Ukuzila ukutya kunye neCarcer: Iinkqubo zeMolcular And Clinical Application

UAlessio Nencioni, uIrene Caffa, uSalvatore Cortellino kwaye UValter D. Longo

Thintela | Umngcipheko weeseli zomhlaza ekuphelekeni izondlo kunye nokuxhomekeka kwazo kwii-metabolites ezithile ziimpawu ezibonakalayo zomhlaza. Ukutya okukhawulezayo okanye okukhawulezayo okulinganisa ukutya (i-FMD) kukhokelela kuguquko olubanzi lwezinto zokukhula kunye namanqanaba e-metabolite, ukuvelisa iimeko ezinokunciphisa amandla eeseli zomhlaza ukuba zihlengahlengise kwaye ziphile kwaye oko kuphucula iziphumo zonyango lomhlaza. Ukongeza, ukuzila ukutya okanye i-FMD yonyusa ukumelana ne-chemotherapy ngendlela eqhelekileyo kodwa ingeyiyo iiseli zomhlaza kwaye ikhuthaze ukuvela ngokutsha kwezicubu eziqhelekileyo, ezinokunceda ukuthintela iziphumo ebezingalunganga nezinokubeka ubomi emngciphekweni. Ngelixa ukuzila kunganyamezeleki kwizigulana, zombini izilwanyana kunye nezifundo zeklinikhi zibonisa ukuba imijikelezo yeekhalori eziphantsi ze-FMD zinokwenzeka kwaye zikhuselekile ngokubanzi. Uvavanyo oluninzi lovavanyo lweklinikhi lokuvavanya isantya sokuzila okanye i-FMD kwimicimbi engentle eyonyukayo kunye nakwiziphumo ezifanelekileyo ziyaqhubeka. Sicebisa ukuba indibaniselwano yee-FMDs ngamachiza amayeza amayeza, unyango olungxamisekileyo okanye unyango olunye libonisa isicwangciso esithembisayo sokukhulisa ukusebenza kakuhle kwezonyango, ukuthintela ukufunyanwa komzimba kunye nokunciphisa iziphumo ebezingalindelekanga.

Ukutya kunye nezinto ezinxulumene nokuphila zizinto eziphambili ezichaphazela umngcipheko wokuhlaselwa ngumhlaza, kunye nomhlaza othile oxhomekeke kakhulu kwimikhwa yokutya kunabanye1�9. Ngokuhambelana nale mbono, ukukhuluphala kuqikelelwa kwi-akhawunti ye-14% ukuya kwi-20% yabo bonke abantu ababulawa ngumhlaza eUnited. I-States7, ekhokelela kwizikhokelo kwisondlo kunye nokusebenza komzimba ukunciphisa umngcipheko wokukhula Umhlaza6. Ukongeza, unikwe amandla okuvela kweeseli zomhlaza, kodwa hayi izihlunu eziqhelekileyo, ukungathobeli imiqondiso echasene nokukhula (ngenxa yeenguqulelo ze-oncogenic) izidlo ezithile ezinomda weekhalori nazo zinokuba yinxalenye yothintelo lomhlaza kwaye, mhlawumbi, kunyango lomhlaza njengendlela yokunyusa ukusebenza kunye nokunyamezelana kweearhente zomhlaza10 11,12.

Nangona kule minyaka ilishumi idlulileyo siye sabona utshintsho olungakhange lubekho kunye nenkqubela phambili kunyango lomhlaza14,15, kusekho isidingo esibaluleke ngakumbi kwaye, iindlela zonyango kuba amathumba kodwa kwakhona, kwaye kubaluleke kakhulu, ngeendlela zamacebo okunciphisa iziphumo ebezingalindelekanga zonyango lomhlaza15,16. Umcimbi weziganeko ezichasayo zonyango (i-TEAEs) sesinye sezona ngxaki ziphambili kwi-oncology15,16 yezonyango. Ngapha koko, uninzi lwezigulana ezinomhlaza zinamava amachaphaza amdaka kunye / okanye nexesha elide lonyango olunomhlaza, olunokuthi lufune isibhedlele kunye nonyango olunobukrakra (olunjengamayeza okubulala iintsholongwane, haematopoietic izinto zokukhula kwaye utofelo-gazi) kwaye luchaphazela kakhulu ubomi babo (umzekelo, ichemotherapyindended i-peripheral neuropathy) 16. Ke, iindlela ezifanelekileyo zokunciphisa ubuthi ziyalungiswa kwaye kulindeleke ukuba zibe nefuthe elikhulu kwezonyango, kwezentlalo nakwezomnotho15,16.

Ukunyanzela iiseli ezinempilo ukuba zingene kwicandelo elicothayo kunye nemo ekhuselweyo ebakhuselayo kwizithuko ezinobuthi ezivela kumachiza e-anticancer ngelixa beziva iintlobo ezahlukeneyo zeseli zomhlaza kwezi zonyango i -11,12,17. Oku kufunyaniswa kuthetha ukuba ungenelelo olulodwa lokutya lunokunceda ekujonganeni neenkalo ezahlukeneyo nezilinganayo zonyango lomhlaza.

Kule nqaku yeembono, sixoxa ngesimo sebhayoloji sokutya okanye sokulinganisa ukutya (ii-FMD) ukugcwala ii-TEAE kodwa sikhusela kunye nokunyanga umhlaza. Sikwabonisa imiqolomba yale ndlela yokuvavanya18,19 kunye nezifundo ezipapashiweyo neziqhubekayo apho kuye kwenziwa khona ukutya okanye ii-FMD kwizigulana ezinomhlaza.

Inkqubo yoPhulo lokuZila ukutya

Ukuzila ukutya kukhokelela kutshintsho emsebenzini weendlela ezininzi ze-metabolic ezinxulunyaniswa notshintsho kwimodi ekwaziyo ukuvelisa amandla kunye neemetabolism zisebenzisa imithombo yekhabhoni ekhutshwa ngokuyintloko kwizicubu zeadipose nakwinxalenye yomsipha. Utshintsho kumanqanaba okujikeleza kwehomoni kunye neemetabolites ziguqulela ekunciphiseni kwesahlulo seseli kwaye umsebenzi we-metabolic iiseli eziqhelekileyo kwaye ekugqibeleni zizikhusele kwizithuko ze-chemotherapeutic11,12. Iiseli zomhlaza, ngokungathobeli ii-anti-grow command ezichazwe yile meko yokufa yindlala, zinokuba nesiphumo esichaseneyo neseli eliqhelekileyo kwaye ke ngoko ziye ziveliswe kwi-chemotherapy kunye nolunye unyango lomhlaza.

Inkqubo yokuphendula ngokuKhawuleza

Impendulo ekuzileni ukutya yenziwa ngamanqanaba eswekile ye-glucose, i-insulin, iglucagon, i-hormone yokukhula (GH), IGF1, glucocorticoids kwaye adrenaline. Ngethuba lesigaba sokuqala sokungenisa, esihlala sihlala kwi-6 24hours, amanqanaba e-insulin aqala ukuhla, kunye namanqanaba eglucagon anyuka, ekhuthaza ukonakala kwevenkile zesibindi se-glycogen (ezigqityiweyo emva kweeyure ezingama-24) kunye nesiphumo sokukhutshwa kweswekile yamandla.

I-Glucagon kunye namanqanaba asezantsi e-insulin nawo akhuthaza ukonakala kwe-triglycerides (egcinwe ikakhulu kwizicubu ze-adipose) kwi-glycerol kunye ne-free fatty acids. Ngexesha lokuzila ukutya, uninzi lwezicubu zisebenzisa i-acid ye-eneji, ngelixa ingqondo ixhomekeke kwiswekile nakwimizimba ye-ketone eveliswa zii-hepatocytes (imizimba ye-ketone inokuveliswa kwi-acetyl-CoA eveliswe kwi-acid acid? -Ooxation okanye kwi-ketogenic amino acid). Kwinqanaba le-ketogenic lokuzila ukutya, imizimba ye-ketone ifikelela kumanqanaba e-millimolar, aqala emva kweentsuku ezi-2 3 ukusuka ekuqaleni kokuzila. Ngokudibeneyo ne-glycerol ethathwe ngamanqatha kunye neeamino acid, imizimba ye-ketone iphembelela i-gluconeogenesis, egcina amanqanaba eglucose koxinzelelo malunga ne-4mM (70mg nge-dl), esetyenziswa kakhulu yingqondo.

I-Glucocorticoids kunye ne-adrenaline nayo inegalelo kulungelelwaniso lwe-metabolic adaptation kuyo ukuzila ukudla, ukunceda ukugcina amanqanaba eswekile yegazi kunye nokukhuthaza i-lipolysis20,21. Ngokukodwa, nangona ukuzila ukutya kunokunyusa okwethutyana amanqanaba e-GH (ukunyusa i-gluconeogenesis kunye ne-lipolysis kunye nokunciphisa ukunyuka kwe-glucose), ukuzila ukutya kunciphisa amanqanaba e-IGF1. Ukongeza, phantsi kweemeko zokuzila, i-IGF1 imisebenzi yebhayoloji ithintelwe kwinxalenye yokwanda kwamanqanaba e-insulin-ukukhula ukukhula okubopha iprotein 1 (IGFBP1), ebophelela ukujikeleza i-IGF1 kwaye ithintele ukusebenzisana kwayo kunye ne-receptor22 yokuhambelana kweseli.

Okokugqibela, ukuzila ukutya kunciphisa amanqanaba okujikeleza i-leptin, ihomoni yenziwa ikakhulu yi-adipocytes ethintela indlala, ngelixa inyusa amanqanaba e-adiponectin, enyusa amanqatha e-acid aqhekezayo23,24. Ke, ukuqukumbela, iimpawu eziphambili zempendulo ye-mammaliic kwinkqubo yokuzila ukutya ngamanqanaba asezantsi eglucose kunye ne-insulin, amanqanaba aphezulu eglucagon kunye nemizimba yeketoni, amanqanaba asezantsi e-IGF1 kunye ne-leptin kunye namanqanaba aphezulu e-adiponectin.

Impendulo yeselfowuni kukuzila

Impendulo yeeseli esempilweni ekuzileni iyalondolozwa ngokwendalo kwaye inika ukhuseleko lweseli, kwaye ubuncinci kwimodeli yezinto eziphilayo, ibonakalisiwe ukuba inyuse ixesha lokuphila kunye ne-healthspan12,22,25-31. I-IGF1 uphawu Umdaniso isisitshixo uphawu Indlela ebandakanyekayo ekulamleni iziphumo zokuzila kwinqanaba leselula. Ngaphantsi kwesondlo esiqhelekileyo, ukusetyenziswa kweprotein kunye nokwanda kwamanqanaba e-amino acid anyusa amanqanaba e-IGF1 kwaye akhuthaze umsebenzi we-AKT kunye ne-mTOR, ngokwenyusa ukuhlanganiswa kweprotein. Ngokuchasene noko, ngexesha lokuzila ukutya, amanqanaba e-IGF1 kunye nokwehla komqondiso osezantsi, ukunciphisa ukuthintela okuphakathi kwe-AKT kwezinto ezikhutshelweyo ze-FOXO kunye nokuvumela ezi zinto zikhutshelweyo ukuba zisebenze zofuzo, ezikhokelela ekusebenziseni ii-enzymes ezinjenge-haem oxygenase 1 (HO1), superoxide dismutase ( I-SOD) kunye ne-catalase enemisebenzi ye-antioxidant kunye neziphumo zokukhusela Amanqanaba aphezulu eswekile akhuthaza iprotein kinase A (PKA) uphawu, elawula kakubi i-sensor energy sensor i-AMPK isebenze nge-proteni kinase (AMPK) 35, yona, ethintela ukubonakaliswa kwengcinezelo yokukhutshelwa kwento yokukhula kokukhula kweproteyini ye-1 (EGR1) (Msn2 kunye / okanye neMnn4 kwi-yegwele) 26,36 .

Ukuzila ukutya kunye nesithintelo se-glucose esithintela umsebenzi we-PKA, yonyusa umsebenzi we-AMPK kwaye wenze ukuba kusebenze i-EGR1 kwaye ngaloo ndlela kufezekiswe iziphumo zokukhusela iiseli, kubandakanya nezo zikwi-myocardium22,25,26. Okokugqibela, ukuzila ukutya kunye nee-FMD (jonga apha ngezantsi ngokwakhiwa kwazo) zikwanakho ukukhuthaza iziphumo ezivuselelayo (Ibhokisi 1) ziindlela zeemolekyuli, ezinye zazo ziye zachaphazeleka kumhlaza, njengokunyuka kwe-autophagy okanye ukwenziwa kwemisebenzi ye-sirtuin22,37-49 .

Iindlela zokutya kwizifo zomhlaza kwii-FMD

Iindlela zokutya esekwe ekuzileni okuye kwaphandwa kakhulu kwi-oncology, kokubini ngokungxamisekileyo naseklinikhi, kubandakanya ukuzila kwamanzi (ukuyeka konke ukutya neziselo ngaphandle kwamanzi) kunye nee-FMDs 11,12,17,25,26,50-60 (Itheyibhile 1). Idatha yokuqala yeklinikhi ibonisa ukuba ukukhawuleza okungenani kweeyure ezingama-48 kunokufuneka ukuba kufikelelwe kwiziphumo zeklinikhi ezinomdla kwi-oncology, njengokuthintela ukonzakala kwe-chemotherapy eyenzelwe i-DNA kwizicubu ezisempilweni kunye nokunceda ukugcina isigulane umgangatho wobomi ngexesha le-chemotherapy52,53,61.

Nangona kunjalo, uninzi lwezigulana ziyala okanye zinobunzima ekugqibeni ukuzila kwamanzi, kwaye umngcipheko onokubakho wekhalori eyandisiweyo kunye nokusilela kwemicronutrient okunxulumene nayo kunzima ukuyithethelela. Ii-FMD ziyilelwe ngurhulumente imilinganiselo yokutya ephantsi kakhulu kwiikhalori (Oko kukuthi, phakathi kwe-300 kunye ne-1,100kcal ngosuku), iswekile kunye neeproteni eziphinda zenze uninzi lweziphumo zokuzila ukutya kwamanzi kuphela kodwa ngokuthobela okungcono kwesigulana kunye nokunciphisa umngcipheko wesondlo22,61,62, 3. Ngexesha le-FMD, izigulana zihlala zifumana inani lamanzi elingathintelwanga, amancinci amancinci emifuno yemifuno, iisuphu, iijusi, ii-nut bar, kunye neetafic herbal, kunye nezongezo zemicronutrients. Kwisifundo seklinikhi semijikelezo yenyanga ye-5 yentsuku ye-1 ye-FMD kwizifundo ezisempilweni ngokubanzi, ukutya bekunyamezelwe kakuhle kwaye kuncitshiswe isiqu kunye namafutha omzimba xa ewonke, uxinzelelo lwegazi kunye namanqanaba e-IGF62. Kwiimvavanyo zeklinikhi zangaphambili kunye nokuqhubekayo, ukuzila ukutya okanye ii-FMDs bezilawulwa rhoqo kwiiveki ezi-3 4, umzekelo, ngokudibeneyo neerejimeni zekhemotherapy, kwaye ixesha labo liphakathi kweentsuku ezi-1 ukuya kwezi-5-52,53,58,61,63 . Ngokubalulekileyo, akukho ziganeko zibi kakhulu (inqanaba le-G68 okanye ngaphezulu, ngokwemiGaqo yesiGama esiQhelekileyo yeziganeko eziGwenxa) ezixeliweyo kwezi zifundo3.

Izidlo zeKetogenic

Ukutya kwe-Ketogenic (KDs) ziirejimeni zokutya ezinekhalori eqhelekileyo, amanqatha aphezulu kunye nomxholo we-carbohydrate omncinci69,70. Kwi-classical KD, umlinganiselo phakathi kobunzima bamafutha kunye nobunzima obudibeneyo be-carbohydrate kunye neprotheni yi-4: 1. Inqaku, ii-FMDs nazo zine-ketogenic kuba zinomxholo onamafutha aphezulu kwaye zinamandla okunyusa ukuphakama okukhulu (? 0.5mmol kwilitha nganye) kumanqanaba okujikeleza kwemizimba ye-ketone. Ebantwini, i-KD inokunciphisa i-IGF1 kunye namanqanaba e-insulin (ngaphezulu kwama-20% ukusuka kumaxabiso asisiseko), nangona ezi ziphumo zichaphazeleka ngamanqanaba kunye nohlobo lweecarbohydrate kunye neeprotein kwi-diet71. Ii-KDs zinokunciphisa amanqanaba eglucose egazini, kodwa zihlala zihlala kuluhlu oluqhelekileyo (Oko kukuthi,> 4.4mmol ilitha nganye) 71.

Ngokukodwa, ii-KDs zinokusebenza ngokuthintela ukwanda kweswekile kunye ne-insulin eyenzeka ngokufuthi ekuphenduleni kwi-PI3K inhibitors, eyayicetyisiwe ukunciphisa ukusebenza kwayo72. Ngokwesiko, ii-KDs bezisetyenziselwa ukunyanga isifo sokuwa, ngakumbi ebantwaneni69. Kwiimodeli zegundane, ii-KD zenza iziphumo ze-anticancer, ngakumbi kwi-glioblastoma70,72-86. Izifundo zeklinikhi zibonisa ukuba ii-KDs mhlawumbi azinayo imisebenzi yokunyanga xa zisetyenziswa njengeearhente ezingatshatanga kwizigulana ezinomhlaza kwaye zicebisa ukuba izibonelelo ezinokubakho zokutya kufuneka zifunwe ngokudityaniswa nezinye iindlela, ezinje ngechemotherapy, iradiotherapy, unyango lwe-antiangiogenic, PI3K inhibitors kwaye FMDs72,73.

Ii-KD zaxelwa ukuba zineziphumo ze-neuroprotective kwi-neripheral nerves nakwi-hippocampus87,88. Nangona kunjalo, kuya kuhlala kusekwe ukuba ii-KDs nazo zineziphumo ezinje ngokuzila ukutya okanye ii-FMDs (Ibhokisi 1) kunye nokuba ngaba ii-KDs zinokusetyenziselwa ukukhusela izilwanyana ezanyisayo kwizityhefu zekhemotherapy. Ngokukodwa, iziphumo ezivuselelayo zokuzila ukutya okanye ii-FMDs zibonakala ngathi zandiswa ngotshintsho olusuka kwindlela yokuphendula yindlala, ebandakanya ukwehla kwezinto zeselfowuni kunye nokufa kweeseli ezininzi, kunye nexesha lokutya kwakhona, apho iiseli kunye nezicubu zihamba khona ukwakhiwa ngokutsha22. Ngenxa yokuba ii-KDs azinyanzeli ukungena kwimowudi yendlala, musa ukukhuthaza ukonakala okukhulu kwezinto zangaphakathi kunye nezicubu kwaye azibandakanyi ixesha lokuhlaziya, akunakulindeleka ukuba zibangele uhlobo lokuvuselelwa okulungelelanisiweyo oluqwalaselweyo ngexesha lokuhlaziywa kwe-FMD.

Ukuthintela i-calorie

Ngelixa isithintelo sekhalori enganyangekiyo (i-CR) kunye nokutya okungonelanga kwii-amino acid ezithile zahluke kakhulu kukuzila ukutya okwenziwa ngamaxesha athile, babelana ngokuzila ukutya kunye nee-FMDs isithintelo esikhethiweyo okanye esingaphantsi kwisondlo, kwaye baneziphumo ze-anticancer81,89 112. I-CR ibandakanya ukuncitshiswa okungapheliyo kwama-20-30% kumandla ombane ukusuka kwi-calorie standard yokutya eya kuthi ivumele umntu ukuba agcine ubunzima obuqhelekileyo113,114. Kuyasebenza kakhulu ekunciphiseni umngcipheko wentliziyo kunye neziganeko zomhlaza kwimodeli yezinto eziphilayo, kubandakanya neeprimates108,109,114.

Nangona kunjalo, i-CR inokubangela iziphumo ebezingalindelekanga, ezinje ngotshintsho kwinkangeleko yomzimba, ukwanda kobuntununtunu, amandla anciphisiweyo, izitenxo zokuya exesheni, ukungachumi, ukuphulukana ne-libido, i-osteoporosis, ukupholisa amanxeba kancinci, ukutyeba kokutya, ukuba nochuku, kunye noxinzelelo. Kwizigulana ezinomhlaza, kukho izinto ezixhalabisayo ezinokuthi zonyuse ukungondleki kwaye ngokungathandabuzekiyo kuya kubangela ilahleko egqithisileyo yomzimba ocekeceke18,113-116. I-CR inciphisa amanqanaba eswekile yegazi, nangona ihlala ikuluhlu oluqhelekileyo114. Ebantwini, i-CR engapheliyo ayichaphazeli amanqanaba e-IGF1 ngaphandle kokuba kuthintelwe isithintelo seprotein esimiselweyo117.

Izifundo zibonakalisa ukuba ukunciphisa i-mTORC1 signaling kwi-Paneth iiseli, i-CR yandise ukusebenza kweseli yazo kwaye ikhusela iiseli zesisu zamathumbu kumonakalo weDNA118,119, kodwa akwaziwa ukuba ngaba iimpembelelo zokuvuseleleka kwamanye amalungu zibangelwa yiCR. Ke, idatha efumanekayo iphakamisa ukuba ukuzila ukutya kunye nee-FMD zenze iprofayikhi yokuhlaziya umzimba, yokuhlaziya kunye neyokhuselo eyahlukileyo kwaye inokuba namandla ngakumbi kunale iphakanyiswe yi-KD okanye i-CR.

Ukuzila ukutya kunye nee-FMD kunyango: Iziphumo kumanqanaba ehomoni kunye nemetabolite

Uninzi lweenguqu kumanqanaba okujikeleza kwehomoni kunye neemetabolites ezijongwa ngokuthe gabalala ekuphenduleni ngokukhawuleza zinamandla okukhupha iziphumo ze-antitumour (Oko kukuthi, amanqanaba ancitshisiweyo eglucose, IGF1, insulin kunye leptin kunye namanqanaba akhulayo e-adiponectin) 23,120,121 kunye / okanye ukufikelela ngokukhuselekileyo kwezicubu ezinempilo kwiziphumo ebezingalindelekanga (oko kukuthi, amanqanaba ancitshisiweyo e-IGF1 kunye neglucose). Ngenxa yokuba imizimba ye-ketone inokuthi ithintele i-histone deacetylases (ii-HDAC), ukunyuka okunyanzeliswa ngokukhawuleza kwemizimba ye-ketone kunokunceda ukucothisa ukukhula kwe-tumor kunye nokukhuthaza umahluko ngokusebenzisa iindlela ze-epigenetic122

Nangona kunjalo, i-ketone body acetoacetate ibonakalisiwe ukuba ikhawulezise, ​​endaweni yokunciphisa, ukukhula kwamathumba athile, anje ngee-melanomas ezine-BRAF123 eziguqulweyo. Olu tshintsho apho kukho ubungqina obomeleleyo bendima kwindima yesiphumo sokuzila ukutya kunye nee-FMD ngokuchasene nomhlaza kukuncipha kwamanqanaba e-IGF1 kunye neglucose. Kwinqanaba leemolekyuli, ukuzila ukutya okanye i-FMD kunciphisa i-intracellular signaling cascades kubandakanya IGF1R AKT mTOR S6K kunye ne-cAMP PKA signaling, yonyusa i-autophagy, inceda iiseli eziqhelekileyo ukumelana noxinzelelo kunye nokukhuthaza ukungakhuseleki komzimba25,29,56,124

Ukuchasana noXinzelelo oluNgafaniyo: Ukonyusa Ukunyangwa kweChemotherapy

Ezinye zeast oncogene orthologues, ezinje ngeRas ne-Sch9 (i-orthologue esebenzayo ye-mammalia S6K), ziyakwazi ukunciphisa ukuncipha koxinzelelo kwinto yemodeli27,28. Ukongeza, ukuguqula okuguqukayo kwe-IGF1R, i-RAS, PI3KCA okanye AKT, okanye ukungasebenzi kwe-PTEN, zibakhona kuninzi lwabantu abakwazi ukukhanuka10. Ngokudibeneyo, oku kukhokelele kwi-hypothesis ukuba indlala iya kubangela iziphumo ezichaseneyo nomhlaza ngokuchasene neeseli eziqhelekileyo ngokubhekiselele kumandla abo okumelana noxinzelelo lweeseli, kubandakanya ne-chemotherapeutics. Ngamanye amagama, ukulamba kungakhokelela umahluko uxinzelelo kuxinzelelo (DSR) phakathi kweeseli zomhlaza oqhelekileyo kunye nomhlaza.

Ngokwe-DSR hypothesis, iiseli eziqhelekileyo ziyasabela kwindlala ngokunciphisa ukwanda okunxulunyaniswa kunye ne-ribosome biogenesis kunye / okanye iindibano zemfuza, ezinyanzela iiseli ukuba zingene kwimowudi yokuzilungisa kwaye ibakhusele kumonakalo obangelwe yi-chemotherapy, i-radiotherapy kunye nezinye izinto ezinetyhefu. Ngokwahlukileyo, kwiiseli zomhlaza, le ndlela yokuzigcina iyakhuselwa ngotshintsho lwe-oncogenic, olubangela ukuthintelwa kwendlela yokuphendula ngoxinzelelo12 (Ikhiwane. 1). Iyahambelana nemodeli yeDSR, indlala yexesha elifutshane okanye ukucinywa kweproto-oncogene homologues (Oko kukuthi, iSch9 okanye zombini iSch9 kunye neRas2) ukonyusa ukhuseleko lweSachcharomyces cerevisiae ngokuchasene noxinzelelo lwe-oxidative okanye iziyobisi ze-chemotherapy ukuya kuthi ga kwi-100-fold xa kuthelekiswa neeseli zegwele ezibonisa i-oncogene esebenzayo umfuziselo I-Ras2val19.

Iziphumo ezifanayo zafunyanwa kwiiseli ezanyisayo: ukubonakaliswa kwimithombo yeendaba esezantsi ye-glucose ekhusela iiseli ze-glia eziphambili ngokuchasene ne-hydrogen peroxide okanye i-cyclophosphamide (iprooxidant chemotherapeutic) kodwa ayizange ikhusele imouse, i-rat kunye ne-glioma yomntu kunye ne-neuroblastoma cell cell. Iyahambelana noku kuqaphela, usuku lwe-2 Ukuzila ukutya kuyinyusa ngempumelelo impilo yeempuku ezanyangwa ngepesidi ephezulu ye-etoposide xa kuthelekiswa neempuku ezingakhawuleziyo kunye nokwandisa ukusinda kwe-neuroblastoma ulungelelaniso iimpuku xa kuthelekiswa ne-mice12 engakhawulezi ukuzala.

Izifundo ezilandelayo ziye zafumanisa ukuba ukunciphisa i-IGF1 ukusayina ekuphenduleni ukuzila kukhusela i-glia ephambili kunye ne-neurons, kodwa hayi iiseli ze-glioma kunye ne-neuroblastoma, ukusuka kwi-cyclophosphamide nakwimixube ye-pro-oxidative kwaye ikhusela imouse embryonic fibroblast kwi-doxorubicin29. Iimpuku zesibindi se-IGF1-deficient (LID), izilwanyana ezi-transgenic ezinesimo se-Igf1 sokususwa kwemfuza esibonisa ukuncitshiswa kwe-70 80% ekujikelezeni amanqanaba e-IGF1 (amanqanaba afanayo nalawo aphunyezwe kukuzila ngokukhawuleza kweeyure ezingama-72 kwiimpuku) ezingama-29,125, zazikhuselwe amayeza amathathu kwamane e-chemotherapy avavanyiwe, kubandakanya i-doxorubicin.

Izifundo ze-Histology zibonise iimpawu ze-doxorubicin-indased cardiac myopathy kuphela kwiimpuku zokulawula unyango lwe-doxorubicin kodwa hayi kwiimpuku ze-LID. Kuvavanyo lwezilwanyana ezinesifo se-melanoma eziphathwe nge-doxorubicin, akukho mahluko ngokubhekisele ekuqhubekeni kwesifo phakathi kolawulo kunye neempuku ze-LID kwajongwa, kubonisa ukuba iiseli zomhlaza azikhuselwanga kwikhemotherapy ngamanqanaba anciphisiweyo e-IGF1. Ukanti, kwakhona, iimpuku ze-LID ezithwele ithumba zibonise ithuba lokusinda elimangalisayo xa kuthelekiswa nezilwanyana zokulawula ngenxa yokukwazi kwabo ukumelana ne-doxorubicin toxicity29. Ke ngoko, xa zizonke, ezi ziphumo ziqinisekisile ukuba i-IGF1 isemgomeni yindlela ephambili yokuzila ukutya ekonyusa ukunyamezelana ngamayeza

Zombini ii-dexamethasone kunye ne-mTOR inhibitors zisetyenziswa kakhulu kunyango lomhlaza, nokuba kungenxa yokusebenza kwawo njenge-anti-emetics kunye anti-allergics (Oko kukuthi, i-corticosteroids) okanye eyabo antitumour iipropati (Oko kukuthi, ii-corticosteroids kunye nee-mTOR inhibitors). Nangona kunjalo, enye yazo ephambili kwaye ihlala ithintela imiphumo emibi hyperglycaemia. Iyahambelana nombono wokonyusa iswekile cAMP PKA uphawu kuncitshiswa ukuxhathisa ubuthi kumachiza amayeza esifo samachiza12,26,126, zombini dexamethasone kwaye I-rapamycin yandisa ubuthi be-doxorubicin kwi-cardiomyocyte yeempuku kunye ne-mice26. Into enomdla kukuba yayinokwenzeka ukuba iphinde iphinde iphinde iphinde iphinde iphinde iphinde ijikeleze i-glucose ejikelezayo ngokuzila okanye nge-insulin injections26.

Olu ngenelelo lunciphisa umsebenzi we-PKA ngelixa lisonyusa imisebenzi ye-AMPK kwaye ngokwenza oko kusebenze i-EGR1, ebonisa ukuba umqondiso we-CAMP-PKA ulamla i-DSR ebangelwe kukuzila nge-EGR1 (ref. 26). I-EGR1 ikwakhuthaza ukubonakaliswa kwee-peptides ze-cardioprotective, ezifana ne-atrial natriuretic peptide (ANP) kunye ne-B-type natriuretic peptide (BNP) kwizicubu zentliziyo, enegalelo ekuchaseni i-doxorubicin. Ngapha koko, ukuzila ukutya kunye / okanye i-FMD inokukhusela iimpuku kwi-doxorubicin-induction cardiomyopathy ngokwandisa i-autophagy, enokuthi ikhuthaze impilo yeselfowuni ngokunciphisa imveliso ye-oksijini esebenzayo (ROS) ngokuphelisa ukungasebenzi kakuhle kwemitochondria kunye nokususwa kwezinto ezinobungozi.

Ukongeza ekunciphiseni i-chemotherapy ukunciphisa ubuthi kwiiseli kunye nokwanda kokusinda kweempuku eziphathwe ngamayeza e-chemotherapy, imijikelezo yokuzila ukudla yokuvuselela umongo wethambo kunye nokuthintela ukunyanzelwa komzimba okubangelwa yi-cyclophosphamide ngendlela enxulumene ne-PKA kunye ne-IGF1-enxulumene25. Ke, iziphumo ezinyanzelekileyo zangaphambi kokubonisa zibonisa amandla okuzila kunye nee-FMDs ukunyusa ukunyamezelana kwe-chemotherapy kunye nokuphepha iziphumo ebezingalindelekanga. Kungenxa yokuba idatha yokuqala yeklinikhi ibolekisa ngenkxaso yoku, kwaye ezi zifundo zangaphambi kokufunda zakha isiseko esomeleleyo sokuvavanya ii-FMDs kuvavanyo lweklinikhi olungenamkhethe kunye neeTEAE njengendawo yokugqibela yokuphela.

Umahluko woxinzelelo loxinzelelo: Ukonyusa ukubulawa kweSeli yomhlaza

Ukuba isetyenziswe yodwa, uninzi lokungenelela kokutya, kubandakanya ukuzila ukutya kunye ne-FMD, kuneziphumo ezinqamlekileyo ngokuchasene nomhlaza. Ngokwe-sensorization sensitization (DSS) eyahlukileyo yoxinzelelo, ukudityaniswa kokuzila okanye i-FMD ngonyango lwesibini kuyathembisa ngakumbi11,12. Le hypothesis icingela ukuba, ngelixa iiseli zomhlaza ziyakwazi ukuziqhelanisa neoksijini kunye nokujongwa kwezondlo, uninzi lweeseli zomhlaza alukwazi ukwenza utshintsho olunokuvumela ukusinda kwimeko yezondlo-enobungozi kunye netyhefu eveliswa yindibaniselwano yokuzila kunye ne-chemotherapy. , umzekelo. Uvavanyo lwangoko lomhlaza webele, i-melanoma kwaye iiseli ze-glioma zifumene ukonyuka okuthe kratya ekubonakalisweni kokungunda okunxulumene ne-geno okanye i-ribosome biogenesis kunye neentlobo zendibano ekuphenduleni i-fast11,12. Olutshintsho luhamba kunye ne-AKT engalindelekanga kunye nokusebenza kweS6K, ubungakanani bokuvelisa iROS kunye nomonakalo weDNA kunye iimvakalelo Kwisiyobisi esonakalisa iDNA (nge-DSS) 11.

Sithatha lempendulo ingalunganga yeeseli zomhlaza kwiimeko eziguqulweyo kubandakanya ukunciphisa i-IGF1 kunye namanqanaba eglucose abangelwa kukuzila ngokukhawuleza okanye i-FMD njengeyona nto iphambili iphantsi kwengqondo antitumour Iipropathi zolu ngenelelo ngoncedo lokutya kunye noncedo lwazo lokwahlulahlula iziphumo zonyango lwe-anticancer kwiiseli eziqhelekileyo xa kuthelekiswa neeseli11,12 (Ikhiwane. 1). Ngokuhambelana ne-DSS hypothesis, imijikelezo yamaxesha athile yokuzila ukutya okanye ii-FMDs zanele ukucothisa ukukhula kweentlobo ezininzi ze ithumba iiseli, ukusukela kwimigca yeseli eqinileyo yethumba ukuya kwiiseli ze-lymphoid leukemia, kwimouse kwaye, okona kubaluleke kakhulu, kukhuthaza iiseli zomhlaza kwii-chemotherapeutics, i-radiotherapy kunye ne-tyrosine kinase inhibitors (TKIs) 11,17,22,25,50,54-57,59,60,124,127,128, XNUMX.

Ngokunciphisa ukufumaneka kweglucose kunye nokwandisa i-acid ye-fatty? -I-oxidation, ukuzila ukutya okanye ii-FMDs nazo zinokukhuthaza utshintsho olusuka kwi-aerobic glycolysis (isiphumo seWarburg) siye kwi-mitochondrial oxidative phosphorylation kwiiseli zomhlaza, eziyimfuneko ekugcineni ukukhula komhlaza weseli kwezona ndawo zinesondlo-50 (Umzobo 2). Olu tshintsho lukhokelela ekwandeni kwemveliso ye-ROS11 njengesiphumo sokwanda kwemiphunga yokuphefumla kwaye inokubandakanya ukuncitshiswa kweselfox enokubakho ngenxa yokuhla kwe-glutathione synthesis evela kwi-glycolysis kunye ne-pentose phosphate path50. Iziphumo ezidibeneyo zokwandiswa kweROS kunye nokunciphisa ukhuselo lwe-antioxidant kukonyusa uxinzelelo lwe-oxidative kwiiseli zomhlaza kunye nokwandisa umsebenzi we-chemotherapeutics. Ngokukodwa, ngenxa yokuba umsebenzi ophakamileyo we-glycolytic oboniswe yimveliso ephezulu ye-lactate uqikelelo lobundlongondlongo kunye nokuqina kokuqina kweentlobo ezahlukeneyo zomhlaza129, iziphumo ezichasene neWarburg zokuzila ukutya okanye i-FMD zinokubanakho ukusebenza ngokuchaseneyo nomhlaza womhlaza.

Ngaphandle kotshintsho lwe-metabolism, ukuzila ukutya okanye ii-FMD zenza ezinye iinguqu ezinokukhuthaza i-DSS kwiiseli zomhlaza wepancreatic. Ukuzila ukutya kunyusa amanqanaba amabinzana e ulungelelaniso Umthuthi we-nucleoside 1 (ENT1), umthuthi we-gemcitabine kwi-membrane ye-plasma, ekhokelela ekuphuculweni komsebenzi weli chiza128. Kwiiseli zomhlaza wamabele, ukuzila ukutya kubangela i-SUMO2-Mediated kunye / okanye i-SUMO3-Mediated modification ye-REV1, i-DNA polymerase kunye ne-p53-binding protein127. Olu hlengahlengiso linciphisa ukubanakho kwe-REV1 yokuthintela i-p53, ekhokelela kukonyuka kwe-p53-Mediated transcription of pro-apoptotic genes and, finally, to cancer cell demise (Fig. 2). Ukuzila ukutya kukonyusa amandla e-TKI elawulwa ngesiqhelo ukuyeka ukukhula kwesifo somhlaza kunye / okanye ukufa ngokuqinisa i-MAPK signaling inhibition kwaye, ngokwenza njalo, kuthintela i-E2F yokukhuphela into exhomekeke kwimfuza kodwa nasekunciphiseni ukuthathwa kweglucose17,54.

Okokugqibela, ukuzila ukutya kunokunyusa i-leptin receptor kunye naphantsi kwayo uphawu ngeprotein ye-PR / SET domain 1 (PRDM1) kwaye ke kuthintele ukuqalwa kunye nokuguqula ukuqhubela phambili kweseli ye-B kunye ne-T yeseli ye-lymphoblastic ikholera (ZONKE), kodwa ingeyiyo eyokubalasela kakhulu ikholera (AML) 55. Into enomdla kukuba isifundo esizimeleyo sibonakalise ukuba ii-cell cell zandulelayo zibonisa imeko yesithintelo esinganyangekiyo kwiswekile nakwizibonelelo zamandla ezibangelwa zizinto ezikhutshelweyo i-PAX5 kunye ne-IKZF1 (ref. 130). Utshintsho kwiijeni ezifake ezi proteni zimbini, ezikhoyo ngaphezulu kwe-80% yamatyala eseli-B yeseli YONKE, kubonisiwe ukwandisa ukuthathwa kweglucose kunye namanqanaba e-ATP. Nangona kunjalo, ukuyakha ngokutsha i-PAX5 kunye ne-IKZF1 kwi-preB-ZONKE iiseli kukhokelele kwingxaki yamandla kunye nokubhubha kweseli. Uthathiwe kunye nophando lwangaphambili, lo msebenzi ubonakalisa ukuba BONKE banokuba novakalelo kwisithintelo samandla kunye namandla esenziwa kukuzila ukutya, ngokunokwenzeka simele umgqatswa olungileyo weklinikhi kuvavanyo lokusebenza kokuzila ukutya okanye i-FMD.

Ngokukodwa, kunokwenzeka ukuba uninzi lweentlobo zeseli zomhlaza, kubandakanya i-AML29, zinokufumana uxhathiso ngokunqanda utshintsho lwe-metabolic olwenziwe kukuzila ukutya okanye ii-FMDs, ithuba elinokuthi lonyuswe ngakumbi yi-metabolic heterogeneity ebonisa uninzi lomhlaza129. Ke, eyona njongo iphambili kwikamva elikufuphi iya kuba kukuchonga iintlobo zomhlaza ezichaphazeleka kakhulu kwezi nkqubo zokutya kusetyenziswa ii-biomarkers. Kwelinye icala, xa zidityaniswe nonyango oluqhelekileyo, ukuzila ukutya okanye ii-FMD kunqabile ukuba kukhokelele ekufumaneni ukuxhathisa kwimodeli yegundane lomhlaza, kwaye ukumelana nokuzila kunye ne-chemotherapy nako akuqhelekanga kwizifundo ze-vitro, kugxininisa ukubaluleka kokuchonga unyango, xa zidityaniswe nee-FMD, zikhokelela kwiziphumo ezinetyhefu ngokuchasene neeseli zomhlaza ezinobungozi obuncinci kwiiseli eziqhelekileyo kunye nezicubu11,17,50,55.

Ukuphucula ukungasebenzi kwe-Antitumour ngokuZila okanye ngeFDD

Idatha yakutshanje iphakamisa ukuba ukuzila ukutya okanye ii-FMD zizodwa, kwaye nangaphezulu xa zidityaniswa ne-chemotherapy, kubangela ukwanda kwee progenitors ze-lymphoid kunye nokukhuthaza ithumba uhlaselo lomzimba ngeendlela ezahlukeneyo25,56,60,124. I-FMD iyinciphisile intetho ye-HO1, iprotein enika ukhuseleko kumonakalo we-oxidative kunye neapoptosis, kwiiseli zomhlaza kwi-vivo kodwa ibonakalise intetho ye-HO1 kwiiseli eziqhelekileyo124,131. Ukwehliswa kwe-HO1 kwiiseli zomhlaza kulamla i-FMD-indased chemosensitization ngokwandisa i-CD8 + ye-cytotoxicity exhomekeke kwi-tumor, enokuqhutywa kukuthotyelwa kwemiqathango ye-T cells124 (Ikhiwane. 2). Olunye uphononongo, oluqinisekisile ukukwazi ukuzila ukutya okanye ii-FMDs kunye ne-CR mimetics yokuphucula i-anticancer immunosurveillance, oko kuthetha ukuba iziphumo zokuzila ukutya okanye ii-FMD zinokufaka isicelo sokuzimela ngokuzenzekelayo, kodwa kungabinakho ukuzimela, ii-cancer .56. Okokugqibela, uphononongo lwakutshanje lweentsuku ezimbini zokuzila ukutya kwiiveki ezi-2 kwimodeli yomhlaza wekolon ibonise ukuba, ngokwenza i-autophagy kwiiseli zomhlaza, ukuzila ukutya kunciphisa ukubonakaliswa kwe-CD73 kwaye ngenxa yoko kunciphise imveliso ye-immunosuppressive adenosine ngamaseli omhlaza60. Ekugqibeleni, i-CD73 yokuthotyelwa komthetho ngokuzila ukutya yaboniswa ukuthintela utshintsho lwe-macrophage kwi-M2 immunosuppressive phenotype (Ikhiwane. 2). Ngokwesiseko solu phononongo, kuyathandeka ukuqikelela ukuba ii-FMDs kunokuba luncedo ngakumbi endaweni okanye ngokudibeneyo ne-immune checkpoint inhibitors132, izitofu zomhlaza okanye ezinye iziyobisi ezikhuthaza antitumour ukungathathi hlangothi, kubandakanya ezinye eziqhelekileyo ze-chemotherapeutics133.

Ukutya okubulala intsholongwane kwiimodeli zegundane

Ngokubanzi, iziphumo zophononongo lwangaphambi kokuzila ukutya okanye ii-FMD kwiimodeli zomhlaza wezilwanyana, kubandakanya iimodeli zomhlaza we-metastatic (Itheyibhile 2), bonisa ukuba ukuzila ukutya ngamaxesha athile okanye ii-FMDs kufezekisa iziphumo ze-anti-cancer ze-pleiotropic kunye nokwenza umsebenzi we-chemotherapeutics kunye ne-TKIs ngelixa kusenziwa iziphumo zokhuselo kunye nokuhlaziya kumalungu amaninzi22,25. Ukufezekisa iziphumo ezifanayo ngaphandle kokuzila ukutya kunye / okanye ii-FMD kuya kufuna kuqala ukuchongwa kwaye emva koko kusetyenziswe iziyobisi ezininzi ezisebenzayo, ezibizayo nezihlala zinetyhefu kwaye zinokubakho ngaphandle kokufumana ukhuselo lweseli olusempilweni. Kuyaphawuleka ukuba ubuncinci kwizifundo ezibini zokuzila ukutya kunye ne-chemotherapy kungqineke kuphela kongenelelo olunakho ukufezekisa ukubuyela umva ngokupheleleyo okanye ukusinda ixesha elide kwisiqwengana esingaguqukiyo sezilwanyana eziphathwayo11,59

Ii-KD ezingapheliyo zibonisa a ithumba ukulibaziseka kokukhula kwempembelelo xa isetyenziswa njenge-monotherapy, ngakumbi kwiimodeli zegundane lomhlaza wobuchopho77,78,80 82,84,134. I-Gliomas kwiimpuku ezigcinwe kwi-KD engapheliyo ziye zanciphisa ukubonakaliswa kwe-hypoxia marker carbonic anhydrase 9 kunye ne-hypoxia-inducible factor 1 ?, yehlise into yenyukliya-? iMatrix Metalloproteinase 2 kunye neVimentin) 2. Kwimodeli ye-glioma ye-intracranial yeempuku, iigundane ezondla i-KD ibonakalisile inyukile isisu esisebenzayo iimpendulo ze-immune zangaphakathi kunye nezilungelelanisiweyo ezaziphikiswa ikakhulu zii-CD8 + T zeeseli79. Ii-KDs zibonisiwe ukuphucula umsebenzi we-carboplatin, cyclophosphamide kunye ne-radiotherapy kwi-glioma, umhlaza wemiphunga kwaye Iimodeli zeempuku ze-neuroblastoma73-75,135. Ukongeza, uphononongo lwamva nje lubonisa ukuba i-KD inokuba luncedo ngokudibeneyo ne-PI3K inhibitors72. Ngokuthintela i-insulin uphawu, ezi agents zikhuthaza ukuqhekeka kwe-glycogen esibindini kunye nokuthintela ukuthathwa kweswekile kwithambo lomthambo, ekhokelela kwisikhashana hyperglycaemia kunye nokukhululwa kwe-insulin kwi-pancreas (into eyaziwa ngokuba yi- insulin feedback ). Kwelinye icala, this ukukhulisa kumanqanaba e-insulin, anokuthi athathwe ixesha elide, ngakumbi kwizigulana ezinokunganyangeki kwe-insulin, iphinda isebenze iPI3K mTOR uphawu in amathumba, ngaloo ndlela kuncitshiswe ngamandla izibonelelo ze-PI3K inhibitors. I-KD ibonakaliswe isebenza kakhulu ekuthinteleni ingxelo ye-insulin ekuphenduleni kula machiza kunye nokuphucula imisebenzi yabo ye-anticancer kwimouse. Okokugqibela, ngokutsho kophando kwimodeli ye-cachexia ye-murine tumor-induced cachexia (MAC16 tumors), ii-KDs zinokunceda ukukhusela ilahleko yamafutha kunye non-fat body mass in izigulana ezinomhlaza85.

I-CR inciphise i-tumorigenesis kwiimodeli zomhlaza wemouse yemfuza, iimodeli zegundane kunye ne-tumorigenesis kunye ne-carcinogen ebangela imodeli yegundane yomhlaza, nakwiinkawu91,92,97,98,101,102,104-106,108,109,136-138. Ngokwahlukileyo, uphononongo lufumanise ukuba i-CR ukusuka kubudala obuphakathi inyusa imeko yeeplasma zeeseli kwi-C57Bl / 6 iimpuku139. Nangona kunjalo, kwakwisifundo esinye, i-CR ikwandise ubude bexesha lokuphila malunga ne-15%, kwaye ukonyuka okuqaphelekayo kweziganeko zomhlaza kwabangelwa kukunyuka kwexesha elide leempuku eziphantsi kweCR, ubudala apho ukuvelisa amathumba iimpuku ezenzeka kwiCR zafa kunye nepesenti ye ukuvelisa amathumba iimpuku ezaziphathwa nguCR Ke, ababhali bagqibile ukuba i-CR mhlawumbi iyakugcina ukukhuthaza kunye / okanye ukuqhubela phambili komhlaza osele ukhona we-lymphoid. Uhlalutyo lwe-meta ngokuthelekisa i-CR enganyangekiyo kunye ne-CR ngokuqhubekayo malunga nokukwazi kwabo ukunqanda umhlaza kwiintonga ukugqiba ukuba i-CR esebenzayo isebenza ngakumbi kwiimodeli zemouse ezenzelwe injini, kodwa ayisebenzi kangako kwiimodeli zerhafu eyenzelwe oko ngekhemikhali90. CR yaboniswa ukuba icothe ithumba ukukhula kunye / okanye ukwandisa ukusinda kwegundwane kwiimodeli ezahlukeneyo zemouse zomhlaza, kubandakanya umhlaza we-ovarian kunye ne-pancreatic140,94 kunye ne-neuroblastoma81.

Ngokubalulekileyo, i-CR iphucule umsebenzi wonyango lwe-anticancer kwiimodeli ezininzi zomhlaza, kubandakanya umsebenzi we-antiIGF1R antibody (ganitumab) ngokuchasene nomhlaza wamathumbu141, cyclophosphamide ngokuchasene neeseli ze-neuroblastoma135 kunye ne-autophagy inhibition kwi-xenogwork ye-HRAS-G12Vtransformed infonntwana yeeseli yePum. Nangona kunjalo, i-CR okanye i-KD ngokudibeneyo kunyango lwe-anticancer lubonakala lungasebenzi kakuhle kunokuzila. Uphononongo lwegundwane lufumene ukuba, ngokuchaseneyo nokuzila kuphela, i-CR iyodwa ayikwazanga ukunciphisa ukukhula kwe-gliomas ye-GL100 ekhula ngokungekho sikweni kwaye, kwakhona, ngokuchaseneyo nokuzila kwexesha elifutshane, i-CR ayizange yandise umsebenzi we-cosplatin ngokuchasene ne-subcutaneous 26T4 isifuba tumours1. Kuphononongo olufanayo, ukuzila ukutya kuye kwangqineka kusebenza ngakumbi kune-CR kunye ne-KD ekwandiseni ukunyamezeleka kwe-doxorubicin51. Nangona ukuzila ukutya okanye i-FMD, i-CR kunye ne-KD kunokwenzeka ukuba zisebenze kwaye zilinganise ukugqagqana uphawu iindlela, ukuzila ukutya okanye i-FMD mhlawumbi ichaphazela iindlela ezinjalo ngendlela evuthayo ngexesha lesigaba esibuhlungu sexesha leentsuku ezimbalwa.

Inqanaba lokuthathwa kwakhona ke u bubele Ukuvuselelwa kwe-homeostasis yelungu lomzimba wonke kodwa kwakhona kusebenze kunye neendlela ezinamandla zokukhuthaza ukwamkelwa kunye nokususwa ithumba kunye nokuhlaziya iiseli ezisempilweni. I-CR kunye ne-KD ngamanyathelo ongenelelo angapheliyo akwaziyo ukuthoba umlinganiso kuphela kwindlela yokuziva unezakha-mzimba, ngokunokwenzeka ngaphandle kokufika kwimibandela ethile eyimfuneko yokuphucula iziphumo zamachiza e-anticancer, ngelixa ebeka umthwalo omkhulu kwaye uhlala uncipha ngokuthoba umzimba. I-CR kunye ne-KD njengeerejimeni zokutya ezingapheliyo kwizigulana ezinomhlaza kunzima ukuzenza kwaye zinokuthwala umngcipheko kwimpilo. I-CR inokuthi ikhokelele ekulahlekelweni okunzima kwesisindo somzimba onqabileyo kunye nokuncitshiswa kweehomoni ze-steroid kunye nokusebenza kwe-immune142. Ii-KD ezinganyangekiyo zidityaniswa ngokufanayo nangona zinemiphumela emibi kakhulu143. Ke, ukuzila ukutya ngamaxesha athile kunye nemijikelezo ye-FMD ehlala ixesha elingaphantsi kweentsuku ze-5 ezisetyenzisiweyo kunye nonyango olusemgangathweni lunamandla aphezulu okuphucula unyango lomhlaza ngelixa linciphisa iziphumo zalo ezibi. Ngokukodwa, kuya kubalulekile ukuba ufunde ngesiphumo sokudityaniswa kwee-FMD ezikwixesha elithile, ii-KD ezingapheliyo kwaye Unyango oluqhelekileyo, ngakumbi unyango lwe-cancers enobushushu njenge-glioma.

Ukuzila ukutya kunye nee-FMD ekuthinteleni umhlaza

Izifundo ze-Epidemiological kunye nezifundo kwizilwanyana, kubandakanya i-monkey108,109,144, kwaye abantu bayababoleka bayayixhasa ingcinga yokuba i-CR engapheliyo kunye nokuzila ukutya okwethutyana kunye / okanye i-FMD inokuba nefuthe lokuthintela umhlaza ebantwini. Nangona kunjalo, i-CR ayinakufezekiswa kuluntu ngokubanzi ngenxa yemicimbi yokuthobela kunye neziphumo ebezinokwenzeka ze115. Ke ngoko, ngelixa iingcebiso ezisekwe kubungqina bokutya onokukhetha (okanye ukunqanda) kunye neengcebiso zendlela yokunciphisa umngcipheko womhlaza ziye zisungulwa6,8,9,15, injongo ngoku kukuchonga kwaye, ngokunokwenzeka, ukubekwa emgangathweni okunyamezelweyo, imilinganiselo yokutya esemthethweni enexesha elincinci okanye alikho Iziphumo ebezingalindelekanga kunye nokuvavanya ukusebenza kwabo kuthintela umhlaza kwizifundo zonyango.

Njengoko sekuxoxwe ngaphambili, imijikelezo ye-FMD ibangela ukuba i-IGF1 kunye neglucose kunye nokunyuka kwe-IGFBP1 kunye nemizimba ye-ketone, lutshintsho olufana nolwabangelwa kukuzila ngokukhawuleza kwaye ibe zii-biomarkers ze-reaction22 zokuzila ukutya. Xa i-C57Bl / 6 iimpuku (ezithi ngokuzenzekelayo ziphuhliswe amathumba, ngokuyintloko i-lymphomas, njengoko bekhula) batyiswa i-FMD enjalo kwiintsuku ze-4 kabini ngenyanga eqala kubudala obuphakathi kunye nokutya okukhuselekileyo kwe-aditum kwixesha eliphakathi kwemijikelezo ye-FMD, imeko ye-neoplasms yancitshiswa ukusuka kwi-70% yeempuku kulawulo ukutya kuya malunga ne-40% kwiigundane kwiqela le-FMD (iyonke i-43% yokunciphisa) i-22. Ukongeza, i-FMD ihlehliswe ngaphezulu kweenyanga ze-3 ukwenzeka kwesifo esinxulumene neoplasm, kwaye inani lezilwanyana ezinezilonda ezininzi ezingaqhelekanga zaphindaphindeka kathathu kwiqela lolawulo kunakwiziimpuku ze-FMD, ebonisa ukuba uninzi amathumba kwiigunduzi ze-FMD zazingenaburhalarhume okanye ziluhlaza.

Uphononongo oludlulileyo lokuzila olunye usuku-lokuzila ukutya, olwenziwe kwiigundane ezineminyaka ephakathi iyonke iinyanga ze4, kwafumaniseka ukuba ukuzila ukutya kunciphisa imeko ye-lymphoma, kuyizisa ivela kwi-33% (yolawulo lweempuku) ukuya kwi-0% izilwanyana) i-145, nangona ixesha elifutshane lokufunda alaziwa ukuba ngaba irejimeni yokuzila ukutya iyathintela okanye balibazisa nje ithumba ukuqala. Ngapha koko, enye into yokuzila ukutya imihla ngemihla ibeka imihla ye-15 ngenyanga yokutya okuphela kwamanzi, ngelixa kulingo lwe-FMD oluchazwe apha ngasentla zabekwa kukutya okunikezela ngesixa esilinganiselweyo sokutya ngeentsuku ze-8 kuphela ngenyanga. Emntwini, imijikelezo ye-3 yemihla ngemihla ye-5-FMD kanye ngenyanga yaboniswa ukunciphisa ukutyeba kwesisu kunye nokuphawula ukuvuvukala kunye ne-IGF1 kunye namanqanaba eglucose kwizifundo ezinamanqanaba aphakamileyo ezi zimakishi62, ebonisa ukuba ukusetyenziswa kwe-FMD kusenokwenzeka Iziphumo zokuthintela izifo ezinxulumene nokukhuluphala okanye ezinxulumene nokuvuvukala, kodwa nezinye, izinto ezinomhlaza ebantwini, njengoko kubonisiwe mice22.

Ke ngoko, iziphumo ezithembisayo zezifundo zangaphambi kokuba zidityaniswe nedatha yezonyango kwisiphumo se-FMD kwimiba yomngcipheko ukwaluphala Izifo, kubandakanya umhlaza62, inkxaso mboleko kwizifundo ezenziwa ngokungahleliwe ze-FMD njengesixhobo esinokwenzeka sokuthintela umhlaza, kunye nezinye ukwaluphala iimeko ezingapheliyo, ebantwini.

Ukusetyenziswa kweKliniki kwi-Oncology

Izifundo ezine ezinokwenzeka zokuzila ukutya kunye nee-FMD kwizigulana eziphantsi kwe-chemotherapy ziye zapapashwa njengazo namhlanje52,53,58,61. Kwichungechunge lwe-10 yezigulana ezifunyaniswe ukuba zinomhlaza, kubandakanya isifuba, i-prostate, i-ovari, isibeleko, imiphunga kunye nomhlaza oesophageal, owazinikelayo ngokuzithandela ukuya kwii-140hours ngaphambili kunye / okanye ukuya kwi-56hours kulandela ichemotherapy. ngokuzila ukutya ngokwayo ngaphandle kwendlala kunye nokukhanya kwentloko kuxelwa58. Abo baguli (abathandathu) abakhe bafumana i-chemotherapy kwaye bengakhange bazile ukutya banike ingxelo yokuncipha kukhathala, ubuthathaka kunye neziganeko ezimbi zesisu ngelixa bezila. Ukongeza, kwizigulana apho uvavanyo lomhlaza kunokuvavanywa, ukuzila ukutya akuzange kuthintele ukuncitshiswa kwechemotherapy kumthamo we-tumor okanye kwizimpawu zokumilisa. Kolunye uphononongo, abasetyhini be-13 abane-HER2 (ekwabizwa ngokuba yi-ERBB2) engalunganga, inqanaba II / III umhlaza wamabele ufumana i-neo-adjuential taxotere, i-adriamycin kunye ne-cyclophosphamide (TAC) chemotherapy yenziwa ngokungathandabuzekiyo ukuzila ukutya (amanzi kuphela) i-24hours ngaphambili nasemva kokuqala kwamayeza amayeza kwisondlo ngokwemigaqo esemgangathweni52.

Ukuzila ukutya okwethutyana kwakunyamezeleka kwaye kuncitshisiwe ukwehla kwe-erythrocyte kunye ne-thrombocyte kubalwa kwiintsuku ze-7 emva kwe-chemotherapy. Into enomdla kukuba kolu phononongo, amanqanaba e-H2AX (umakishi womonakalo we-DNA) anyuswe nge-30minutes emva kwe-chemotherapy kwii-leukocyte ezivela kwizigulana ezingazilelanga kodwa hayi kwizigulana ezikhawulezayo. Kwidosi yokunyuka kokuzila kwizigulana ezisebenzisa ichemotherapy esekwe kwiplatinam, izigulana ezingama-20 (ezazinyangelwa ikakhulu i-urothelial, ovarian okanye umhlaza webele) zazicwangciselwe ukukhawuleza i-24, 48 okanye i-72hours (yahlulwe njenge-48hours ngaphambi kwe-chemotherapy kunye ne-24hours emva kwekhemotherapy 53. Iikhrayitheriya zokufezekisa (ezichazwe njengezithathu okanye nangaphezulu kwezifundo ezithandathu kwiqela ngalinye elisebenzisa i-200kcal ngemini ngexesha elikhawulezayo ngaphandle kwetyhefu egqithisileyo) zafezekiswa. Ukuzila ukutya okunxulumene nokuzila babehlala bebakala I-2 okanye ngezantsi, eyona iqhelekileyo kukudinwa, intloko kwaye isiyezi. Njengakwisifundo esandulelayo, ukunciphisa ukonakaliswa kweDNA (njengoko kufunyanwe yi-comet assay) kwii-leukocytes ezivela kwizifundo ezizile ukutya ubuncinci ii-48hours (ngokuthelekiswa nezifundo ezizila ukutya nge-24hours kuphela) zinokubhaqwa kolu vavanyo lincinci. Ukongeza, umkhwa ongathandekiyo ukuya kwinqanaba elincinci le-3 okanye iBanga le-4 neutropenia kwizigulana ezikhawulezela i-48 kunye ne-72hours ngokuthelekisa abo bazila I-24hours nayo yabhalwa.

Kutshanje, uvavanyo lweklinikhi lweklinikhi olungakhethwanga lwenziwa kuvavanywa iziphumo ze-FMD kumgangatho wobomi kunye neziphumo ebezichemotherapy kwizigulana ezi34 zizonke ezinomhlaza webele okanye we-ovarian cancerNNXX. I-FMD yayiquka mihla le ikhalori yokungenisa i- <400kcal, ubukhulu becala ziijusi kunye neebroths, ukuqala iiyure ezingama-36 48 ngaphambi kokuqala kwekhemotherapy kunye nokuhlala kude kube ziiyure ezingama-24 emva kokuphela kwekhemotherapy. Kolu phando, i-FMD ithintele i-chemotherapy ibangele ukunciphisa umgangatho wobomi kwaye yanciphisa nokudinwa. Kwakhona, akukho ziganeko zibi ze-FMD ezixeliweyo. Olunye uvavanyo lwezonyango lwe-FMD ngokudibeneyo ne-chemotherapy okanye ezinye iintlobo zonyango olusebenzayo ziyaqhubeka ngoku kwizibhedlele zase-US nase-Europe, ikakhulu kwizigulana ezifunyenwe zinomhlaza webele okanye we-Prostate63,65-68. Ezi zezifundo zengalo enye yokuhlola ukhuseleko lwe-FMD kunye nokufezekisa okanye ukufundwa kweeklinikhi ngokungahleliwe kugxile kwisiphumo se-FMD kwityhefu ye-chemotherapy okanye kumgangatho wobomi bezigulana ngexesha le-chemotherapy uqobo. Lilonke, ezi zifundo ngoku zibhalise ngaphezulu kwezigulana ze-300, kwaye iziphumo zabo zokuqala kulindeleke ukuba zifumaneke kwi-2019.

Imiceli mngeni kwikliniki

Isifundo sokuzila ukutya okwethutyana okanye i-FMD kwii-oncology asizizo izinto ezixhalabisayo, ngakumbi ngokubhekisele kwinto yokuba olu hlobo lwerejimeni yendlela yokutya inokuphelisa ukungondleki, isarcopenia, kwaye i-cachexia kwizigulana ezichazwe kwangaphambili okanye ezibuthathaka (umzekelo, abaguli abaphuhlisa i-anorexia njengesiphumo se-chemotherapy) 18,19. Nangona kunjalo, akukho matyala obunzima (ngaphezulu kwebanga lesi-3) lokwehla kobunzima okanye ukungondleki kuxeliweyo kwizifundo zekliniki zokuzila ukutya ngokudibanisa ne-chemotherapy epapashwe njengangoku, kwaye abo baguli bafumana ukwehla kobunzima ngexesha lokuzila bazibuyisa ubunzima babo ngaphambi kokuba Umjikelo olandelayo ngaphandle komonakalo obonakalayo. Nangona kunjalo, sicebisa ukuba i-anorexia yamaxesha ngamaxesha kunye novavanyo lobume besondlo kusetyenziswa iindlela ezikumgangatho wegolide18,19,146 150 kufuneka ibe yinxalenye yezi zifundo kwaye nokuba nakuphi na ukungalunganga kwezondlo kwizigulana ezila ukutya kunye / okanye ii-FMD zilungiswa ngokukhawuleza.

izigqibo

Ukuzila ukutya okwexeshana okanye ii-FMD ngokungaguqukiyo kubonisa iimpembelelo ezinamandla zomhlaza kwimodeli yomhlaza wempuku kubandakanya amandla okwenza i-chemoradiotherapy kunye nee-TKIs kunye nokubangela ukungazinzi komzimba. Imijikelezo ye-FMD inokwenzeka ngakumbi kunendlela yokutya engapheliyo kuba ivumela abaguli ukuba batye ukutya rhoqo ngexesha le-FMD, bagcine ukutya okuqhelekileyo phakathi kwemijikelezo kwaye kungakhokeleli ekulahlekeni kobunzima obukhulu kwaye kunokuba neziphumo ezibi kumajoni omzimba kunye neenkqubo ze-endocrine. Ngokukodwa, njengonyango oluzimeleyo, ukuzila ukutya ngamaxesha athile okanye imijikelezo ye-FMD inokubonisa ukusebenza ngokulinganiselweyo ngokuchasene namathumba amiselweyo. Ngapha koko, kwiimpuku, ukuzila ukutya okanye ii-FMDs zichaphazela ukuqhubekeka kwenani lomhlaza ngokufanayo nakwichemotherapy, kodwa iyodwa, kunqabile ukuba bafanise isiphumo esifunyenwe ngokudibeneyo nesiyobisi somhlaza esinokubangela ukusinda ngaphandle komhlaza11,59. Ke, sicebisa ukuba kukudityaniswa kwemijikelezo ye-FMD yamaxesha athile kunye nonyango olusemgangathweni oluphethe eyona nto iphambili ekukhuthazeni ukusinda komhlaza kwizigulana, njengoko kucetyisiwe yimodeli yegundane11,59 (Ikhiwane.

Olu dibaniso lunokubakho ikakhulu ngenxa yezizathu ezininzi: okokuqala, amayeza omhlaza kunye nolunye unyango lunokusebenza, kodwa icandelo lezigulana aliphenduli kuba iiseli zomhlaza zithatha ezinye iindlela ze-metabolic ezikhokelela ekusindeni. Ezi ndlela zimbi ze-metabolic zinzima ngakumbi ukuzixhasa phantsi kweemeko zokuzila okanye ze-FMD ngenxa yokusilela okanye utshintsho kwiglucose, ii-amino acid ezithile, iihomoni, kunye nezinto zokukhula, kunye nakwezinye iindlela ezingaziwayo ezikhokelela ekufeni kweseli. Okwesibini, ukuzila ukutya okanye i-FMD kunokuthintela okanye kunciphise ukufunyanwa kokunganyangeki. Okwesithathu, ukuzila ukutya okanye i-FMD kukhusela iiseli eziqhelekileyo kunye nezifo kwiziphumo ebezinokubangelwa ziintlobo ezahlukeneyo zamachiza omhlaza. Kwisiseko sobungqina bengqibelelo kunye neklinikhi yokwenzeka, ukhuseleko kunye nokusebenza (ekunciphiseni i-IGF1, i-visceral fat kwaye Imingcipheko yengozi yentliziyo), ii-FMD zikwabonakala njengendlela esebenzayo yokutya ukuze ifundwe kuthintelo lomhlaza. Umngeni obalulekileyo wexesha elizayo iya kuba kukuchonga ezo amathumba abona bagqatswa babalaseleyo ukuba baxhamle ngokuzila ukutya okanye kwii-FMD. Nokuba kwiindidi zomhlaza ezibonakala zingaphenduli ngokukhawuleza ekuzileni okanye kwii-FMD, kusenokwenzeka ukuba zichaze iindlela zokumelana nokungenelela kumachiza okwazi ukubuyisa oosulelo. Kwelinye icala, kufuneka kulunyukiswe ngakumbi ezinye iintlobo zokutya, ngakumbi ukuba ziphezulu kwiikhalori, njengoko zinokukhokelela ekwandeni kwaye kungathinteleki. ukukhula ezithile zomhlaza. Umzekelo, i-KD iyanda ukukhula Imodeli ye-melanoma ene-BRAF eguqukayo kwi-mice123, kwaye kwathiwa ikwakhawulezisa ukuqhubekeka kwesifo kwimodeli ye-AML yeXLUMX.

Ngaphaya koko, kubalulekile ukusebenzisa ii-FMD ngokuqonda kweendlela zokusebenza, kuba amandla abo ukuba isetyenziswe ngokungachanekanga inokuvelisa iziphumo ezibi. Umzekelo, xa iigundane zazikhawuleza kwaye ziphathwa nge-carcinogen enamandla ngaphambi kokuthatha kwakhona, oku kukhokelela ekukhuleni kokugxila kwe-aberrant kwi-ini, kwikholoni kwaye i-rectum xa ithelekiswa nee-rats151,152 ezingakhawuleziyo. Nangona iindlela ezibandakanyekayo kwezi ziphumo zingaqondwa, kwaye ezi zijolise kuzo kungenzeka zingakhange zibekho amathumba, Olu phononongo lubonisa ukuba ubuncinci bexesha elingu-24-48hours phakathi konyango lwe-chemotherapy kunye nokubuyela kwisidlo esiqhelekileyo kubalulekile ukunqanda ukudibanisa imiqondiso yokubuya kwakhona ekhoyo ngexesha lokuphinda usebenze emva kokuzila ukutya kunye namanqanaba aphezulu eziyobisi ezinetyhefu ezinje ngekhemotherapy. Izifundo zeklinikhi zokuzila ukutya okanye i-FMD kwizigulana ezenza inkxaso ye-chemotherapy ukusebenza kwayo kunye nokhuseleko ngokubanzi52,53,58,61. Kwilingo elincinci elincinci elingenamkhethe elibhalise abaguli abangama-34, i-FMD yanceda abaguli bagcina umgangatho wobomi babo ngexesha le-chemotherapy kunye nokunciphisa ukudinwa61. Ukongeza, idatha yokuqala iphakamisa ukubakho kokuzila ukutya okanye ii-FMDs ukunciphisa ichemotherapy eyenziweyo Ukulimala kweDNA kwiiseli ezinempilo kwizigulana52,53.

Izifundo zeklinikhi eziqhubekayo ze-FMDs kwizigulana ezinomhlaza63,65-68 ziya kubonelela ngeempendulo ezomeleleyo zokuba ngaba ukumisela ii-FMD ngamaxesha athile ngokudibanisa ne-arhente yesiqhelo ye-anticancer kuyanceda ukuphucula ukunyamezelana kunye nomsebenzi wale yokugqibela. Kubalulekile ukuba uqaphele ukuba ii-FMDs azizukusebenza ekunciphiseni iziphumo ebezingalindelekanga kunyango kuzo zonke izigulana kwaye ngekhe zisebenze ukuphucula ukusebenza kwazo zonke iindlela zonyango, kodwa zinamandla amakhulu okwenza oko ubuncinci kwinxalenye kwaye mhlawumbi kwinxalenye enkulu yezigulana kunye neziyobisi. Ukunyanga okanye abaguli abangondlekanga okanye abaguli abasemngciphekweni wokungondleki akufuneki babhaliswe kwizifundo zekliniki zokuzila ukutya okanye ii-FMD, kwaye imeko yesondlo sesigulana kunye neanorexia kufuneka zijongwe ngononophelo kuzo zonke izilingo zeklinikhi. Ifanelekile Ukufunxa iiprotein, ii-acids ezibalulekileyo, iivithamini kwaye iiminerali zidibeneyo, apho kunokwenzeka khona, kunye nokukhanya kunye / okanye umthambo omileyo wokusebenza ojolise ekwandiseni umsipha Bunzima kufuneka ifakwe phakathi kwemijikelezo yokuzila okanye ye-FMD ukwenzela ukuba abaguli bagcine ubunzima be-bodyXXUMX esempilweni. Le ndlela yokutya yokutya okuninzi iya kukhulisa izibonelelo zokuzila okanye ze-FMD ngelixa kwangaxeshanye ukhusela izigulana kukungondleki.

Iingxelo:

• 

• 

• 

•