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, with certain cancers being more dependent on dietary habits than others1�9 . Consistent with this notion, obesity is estimated to account for 14% to 20% of all cancer-related mortality in the United States7 , leading to guidelines on nutrition and physical activity for reducing the risk of developing cancer6 . In addition, given the emerging propensity of cancer cells, but not of normal tissues, to disobey anti-growth signals (owing to oncogenic mutations)10 and their inability to properly adapt to fasting conditions11,12, there is growing interest in the possibility that certain calorie-limited diets could also become an integral part of cancer prevention and, perhaps, of cancer treatment as a means to increase efficacy and tolerability of anticancer agents11�13.

Even though in the past decade we have witnessed unprecedented changes and remarkable advances in cancer treatment14,15, there remains a crucial need for more effective and, possibly, curative approaches for tumours but also, and just as importantly, for strategies to reduce the side effects of cancer treatments15,16. The issue of treatment-emergent adverse events (TEAEs) is one of the key hurdles in medical oncology15,16. In fact, many patients with cancer experience acute and/or longterm side effects of cancer treatments, which may require hospitalization and aggressive treatments (such as antibiotics, haematopoietic growth factors and blood transfusions) and profoundly affect their quality of life (for example, chemotherapyinduced peripheral neuropathy)16. Thus, effective toxicity-mitigating strategies are warranted and anticipated to have major medical, societal and economic impact15,16.

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

The response to fasting is orchestrated in part by the circulating levels of glucose, insulin, glucagon, growth hormone (GH), IGF1, glucocorticoids and adrenaline. During an initial post-absorptive phase, which typically lasts 6�24hours, insulin levels start to fall, and glucagon levels rise, promoting the breakdown of liver glycogen stores (which are exhausted after approximately 24hours) and the consequent release of glucose for energy.

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.

Glucocorticoids and adrenaline also contribute to direct the metabolic adaptations to fasting, helping maintain blood sugar levels and stimulating lipolysis20,21. Notably, although fasting can at least temporarily increase GH levels (to increase gluconeogenesis and lipolysis and to decrease peripheral glucose uptake), fasting reduces IGF1 levels. In addition, under fasting conditions, IGF1 biological activity is restrained in part by an increase in the levels of insulin-like growth factor binding protein 1 (IGFBP1), which binds to circulating IGF1 and prevents its interaction with the corresponding cell surface receptor22.

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

The response of healthy cells to fasting is evolutionarily conserved and confers cell protection, and at least in model organisms, has been shown to increase lifespan and healthspan12,22,25�31. The IGF1 signalling cascade is a key signalling pathway involved in mediating the effects of fasting at the cellular level. Under normal nutrition, protein consumption and increased levels of amino acids increase IGF1 levels and stimulate AKT and mTOR activity, thereby boosting protein synthesis. Vice versa, during fasting, IGF1 levels and downstream signalling decrease, reducing AKT-mediated inhibition of mammalian FOXO transcription factors and allowing these transcription factors to transactivate genes, leading to the activation of enzymes such as haem oxygenase 1 (HO1), superoxide dismutase (SOD) and catalase with antioxidant activities and protective effects32�34. High glucose levels stimulate protein kinase A (PKA) signalling, which negatively regulates the master energy sensor AMP-activated protein kinase (AMPK)35, which, in turn, prevents the expression of the stress resistance transcription factor early growth response protein 1 (EGR1) (Msn2 and/or Msn4 in yeast)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

The dietary approaches based on fasting that have been investigated more extensively in oncology, both preclinically and clinically, include water fasting (abstinence from all food and drinks except for water) and FMDs11,12,17,25,26,50�60 (Table 1). Preliminary clinical data indicate that a fast of at least 48hours may be required to achieve clinically meaningful effects in oncology, such as preventing chemotherapy-induced DNA damage to healthy tissues and helping to maintain patient quality of life during 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.

Notably, KDs may be effective for preventing the increase in glucose and insulin that typically occurs in response to PI3K inhibitors, which was proposed to limit their efficacy72. Traditionally, KDs have been used for treating refractory epilepsy, mainly in children69. In mouse models, KDs induce anticancer effects, particularly in glioblastoma70,72�86. Clinical studies indicate that KDs probably have no substantial therapeutic activity when used as single agents in patients with cancer and suggest that potential benefits of these diets should be sought in combination with other approaches, such as chemotherapy, radiotherapy, antiangiogenic treatments, PI3K inhibitors and 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

Some yeast oncogene orthologues, such as Ras and Sch9 (functional orthologue of mammalian S6K), are able to decrease stress resistance in model organisms27,28. In addition, mutations that activate IGF1R, RAS, PI3KCA or AKT, or that inactivate PTEN, are present in the majority of human cancers10. Together, this led to the hypothesis that starvation would cause opposite effects in cancer versus normal cells in terms of their ability to withstand cell stressors, including chemotherapeutics. In other words, starvation can lead to a differential stress resistance (DSR) between normal and cancer cells.

According to the DSR hypothesis, normal cells respond to starvation by downregulating proliferation associated and ribosome biogenesis and/or assembly genes, which forces cells to enter a self-maintenance mode and shields them from the damage caused by chemotherapy, radiotherapy and other toxic agents. By contrast, in cancer cells, this self-maintenance mode is prevented through oncogenic changes, which cause constitutive inhibition of stress response pathways12 (Fig. 1). Consistent with the DSR model, short-term starvation or the deletion of proto-oncogene homologues (that is, Sch9 or both Sch9 and Ras2) increased protection of Saccharomyces cerevisiae against oxidative stress or chemotherapy drugs by up to 100-fold as compared with yeast cells expressing the constitutively active oncogene homologue Ras2val19.

Similar results were obtained in mammalian cells: exposure to low-glucose media protected primary mouse glia cells against toxicity from hydrogen peroxide or cyclophosphamide (a prooxidant chemotherapeutic) but did not protect mouse, rat and human glioma and neuroblastoma cancer cell lines. Consistent with these observations, a 2-day fasting effectively increased the survival of mice treated with high-dose etoposide compared with non-fasted mice and increased the survival of neuroblastoma allograftbearing mice compared with non-fasted tumor-bearing mice12.

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

Both dexamethasone and mTOR inhibitors are widely used in cancer treatment, either because of their efficacy as anti-emetics and anti-allergics (that is, corticosteroids) or for their antitumour properties (that is, corticosteroids and mTOR inhibitors). However, one of their main and frequently dose-limiting side effects is hyperglycaemia. Consistent with the notion that increased glucose�cAMP� PKA signalling reduces resistance to toxicity of chemotherapeutic drugs12,26,126, both dexamethasone and rapamycin increase toxicity of doxorubicin in mouse cardiomyocytes and mice26. Interestingly it was possible to reverse such toxicity by reducing circulating glucose levels through either fasting or 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

If used alone, most dietary interventions, including fasting and FMDs, have limited effects against cancer progression. According to the differential stress sensitization (DSS) hypothesis, the combination of fasting or FMDs with a second treatment is much more promising11,12. This hypothesis predicts that, while cancer cells are able to adapt to limited oxygen and nutrient concentrations, many types of cancer cells are not able to execute changes that would allow survival in the nutrient-deficient and toxic environment generated by the combination of fasting and chemotherapy, for example. Early experiments in breast cancer, melanoma and glioma cells found a paradoxical increase in the expression of proliferation-associated genes or of ribosome biogenesis and assembly genes in response to fasting11,12. Such changes were accompanied by unexpected AKT and S6K activation, a propensity to generate ROS and DNA damage and a sensitization to DNA-damaging drugs (via DSS)11.

We consider such an inappropriate response of cancer cells to the altered conditions including the reduction in IGF1 and glucose levels caused by fasting or FMDs as a key mechanism underlying the antitumour properties of these dietary interventions and their potential usefulness for separating the effects of anticancer treatments on normal versus malignant cells11,12 (Fig. 1). In line with the DSS hypothesis, periodic cycles of fasting or of FMDs are sufficient to slow the growth of many types of tumour cells, ranging from solid tumour cell lines to lymphoid leukaemia cells, in the mouse and, most importantly, to sensitize cancer cells to chemotherapeutics, radiotherapy and tyrosine kinase inhibitors (TKIs)11,17,22,25,50,54�57,59,60,124,127,128.

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.

Apart from a change in metabolism, fasting or FMDs elicit other changes that can promote DSS in pancreatic cancer cells. Fasting increases the expression levels of equilibrative nucleoside transporter 1 (ENT1), the transporter of gemcitabine across the plasma membrane, leading to improved activity of this drug128. In breast cancer cells, fasting causes SUMO2-mediated and/or SUMO3-mediated modification of REV1, a DNA polymerase and a p53-binding protein127. This modification reduces the ability of REV1 to inhibit p53, leading to increased p53-mediated transcription of pro-apoptotic genes and, ultimately, to cancer cell demise (Fig. 2). Fasting also increases the ability of commonly administered TKIs to stop cancer cell growth and/or death by strengthening MAPK signalling inhibition and, thereby, blocking E2F transcription factor-dependent gene expression but also by reducing glucose uptake17,54.

Finally, fasting can upregulate the leptin receptor and its downstream signalling through the protein PR/SET domain 1 (PRDM1) and thereby inhibit the initiation and reverse the progression of B cell and T cell acute lymphoblastic leukaemia (ALL), but not of acute myeloid leukaemia (AML)55. Interestingly, an independent study demonstrated that B cell precursors exhibit a state of chronic restriction in glucose and energy supplies imposed by the transcription factors PAX5 and IKZF1 (ref. 130). Mutations in the genes encoding these two proteins, which are present in more than 80% of the cases of pre-B cell ALL, were shown to increase glucose uptake and ATP levels. However, reconstituting PAX5 and IKZF1 in preB-ALL cells led to an energy crisis and cell demise. Taken together with the previous study, this work indicates that ALL may be sensitive to the nutrient and energy restriction imposed by fasting, possibly representing a good clinical candidate for testing the efficacy of fasting or 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

Recent data suggest that fasting or FMDs by themselves, and to a greater extent when combined with chemotherapy, trigger the expansion of lymphoid progenitors and promote tumour immune attack via different mechanisms25,56,60,124. An FMD reduced the expression of HO1, a protein that confers protection against oxidative damage and apoptosis, in cancer cells in vivo but upregulated HO1 expression in normal cells124,131. HO1 downregulation in cancer cells mediates FMD-induced chemosensitization by increasing CD8+ tumour-infiltrating lymphocyte-dependent cytotoxicity, which may be facilitated by the downregulation of regulatory T cells124 (Fig. 2). Another study, which confirmed the ability of fasting or FMDs and CR mimetics to improve anticancer immunosurveillance, implies that the anticancer effects of fasting or FMDs may apply to autophagy competent, but not autophagy-deficient, cancers56. Finally, a recent study of alternate-day fasting for 2 weeks in a mouse colon cancer model showed that, by activating autophagy in cancer cells, fasting downregulates CD73 expression and consequently decreases the production of immunosuppressive adenosine by cancer cells60. Ultimately, CD73 downregulation via fasting was shown to prevent macrophage shift to an M2 immunosuppressive phenotype (Fig. 2). On the basis of these studies, it is appealing to speculate that FMDs could be particularly useful instead of or in combination with immune checkpoint inhibitors132, cancer vaccines or other drugs that prompt antitumour immunity, including some conventional 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

Chronic KDs also show a tumour growth-delaying effect when used as a monotherapy, particularly in brain cancer mouse models77,78,80�82,84,134. Gliomas in mice maintained on a chronic KD have reduced expression of the hypoxia marker carbonic anhydrase 9 and of hypoxia-inducible factor 1?, decreased nuclear factor-?B activation and reduced vascular marker expression (that is, vascular endothelial growth factor receptor 2, matrix metalloproteinase 2 and vimentin)86. In an intracranial mouse model of glioma, mice fed a KD exhibited increased tumour-reactive innate and adaptive immune responses that were primarily mediated by CD8+ T cells79. KDs were shown to improve the activity of carboplatin, cyclophosphamide and radiotherapy in glioma, lung cancer and neuroblastoma mouse models73�75,135. In addition, a recent study shows that a KD could be very useful in combination with PI3K inhibitors72. By blocking insulin signalling, these agents promote glycogen breakdown in the liver and prevent glucose uptake in the skeletal muscle, which leads to transient hyperglycaemia and to a compensatory insulin release from the pancreas (a phenomenon known as �insulin feedback�). In turn, this raise in insulin levels, which can be protracted, particularly in patients with insulin resistance, reactivates PI3K�mTOR signalling in tumours, thus strongly limiting the benefit of PI3K inhibitors. A KD was shown to be very effective at preventing insulin feedback in response to these drugs and to strongly improve their anticancer activity in the mouse. Finally, according to a study in a murine tumour-induced cachexia model (MAC16 tumours), KDs could help prevent the loss of fat and non-fat body mass in patients with cancer85.

CR reduced tumorigenesis in genetic mouse cancer models, mouse models with spontaneous tumorigenesis and carcinogen induced cancer mouse models, as well as in monkeys91,92,97,98,101,102,104�106,108,109,136�138. By contrast, a study found that CR from middle age actually increases the incidence of plasma cell neoplasms in C57Bl/6 mice139. However, in the same study, CR also extended maximum lifespan by approximately 15%, and the observed increase in cancer incidence was attributed to the increased longevity of mice undergoing CR, the age at which tumour-bearing mice undergoing CR died and the percentage of tumour-bearing mice undergoing CR that died. Thus, the authors concluded that CR probably retards promotion and/or progression of existing lymphoid cancers. A meta-analysis comparing chronic CR with intermittent CR in terms of their ability to prevent cancer in rodents concluded that intermittent CR is more effective in genetically engineered mouse models, but it is less effective in chemically induced rat models90. CR was shown to slow tumour growth and/or to extend mouse survival in various cancer mouse models, including ovarian and pancreatic cancer140,94 and neuroblastoma81.

Importantly, CR improved the activity of anticancer treatment in several cancer models, including the activity of an antiIGF1R antibody (ganitumab) against prostate cancer141, cyclophosphamide against neuroblastoma cells135 and autophagy inhibition in xenografts of HRAS-G12Vtransformed immortal baby mouse kidney epithelial cells100. However, CR or a KD in combination with anticancer therapies seems to be less effective than fasting. A mouse study found that, in contrast to fasting alone, CR alone was not able to reduce the growth of subcutaneously growing GL26 mouse gliomas and that, again, in contrast to short-term fasting, CR did not increase cisplatin activity against subcutaneous 4T1 breast tumours51. In the same study, fasting also proved substantially more effective than CR and a KD at increasing the tolerability of doxorubicin51. Although fasting or an FMD, CR and a KD likely act on and modulate overlapping signalling pathways, fasting or an FMD probably affects such mechanisms in a more drastic fashion during an intense acute phase of a maximum duration of a few days.

The phase of refeeding could then favour the recovery of homeostasis of the whole organism but also activate and invigorate mechanisms that can promote the recognition and removal of the tumour and regenerate the healthy cells. CR and a KD are chronic interventions that are able to only moderately repress nutrient-sensing pathway, possibly without reaching certain thresholds necessary to improve the effects of anticancer drugs, while imposing a major burden and often a progressive weight loss. CR and a KD as chronic dietary regimens in patients with cancer are difficult to implement and likely bear health risks. CR would likely lead to severe loss of lean body mass and the reduction of steroid hormones and possibly immune function142. Chronic KDs are also associated with similar although less severe side effects143. Thus, periodic fasting and FMD cycles lasting less than 5 days applied together with standard therapies have a high potential to improve cancer treatment while reducing its side effects. Notably, it will be important to study the effect of the combination of periodic FMDs, chronic KDs and standard therapies, particularly for the treatment of aggressive cancers such as 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.

As discussed earlier, FMD cycles cause downregulation of IGF1 and glucose and upregulation of IGFBP1 and ketone bodies, which are changes similar to those caused by fasting itself and are biomarkers of the fasting response22. When C57Bl/6 mice (which spontaneously develop tumours, primarily lymphomas, as they age) were fed such an FMD for 4 days twice a month starting at middle age and an ad libitum diet in the period between FMD cycles, the incidence of neoplasms was reduced from approximately 70% in mice on the control diet to approximately 40% in mice in the FMD group (an overall 43% reduction)22. In addition, the FMD postponed by over 3 months the occurrence of neoplasm related deaths, and the number of animals with multiple abnormal lesions was more than threefold higher in the control group than in the FMD mice, indicating that many tumours in the FMD mice were less aggressive or benign.

A previous study of alternate-day fasting, which was performed in middle-aged mice for a total of 4 months, also found that fasting reduced the incidence of lymphoma, bringing it from 33% (for control mice) to 0% (in fasted animals)145, although because of the short duration of the study it is unknown whether this fasting regimen prevented or simply delayed the tumour onset. Furthermore, alternate-day fasting imposes 15 days per month of complete water-only fasting, whereas in the FMD experiment described above mice were placed on a diet that provided a limited amount of food for only 8 days per month. In humans, 3 cycles of a 5-day FMD once a month were shown to reduce abdominal obesity and markers of inflammation as well as IGF1 and glucose levels in subjects with elevated levels of these markers62, indicating that periodic use of an FMD could potentially have preventive effects for obesity-related or inflammation-related, but also other, cancers in humans, as it has been shown for mice22.

Therefore, the promising results of preclinical studies combined with the clinical data on the effect of an FMD on risk factors for ageing-associated diseases, including cancer62, lend support to future randomized studies of FMDs as a possibly effective tool to prevent cancer, as well as other ageing-associated chronic conditions, in humans.

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.

Short-term fasting was well tolerated and reduced the drop in mean erythrocyte and thrombocyte counts 7 days after chemotherapy. Interestingly, in this study, the levels of ?-H2AX (a marker of DNA damage) were increased 30minutes after chemotherapy in leukocytes from non-fasted patients but not in patients who had fasted. In a dose escalation of fasting in patients undergoing platinum-based chemotherapy, 20 patients (who were primarily treated for either urothelial, ovarian or breast cancer) were randomized to fast for 24, 48 or 72hours (divided as 48hours before chemotherapy and 24hours after chemotherapy)53. Feasibility criteria (defined as three or more out of six subjects in each cohort consuming?200kcal per day during the fast period without excess toxicity) were met. Fasting-related toxicities were always grade 2 or below, the most common being fatigue, headache and dizziness. As in the previous study, reduced DNA damage (as detected by comet assay) in leukocytes from subjects who fasted for at least 48hours (as compared with subjects who fasted for only 24hours) could also be detected in this small trial. In addition, a nonsignificant trend towards less grade 3 or grade 4 neutropenia in patients who fasted for 48 and 72hours versus those who fasted for only 24hours was also documented.

Very recently, a randomized crossover clinical trial was conducted assessing the effects of an FMD on quality of life and side effects of chemotherapy in a total of 34 patients with breast or ovarian cancer61. The FMD consisted of a daily caloric intake of<400kcal, primarily by juices and broths, starting 36�48hours before the beginning of chemotherapy and lasting until 24hours after the end of chemotherapy. In this study, the FMD prevented the chemotherapy induced reduction in quality of life and it also reduced fatigue. Again, no serious adverse events of the FMD were reported. Several other clinical trials of FMDs in combination with chemotherapy or with other types of active treatments are currently ongoing at US and European hospitals, primarily in patients who are diagnosed with breast or prostate cancer63,65�68. These are either one-arm clinical studies to assess FMD safety and feasibility or randomized clinical studies focusing either on the effect of the FMD on the toxicity of chemotherapy or on the quality of life of patients during chemotherapy itself. Altogether, these studies have now enrolled over 300 patients, and their first results are expected to become available in 2019.

Imiceli mngeni kwikliniki

The study of periodic fasting or of FMDs in oncology is not devoid of concerns, particularly in relation to the possibility that this type of dietary regimen could precipitate malnutrition, sarcopenia, and cachexia in predisposed or frail patients (for example, patients who develop anorexia as a consequence of chemotherapy)18,19. However, no instances of severe (above grade 3) weight loss or of malnutrition were reported in the clinical studies of fasting in combination with chemotherapy published as of now, and those patients who did experience a weight loss during fasting typically recovered their weight before the subsequent cycle without detectable harm. Nevertheless, we recommend that periodic anorexia and nutritional status assessments using gold-standard approaches18,19,146�150 should be an integral part of these studies and that any ensuing nutritional impairment in patients undergoing fasting and/or FMDs is rapidly corrected.

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.

This combination may be particularly potent for several reasons: first, cancer drugs and other therapies can be effective, but a portion of patients do not respond because cancer cells adopt alternative metabolic strategies leading to survival. These alternative metabolic modes are much more difficult to sustain under fasting or FMD conditions because of the deficiencies or changes in glucose, certain amino acids, hormones, and growth factors, as well as in other unknown pathways leading to cell death. Second, fasting or FMDs can prevent or reduce resistance acquisition. Third, fasting or FMDs protect normal cells and organs from the side effects caused by a wide variety of cancer drugs. On the basis of preclinical and clinical evidence of feasibility, safety and efficacy (at reducing IGF1, visceral fat and cardiovascular risk factors), FMDs also appear as a viable dietary approach to be studied in cancer prevention. An important future challenge will be to identify those tumours that are the best candidates to benefit from fasting or FMDs. Even in cancer types that are apparently less responsive to fasting or FMDs, it may still be possible to identify the mechanisms of resistance and to intervene with drugs able to revert that resistance. Conversely, more caution should be adopted with other types of diets, especially if high in calories, as they could lead to exacerbated and not inhibited growth of certain cancers. For example, the KD increases growth of a melanoma model with mutated BRAF in mice123, and it was also reported to accelerate disease progression in a mouse AML model72.

Furthermore, it is essential to apply FMDs with an understanding of the mechanisms of action, since their potency if applied incorrectly could generate negative effects. For example, when rats were fasted and treated with a potent carcinogen before refeeding, this resulted in the growth of aberrant foci in liver, colon and rectum when compared with non-fasted rats151,152. Although the mechanisms involved in this effect are not understood, and these foci may have not resulted in tumours, these studies suggest that a minimum period of 24�48hours between the chemotherapy treatment and the return to the normal diet is important to avoid combining the regrowth signals present during the refeeding after fasting with high levels of toxic drugs such as chemotherapy. The clinical studies of fasting or FMD in patients undergoing chemotherapy support its feasibility and overall safety52,53,58,61. In a small-size randomized trial that enrolled 34 patients, an FMD helped patients maintain their quality of life during chemotherapy and reduced fatigue61. In addition, preliminary data suggest the potential of fasting or FMDs to reduce chemotherapy induced DNA damage in healthy cells in patients52,53.

Ongoing clinical studies of FMDs in patients with cancer63,65�68 will provide more solid answers as to whether prescribing periodic FMDs in combination with conventional anticancer agents helps improve tolerability and activity of the latter. It is important to consider that FMDs will not be effective in reducing the side effects of cancer treatments in all patients and neither will they work to improve the efficacy of all therapies, but they have great potential to do so at least for a portion and possibly for a major portion of patients and drugs. Frail or malnourished patients or patients at risk of malnutrition should not be enrolled in clinical studies of fasting or FMDs, and patient nutritional status and anorexia should be carefully monitored throughout clinical trials. An appropriate intake of proteins, essential fatty acids, vitamins and minerals combined, where possible, with light and/or moderate physical activity aimed at increasing muscle mass should be applied between fasting or FMD cycles in order for the patients to maintain a healthy lean body mass18,19. This multimodal dietary approach will maximize the benefits of fasting or FMDs while at the same time protecting patients from malnutrition.

Iingxelo: