvisinganzwisiswi, uye idzi fokisi dzingave dzisina kuitika matumbo, izvi zvidzidzo zvinoratidza kuti nguva shoma ye24-48hours pakati pemakemikari kurapwa kurapwa uye kudzoka kune zvakajairwa kudya kwakakosha kudzivirira kusanganisa iyo regrowth zviratidzo zviripo panguva yekudzoreredza mushure mekutsanya nemazinga akakwirira emishonga ine chepfu senge chemotherapy. Iwo makiriniki ezvidzidzo zvekutsanya kana FMD mune varwere vari kurapwa chemotherapy tsigiro kugona kwayo uye kwakazara kuchengetedzeka52,53,58,61. Mune diki-saizi yakasarudzika muyedzo yakanyoresa varwere makumi matatu nemana, FMD yakabatsira varwere kuchengetedza hupenyu hwavo panguva yekemotherapy uye kuderedzwa kuneta34. Uye zvakare, yekutanga data inoratidza kugona kwekutsanya kana maMFMs kudzikisa chemotherapy induced DNA inokuvara mumasero ane utano muvarwere52,53.

Kuenderera mberi kwezvidzidzo zvekiriniki zveMMMs kune varwere vane gomarara63,65-68 ichapa mhinduro dzakasimba dzekuti kunyora nguva nenguva maMFM pamwe neanowanzoitwa anticancer vamiririri kunobatsira kugadzirisa kushivirirana uye chiitiko chekupedzisira. Izvo zvakakosha kuti utarise kuti maMFM haazove anoshanda mukuderedza mhedzisiro yekurapa kenza mune vese varwere uye zvakare havazoshanda kuvandudza kushanda kweese marapirwo, asi vane mukana wakakura wekuzviita zvirinani kwechikamu uye pamwe kwechikamu chikuru chevarwere uye zvinodhaka. Vakasviba kana vasina kudya zvinovaka muviri varwere kana varwere vari panjodzi yekushaya kudya zvinovaka muviri havafanirwe kunyoreswa muzvidzidzo zvekiriniki zvekutsanya kana maMMM, uye chimiro chevarwere chekudya uye anorexia inofanirwa kuongororwa zvakaringana mumakiriniki ekuedzwa. Anokodzera kudya mapuroteni, anokosha mafuta akawanda, mavitamini uye maminerari akabatanidzwa, kana zvichibvira, neine chiedza uye / kana kuti zvishoma nezvishoma basa rinoita kuti kuwedzera musuru uremu inofanira kushandiswa pakati pekutsanya kana maMFD maitiro kuitira kuti varwere varambe vachichengetedza muviri hutano hwakanaka hukuru18,19. Iyi nzira yekudya yakakwana inowedzera zvakanakisisa zvekutsanya kana maMMM panguva imwe chete kudzivirira varwere kubva pakushaiwa zvokudya.

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