Thawj qhov ua rau qog yog tias oxidative ua pa ntawm lub cev ib txwm hloov los ntawm fermentation ntawm carbohydrates. Raws li ib txwm muaj, txhua tus tib neeg lub hlwb yog lub luag haujlwm aerobic hlwb, thaum qee cov qog hlwb yog cov hlwb anaerobic. "
Thaum lub rooj sib tham Nobel nqi zog hauv xyoo 1966, Otto Warburg tau piav qhia luv luv txog nws txoj kev xav tias "cov qog nqaij hlav yog kab mob metabolic". Niaj hnub no, kev tshawb fawb ntawm cov tshuaj tiv thaiv qog tau ua tiav los ntawm "kev kho tus kheej", txhawm rau nrhiav cov tshuaj uas tuaj yeem cuam tshuam cov kev ua haujlwm tshwj xeeb uas cuam tshuam rau cov qog cell proliferation. Nrog rau txoj kev loj hlob ntawm tib neeg chromosome sequencing thiab kev txheeb xyuas ntawm cov qog nqaij hlav genetic susceptibility noob, ntau cov tshuaj tsom rau cov noob caj noob ces tshwj xeeb lossis cov khoom lag luam tau pom.
Vim tias cov kab mob tshwj xeeb lossis cov noob hloov pauv tsis tsim nyog rau txhua hom qog nqaij hlav, nws yog ib qho tsim nyog yuav tsum nrhiav cov biomarkers tshwj xeeb txhawm rau txiav txim siab seb cov neeg mob twg tuaj yeem tau txais txiaj ntsig los ntawm kev kho mob. Txawm li cas los xij, yog tias mob qog nqaij hlav yog "qhov tshwm sim ntawm mitochondrial dysfunction" raws li Warburg tau piav qhia, tom qab ntawd qhov inhibition ntawm ATP synthesis yuav ua rau muaj kev cuam tshuam nyiaj ntxiv hauv fermentation, yog li qog yog kab mob tshwm sim los ntawm lub zog tsis txaus.
Qhov kev pom no los ntawm cov metabolism yog qhov tsis sib xws rau tam sim no lub ntsiab saib, uas tuav tau tias kev hloov pauv polygenic yog lub hauv paus ntawm ntau hom kab mob. Raws li Warburg txoj kev xav, gene mutation tsuas yog ib tug neeg nyob hauv qhov kev ua txhaum ntawm cov qog nqaij hlav, tab sis "cov neeg ua phem tiag" ferment thiab khiav tawm txoj cai, tab sis Warburg tsis tau txheeb xyuas qhov tseeb ntawm qhov kev tshuaj ntsuam no.
Nyob rau hauv luv luv, irreversible mitochondrial dysfunction ua rau ib tug series ntawm noob hloov pauv cov tshuaj tiv thaiv, uas zoo heev txhawb lub "thib ob zoo tshaj" ATP ntau lawm hom-glycolysis. Qhov tseeb, kev hloov noob caj noob ces feem ntau suav tias yog thawj qhov ua rau qog tshwm sim, tab sis kev hloov noob caj noob ces yuav yog qhov tshwm sim ntawm metabolic thiab lub zog tsis txaus lossis cov tshuaj tiv thaiv.
Txuas ntxiv, txawm hais tias Warburg tsis tau hais ncaj qha tias kev hloov pauv lossis tshaj tawm ntawm HIF1- , c-myc, ras, IGF-1 thiab PI3K/Akt/mTOR ncaj qha lossis ncaj qha txhawb nqa glycolytic metabolism, noob hloov pauv. tej zaum yuav ua si "lub luag haujlwm thib ob" es tsis yog "lub luag haujlwm ntawm tus neeg ntxeev siab" hauv cov qog nqaij hlav. Vim tias yam xws li HIF1-, c-myc, ras, IGF-1 thiab PI3K/Akt/mTOR ua lub luag haujlwm tseem ceeb hauv glycolytic metabolism.
Nyob rau hauv ib puag ncig hypoxia, qog hlwb xaiv qhib glycolysis metabolism thiab nce-tswj cov kev qhia ntawm angiogenic yam, uas thaum kawg txhawb kev tshwm sim thiab metastasis ntawm cov qog. Pom tseeb, lub voj voog vicious raws li ATP qhov chaw tsis yog oxidative phosphorylation thaum kawg tsim. Interestingly, qee cov qog tseem tuaj yeem xaiv glycolysis metabolism hauv thiaj li yuav tau txais ntau lub zog txiaj ATP, uas ua rau mob qog noj ntshav rau qee yam.
Los ntawm txoj kev kho qhov muag, imatinib, ib zaug lub npe hu ua targeted inhibitor, deviated los ntawm nws cov hom phiaj qub ntawm cov piam thaj transporter -1(GLUT-1) thiab qabzib -6- phosphate dehydrogenase (G6PD) nyob rau hauv kev kho mob daim ntawv thov, yog li nws kuj poob nws lub peev xwm los cuam tshuam nrog cell zog metabolism. Nws tuaj yeem pom tau tias kev txhim kho ntawm tus kheej cov tshuaj gene tsis tau muab cov tswv yim zoo los tiv thaiv qog.
Tsis tas li ntawd, ntau tus kws tshawb fawb xws li Seyfried ntseeg tias ib qho "rov qab txoj kev xav", xws li Warburg effect, yuav ua rau muaj kev cuam tshuam tsis zoo thaum nws sib txawv ntawm cov noob hauv nruab nrab ntawm cov kev tshawb fawb tseem ceeb tam sim no. Kev tshawb fawb thiab kev tsim cov txheej txheem ntawm cov tshuaj tiv thaiv qog tsom rau cov qog lub zog metabolism tau hloov zuj zus mus rau hauv "kev yos hav zoov dab" ntawm qib molecular.
Thawj qhov ua rau mob qog nqaij hlav yog qhov oxidative ua pa ntawm cov hlwb ib txwm hloov los ntawm fermentation ntawm carbohydrates. Raws li ib txwm muaj, txhua lub hlwb tib neeg yog cov hlwb tshwj xeeb aerobic, thaum qee cov qog hlwb yog cov hlwb anaerobic.
Nyob rau xyoo 1966 Nobel Prize Conference, Otto Warburg tau sau tseg nws txoj kev xav tias 'cov qog yog kab mob metabolic'. Niaj hnub no, kev tshawb fawb ntawm cov tshuaj tiv thaiv qog tau ua tiav los ntawm "kev kho tus kheej", txhawm rau nrhiav cov tshuaj uas tuaj yeem cuam tshuam cov kev ua haujlwm tshwj xeeb uas cuam tshuam rau cov qog cell proliferation. Nrog rau txoj kev loj hlob ntawm tib neeg chromosome sequencing thiab kev txheeb xyuas ntawm cov qog nqaij hlav genetic susceptibility noob, ntau yam tshuaj tsom rau cov noob caj noob ces los yog cov khoom lag luam tau tshawb pom.
Txij li cov kab mob tshwj xeeb lossis kev hloov pauv tsis tsim nyog rau kev loj hlob ntawm txhua hom qog nqaij hlav, nws yog ib qho tsim nyog yuav tsum tshawb nrhiav cov biomarkers tshwj xeeb txhawm rau txiav txim siab seb cov neeg mob twg tuaj yeem tau txais txiaj ntsig los ntawm kev kho mob. Txawm li cas los xij, yog tias cov qog nqaij hlav tsis zoo yog qhov tshwm sim ntawm mitochondrial dysfunction, raws li tau piav qhia los ntawm Warburg, tom qab ntawd ATP synthesis inhibition tuaj yeem ua rau muaj kev cuam tshuam nyiaj ntxiv hauv fermentation, ua rau cov qog ua kab mob tshwm sim los ntawm lub zog tsis txaus.
Qhov kev xav ntawm metabolic no cuam tshuam qhov kev pom tam sim no, uas tuav tau tias kev hloov pauv polygenic yog lub hauv paus rau qhov tshwm sim ntawm ntau hom kab mob. Raws li Warburg txoj kev xav, kev hloov pauv caj ces tsuas yog "tus neeg sawv cev" ntawm "kev ua txhaum cai" qhov twg cov qog tshwm sim, thaum "cov neeg ua phem tiag tiag" ferment thiab khiav tawm txoj cai. Txawm li cas los xij, Warburg tsis tau txheeb xyuas qhov tseeb ntawm qhov kev tshuaj ntsuam no.
Nyob rau hauv luv luv, irreversible mitochondrial dysfunction ua rau ib tug saw cov tshuaj tiv thaiv ntawm noob hloov, uas zoo heev txhawb lub "thib ob zoo tshaj" ATP ntau lawm hom - glycolysis. Tseeb tiag, kev hloov pauv caj ces feem ntau suav tias yog thawj qhov ua rau mob qog nqaij hlav, tab sis lawv yuav yog qhov tshwm sim ntawm metabolic thiab lub zog tsis txaus lossis cov lus teb rov qab.
Los ntawm kev txuas ntxiv, txawm hais tias Warburg tsis tau hais ncaj qha tias kev hloov pauv lossis kev nthuav tawm ntau dhau ntawm HIF-1- , myc, ras, IGF-1, thiab PI3K / Akt / mTOR cov noob ncaj qha lossis ncaj qha txhawb nqa glycolysis metabolism, cov noob hloov pauv tuaj yeem ua si. yog "lub luag haujlwm thib ob loj tshaj" es tsis yog "lub luag haujlwm sab hauv" hauv cov qog nqaij hlav. Vim tias yam xws li HIF-1- , c-myc, ras, IGF-1, thiab PI3K/Akt/mTOR ua lub luag haujlwm tseem ceeb hauv glycolytic metabolism.
Nyob rau hauv cov xwm txheej hypoxic, qog hlwb xaiv los qhib glycolytic metabolism thiab txhawb kev qhia ntawm angiogenic yam, thaum kawg txhawb cov qog tshwm sim thiab metastasis. Nws pom tseeb tias lub voj voog tsis zoo raws li ATP cov peev txheej ntau dua li oxidative phosphorylation tau tsim thaum kawg. Nws yog qhov nthuav tias qee cov qog tseem tuaj yeem xaiv glycolysis metabolism hauv lub xeev aerobic kom tau txais ntau lub zog txiaj ATP, uas rau qee qhov ua rau mob qog nqaij hlav phenotype.
Los ntawm kev xav txog kev kho mob, lub npe hu ua targeted inhibitor imatinib tau deviated los ntawm nws thawj lub hom phiaj glucose transporter -1 (GLUT) hauv kev siv tshuaj kho mob
Ntxiv nrog rau kev cia siab rau glycolysis, qog hlwb kuj xav tau glutamine. Zoo li qabzib, glutamine kuj yog ib qho khoom siv ntxiv uas tuaj yeem muab lub zog ua ntej xws li oxaloacetate rau Krebs cycle (tricarboxylic acid cycle).
Vim tias qhov nce hauv cov roj carbon flux tshwm sim los ntawm glycolysis thiab glutamine metabolism, kev sib sau ntawm Krebs lub voj voog ua ntej nruab nrab ua rau lwm txoj hauv kev metabolic, Pentose Phosphate txoj kev.
Txoj kev pentose phosphate tuaj yeem tsim muaj ntau ntawm NADPH, uas tuaj yeem txo glutathione thiab txo qis oxidative kev ntxhov siab hauv hlwb. Tsis tas li ntawd, txoj hauv kev pentose phosphate tuaj yeem tsim muaj ntau ntawm ribose -5-phosphate, uas yog ib qho tseem ceeb ntawm cov molecule rau nucleic acid biosynthesis.
Nyob rau hauv lub ntsej muag ntawm genotoxic kev nyuaj siab los ntawm chemotherapy thiab radiotherapy, cov qog yuav tsum tau hloov mus rau qhov chaw no thiab pib tiv thaiv tus kheej mechanisms, nrog rau cov tshuaj efflux, DNA puas kho, up-regulation ntawm ciaj sia taus-hais txog cov noob qhia, anti-apoptosis thiab ua kom muaj zog. intracellular nyob teeb liab txoj kev. Tag nrho cov kev ua ub no hauv lub neej xav tau ntau cov khoom siv ATP txuas ntxiv.
Ib qho ntawm cov kev hloov kho / kev tiv thaiv saum toj no yuav tsum tau hla-txuas txoj hauv kev cuam tshuam nrog ATP ntau lawm, xws li aerobic glycolysis / glutamine metabolism / pentose phosphate txoj hauv kev. Txawm li cas los xij, cov khoom tsim tau zoo ntawm cov txheej txheem metabolic no qis dua li ntawm oxidative phosphorylation. Yog tias qhov kev thov rau ATP tshaj qhov khoom, yuav muaj "zog tsis txaus". Lub sijhawm no, cov qog nqaij hlav yuav muaj peb lub tswv yim daws teeb meem: nce ATP ntau lawm, thiab "replenishing" ATP los ntawm autophagy lossis txo ATP noj.
Nrog rau qhov txo qis ntawm ATP cov khoom, ntau cov haujlwm ntawm tes raug txwv, xws li tshuaj efflux kho los ntawm ATP-dependent multidrug resistance twj tso kua mis thiab epigenetic silencing ntawm qog suppressor noob xws li p53. Chen et al. pom tias kev txwv tsis pub siv hluav taws xob (2-deoxyglucose thiab 3-bromopryuvate) tuaj yeem rov ua kom cov qog ua ntsiag to ntawm KLF6.
Zhou et al. pom tias cov chemosensitivity ntawm cov tshuaj tiv thaiv qog hlwb tau nce thaum ATP tag lawm, thaum lub chemoresistance ntawm cov tshuaj-sensitive qog hlwb nce thaum exogenous ATP tau muab. Piv nrog rau cov ntaub so ntswg ib txwm muaj, cov qog hlwb xav tau ATP ntau dua, tab sis lawv qhov kev hloov pauv ntawm lub zog tsis zoo. Yog li, txo qis ATP qib los ntawm inhibiting glycolysis tuaj yeem xaiv tua cov qog hlwb.
Qhov no ua rau "kev ciaj sia tseem ceeb dua li kev loj hlob" thiab tau txais kev zam txim. Lub tswv yim no, zoo li Warburg effect, tau dhau los ua tus qauv sib koom ua ke ntawm kev kho mob qog noj ntshav, thiab nws kuj yog lub hauv paus thiab yog vim li cas rau kev hloov pauv ntawm kev kho mob qog noj ntshav. Txawm li cas los xij, txoj kev tshawb fawb ntawm cov tswv yim kho mob yuav tsum tsis txwv rau cov metabolism hauv nws tus kheej, tab sis yuav tsum tau ua los ntawm kev xav ntawm tag nrho ATP thiab NADH ntau lawm.
Nws tsis yog Darwinian kom zoo dua, thiab qhov kev vam khom ntawm cov qog ntawm fermentation tsuas yog ib qho kev tsis muaj zog nyob rau hauv qhov xwm txheej ntawm lub zog tsis txaus, uas yog qhov tsis zoo sib tw piv nrog cov ntaub so ntswg. Yog li ntawd, qhov tsis txaus ntawm cov qog no tuaj yeem siv rau qib kev kho mob, tshwj xeeb tshaj yog txhawm rau txhim kho qhov rhiab heev ntawm kev siv tshuaj khomob.
Cov tswv yim kho mob qog nqaij hlav yav dhau los feem ntau ua tsis tiav vim tias tsis muaj chemosensitivity. Tam sim no muaj txoj hauv kev los txhim kho cov chemosensitivity ntawm cov qog, thiab kev kho mob qog tau dhau los ua tus kab mob ntev thiab kho tau, thiab nws tuaj yeem ua duab hauv technetium 99m (99mTc)-methoxyisobutyl isocyanide (sestamibi) scanner.
Methoxyisobutyl isonitrile yog lub substrate ntawm ATp- nyob ntawm P-glycoprotein twj tso kua mis (Pgp, encoded los ntawm MDR-1 noob). Tus neeg saib xyuas radionuclide no tuaj yeem kuaj pom qhov inhibition ntawm Pgp, yog li cuam tshuam txog kev kho mob rhiab heev ntawm cov qog uas cuam tshuam rau theem pib. Raws li txoj kev ntsuas no, txoj haujlwm ntawm "ua raws ATP" tuaj yeem ua tiav tiav.
2. Glucose metabolism
2.1 glucose transporter inhibitors
Vim tias cov piam thaj yog polar thiab hydrophilic, nws tsis tuaj yeem nkag mus rau hydrophobic cell membrane, yog li xav tau ib qho tshwj xeeb transmembrane transporter-Glucose Transporters (GLUT) . Qhov kev qhia ntawm GLUT hauv cov qog hlwb tau tswj hwm tau zoo, uas qhia tau tias cov qog hlwb siv cov piam thaj los ua lub zog ATP lub zog loj. Cov piam thaj ntau npaum li cas los ntawm cov qog yuav inevitably nce qabzib kom tsawg thiab nws thiaj li ua rau cov piam thaj metabolism ntxiv.
Nws tau pom tias qhov overexpression ntawm ATP yog ze ze rau qhov malignancy, invasiveness thiab tsis zoo prognosis ntawm cov qog. Peb tau teev ntau yam ntawm GLUT-1 inhibitors, xws li irreversible inhibitors (WZB117 thiab Phloretin phloretin), diclofenac (diclofenac), apigegnin, fasentin, STF-31, thiab ritonavir, ib qho tshuaj pom zoo hauv kev kho mob.
WZB117 thiab Phloretin yog irreversible inhibitors ntawm GLUT1, uas yuav txo tau cov piam thaj kom tsawg thiab intracellular ATP theem, yog li inhibiting glycolysis thiab cell loj hlob. Kev ntxiv ntawm exogenous ATP tuaj yeem txo WZB117- induced cytotoxicity ntawm cov qog hlwb, uas qhia tau hais tias GLUT inhibitors xws li WZB117 tuaj yeem cuam tshuam kev loj hlob ntawm cov qog hlwb los ntawm kev txo qis hauv cov hlwb ATP.
Diclofenac tsis tsuas yog muaj kev tiv thaiv kab mob thiab tiv thaiv qog nqaij hlav (kev kho los ntawm COX-1 thiab COX-2), tab sis kuj yog GLUT-1 inhibitor. Cov kev tshawb fawb tsis ntev los no tau pom tias Diclofenac tuaj yeem cuam tshuam cov piam thaj los ntawm cov hlwb melanoma. Zoo li Diclofenac, apigenin, ntuj flavonoid, kuj yog GLUT-1 inhibitor.
Yav dhau los, nws tau kwv yees tias apigenin tuaj yeem tawm tsam nws cov qog nqaij hlav los ntawm kev kaw lub voj voog ntawm tes, tab sis cov kev tshawb fawb tsis ntev los no tau pom tias apigenin tuaj yeem cuam tshuam qhov kev qhia ntawm GLUT-1, yog li txo cov piam thaj kom tsawg ntawm tib neeg cov qog nqaij hlav qog noj ntshav. Saib mus rau lub vev xaib raug cai ntawm kev sim tshuaj, peb tuaj yeem pom tias muaj kev sim tshuaj ntsuam xyuas (NCT00609310) tsom rau kev kawm txog cov nyhuv ntawm apigenin ntawm kev rov tshwm sim ntawm cov qog nqaij hlav hauv plab, tab sis qhov kev sim no tseem tsis tau ua tiav.
Cov kev tshawb fawb txog kab mob kis tau pom tias cov tshuaj tiv thaiv kab mob HIV tuaj yeem txo qhov tshwm sim ntawm qee cov qog, thiab HIV protease inhibitors muaj kev tiv thaiv qog nqaij hlav? Nws tau pom tias Ritonavir tuaj yeem ua rau apoptosis ntawm ntau lub hlwb myeloma (McBrayer) thiab qog noj ntshav zes qe menyuam (Kumar). Kev nthuav qhia siab ntawm cov piam thaj thauj mus los (GLUT 1 thiab GLUT 3) hauv cov ntaub so ntswg ntawm zes qe menyuam muaj feem cuam tshuam rau qhov tsis zoo.
Txawm hais tias apoptosis-inducing nyhuv ntawm Ritonavir ntawm zes qe menyuam qog noj ntshav tej zaum yuav muaj feem xyuam rau inhibition ntawm PI3K / Akt txoj kev, muaj pov thawj tias Ritonavir tuaj yeem inhibit insulin-dependent GLUT4 kev ua. Cov txiaj ntsig ntawm kev tshawb fawb ntawm ntau lub hlwb myeloma qhia tias GLUT8 thiab GLUT11 yog qhov tsim nyog rau kev loj hlob ntawm tes thiab kev ciaj sia, thiab GLUT4 yog qhov tsim nyog rau cell glucose metabolism (ATP ntau lawm).
Hauv vivo cov kev tshawb fawb tau pom tias inhibition ntawm glucose transporter tuaj yeem txo qis-tswj theem ntawm ATp- nyob ntawm P-glycoprotein twj tso kua mis, yog li ua kom cov chemosensitivity ntawm cov qog hlwb. Ritonavir tuaj yeem ua rau muaj kev nkag siab ntawm ntau lub hlwb myeloma rau doxorubicin. Qee cov qog nqaij hlav tiv taus daunorubicin vim muaj ntau dhau ntawm P-glycoprotein. Gluc-1 inhibitor phloretin tuaj yeem txo qhov tsis kam ntawm cov qog hlwb rau daunorubicin.
Piv nrog rau cov lus hais saum toj no nrog lub hom phiaj tsis muaj zog rau GLUT-1 lossis cov khoom ntuj tsim nrog cov txheej txheem ntawm kev ua haujlwm, fasentin yog ib qho me me molecular selective inhibitor ntawm GLUT-1. Nws tau pom tias fasentin tuaj yeem khi rau qhov chaw tshwj xeeb ntawm cov neeg thauj khoom qabzib, txwv tsis pub noj cov piam thaj thiab cov as-ham los ntawm cov hlwb, yog li txhim kho cov rhiab heev ntawm cov hlwb rau FAS thiab qog necrosis factor apoptosis-inducing ligand (TRAIL).
Txawm hais tias fasentin tsis tuaj yeem ntxias cov cell tuag los ntawm nws tus kheej, nws yog qhov pib zoo rau kev nrhiav cov khoom lag luam tsis zoo ntawm cov piam thaj thauj khoom inhibitors, xws li STF-31, uas muaj cov khoom ua kom tuag taus.
2.2 Glucose transporter -1 thiab lub raum cell carcinoma
Lub raum cell carcinoma (RCC) yog qhov piv txwv zoo tshaj plaws uas txoj kev metabolic ua lub luag haujlwm tseem ceeb hauv qog. Lub raum cell carcinoma yog ib qho qog hypoxic, uas feem ntau yog nyob ntawm glycolysis kom tau txais ATP. Piv txwv li, qhov inhibition lossis kev ua haujlwm tsis zoo ntawm cov qog nqaij hlav succinate dehydrogenase (SDH) thiab fumarate hydratase (FH) yuav ua rau kev sib sau ntawm cov dej hauv qab (succinate thiab fumarate).
Lawv yog cov teeb meem metabolic thiab tuaj yeem cuam tshuam kev ua haujlwm ntawm prolyl hydroxylase (PHD). Cov hydroxylases no tsim nyog los tiv thaiv kev sib sau ntawm HIF-1 . Kev sib sau ntawm HIF-1 tuaj yeem ua rau muaj kev tshaj tawm ntawm VEGF, TGF-, PDGF, GLUT1 thiab EPO cov noob, yog li txhawb nqa angiogenesis, cell sib txawv, cell migration thiab cell proliferation. Hauv particular, overexpression ntawm GLUT1 yuav ua rau qog hlwb "addicted" rau qabzib.
Lub raum cell carcinoma yog mob raum mob cancer tshaj plaws rau cov neeg laus, suav txog li 90-95%. Lub raum cell carcinoma hlwb muaj zog heev rau chemotherapy, radiotherapy thiab immunotherapy. Tsis ntev los no, cov tshuaj tiv thaiv kab mob tshiab tau ua tiav, xws li Sutent thiab Nexavar.
Nyob rau hauv feem ntau cov neeg mob uas muaj lub raum cell carcinoma, lub qog suppressor gene von Hippel-Lindau (VHL) yog inactivated, uas yuav ua rau tsub zuj zuj ntawm HIF-1 thiab siab dependence ntawm qog hlwb ntawm GLUT1. Yog li, peb tuaj yeem tsim GLUT1 inhibitors nrog hluavtaws toxicity los kho cov neeg mob lub raum cell carcinoma nrog inactivated VHL.
STF-31 yog ib qho me me molecule GLUT1 inhibitor, uas muaj peev xwm zoo rau kev hloov pauv, tshwj xeeb tshaj yog rau cov qog hlwb inactivated los ntawm VHL. Tsiaj cov qauv kev tshawb fawb qhia tias STF-31 tuaj yeem cuam tshuam cov piam thaj kom tsawg thiab ATP ntau lawm nyob rau hauv VHL-nyob, yog li inducing cell tuag thiab thaum kawg inhibiting qog loj hlob. Vim tias GLUT receptors kuj muaj nyob rau hauv cov ntaub so ntswg ib txwm muaj, koob tshuaj ntau ntawm GLUT inhibitors tuaj yeem ua rau muaj kab mob toxicity.
Txawm li cas los xij, cov tshuaj qis qis GLUT inhibitors tuaj yeem txhim kho qhov rhiab heev ntawm cov hlwb rau cov tshuaj khomob los ntawm kev txo qis ATP qib thiab txo qis cov kev qhia ntawm MDR transporters, tab sis lawv yuav tsis tsim cov kab mob toxicity. Yog li ntawd, nyob rau hauv cov ntaub ntawv ntawm cov tshuaj tsawg, GLUT inhibitors thiab tshuaj cytotoxic tuaj yeem ua ke los tiv thaiv thiab kho cov tshuaj tiv thaiv kab mob.
2.3 Hexose kinase inhibitors
Thaum cov piam thaj hla cov cell membrane thiab nkag mus rau hauv cytoplasm, nws yuav raug phosphorylation los ua cov piam thaj -6- phosphate (G6P). Qhov no yog thawj kauj ruam tseem ceeb ntawm glycolysis, uas yog catalyzed los ntawm hexokinase. Hexokinase hloov cov piam thaj tsis-ionized rau hauv qabzib -6- phosphate los ntawm phosphorylation. Glucose -6- phosphate tsis yog lub substrate ntawm cov piam thaj thauj khoom, yog li cov piam thaj nkag mus rau hauv cov hlwb.
Lonidamine yog ib qho indole derivative, uas yog siv los ua ib qho tshuaj hexokinase hauv qhov ncauj thiab tshuaj tiv thaiv trypanosoma. Nws tau pom tias lonidamine muaj cov tshuaj tiv thaiv qog nqaij hlav, uas tuaj yeem decouple hexokinase los ntawm mitochondria, thiab nws tau nkag mus rau theem ua ntej thiab kev sim tshuaj. Cov txiaj ntsig ntawm kev sim tshuaj ntsuam pom tau hais tias qhov kev kho mob ntawm lonidamine ib leeg tsis pom tseeb.
Txawm li cas los xij, lonidamine kev sib xyaw ua ke ntawm cov tshuaj thiab kws khomob tau zoo. Piv txwv li, kev sib xyaw ntawm lonidamine thiab epirubicin tuaj yeem txo cov tshuaj tiv thaiv mob qog noj ntshav rau epirubicin. Lonidamine kuj tuaj yeem txhim kho cov chemosensitivity ntawm zes qe menyuam qog noj ntshav thiab mob ntsws cancer. Txawm hais tias cov txiaj ntsig tau zoo siab, lawv tsis nruj, uas qhia tau tias yuav tsum tau tshawb fawb ntxiv.
Malignant glioma yog cov qog uas nyob ntawm glycolysis, yog li siv mitochondrial coupled hexokinase los ua lub hom phiaj ntawm kev kho lonidamine? Cov kev tshawb fawb soj ntsuam tau pom tias lonidamine, raws li kev siv hluav taws xob kho hluav taws xob thiab hluav taws xob hluav taws xob hluav taws xob (XRT thiab temizolamide), tuaj yeem kho cov kab mob glioma zoo thiab txhim kho kev ciaj sia ntawm cov neeg mob qog.
Tsis ntev los no, lonidamine tau siv rau hauv kev kho mob ntawm benign prostatic hyperplasia, tab sis tshuaj cuam tshuam txog hepatotoxicity tshwm sim thaum kho, yog li kev tshawb fawb txog kev kho mob raug tso tseg. Kev tshawb nrhiav pom tias tsis muaj kev sim tshuaj tsis tu ncua hauv lonidamine. Txawm li cas los xij, tib neeg txoj kev txaus siab rau lonidamine tsis tau poob qis, thiab lawv tab tom sim txo nws lub cev toxicity los ntawm kev hloov daim ntawv ntau npaum.
2- deoxy -D- qabzib (2-DG) thiab 3- bromopyruvic acid (3-BP) yog cov me me molecular inhibitors ntawm hexokinase -II, uas tuaj yeem ua rau kom cov hlwb rhiab heev. mus rau chemotherapy tshuaj los ntawm kev txo cov theem ntawm intracellular ATP. 2- deoxy -D- qabzib yog cov piam thaj analogue, uas tuaj yeem nkag mus rau cov hlwb thiab tsim 2-DG-P los ntawm phosphorylation. Txawm li cas los xij, 2-DG-P yog ib qho "tawm", uas tsis tuaj yeem koom nrog cov tshuaj tiv thaiv metabolic ntxiv, yog li thaiv glycolysis.
Hauv vivo cov kev tshawb fawb tau pom tias qhov kev kho mob ntawm 2- deoxy -D- qabzib ib leeg tsuas yog txwv, vim tias cov piam thaj endogenous yuav sib tw nrog nws rau qhov chaw nquag ntawm hexokinase. Txawm li cas los xij, thaum 2- deoxy -D- qabzib yog siv ua ke nrog adriamycin thiab paclitaxel, nws tuaj yeem txhim kho cov qog nqaij hlav tom kawg, thiab nws cov txheej txheem yuav cuam tshuam txog kev txo qis ntawm intracellular ATP qib thiab inhibition. ntawm multidrug resistance twj tso kua mis, vim hais tias cov tshuaj efflux yuav tsum tau ntau ATP.
Trastuzumab yog humanized monoclonal antibody tiv thaiv ErbB2, thiab nws tau pom tias nws tuaj yeem txo qhov mob ntawm cov neeg mob ErbB2 zoo mob qog noj ntshav. Txawm li cas los xij, tau txais kev tiv thaiv rau trastuzumab yuav tshwm sim thaum kho, uas yog qhov tsis zoo ntawm trastuzumab. Cov pov thawj tsis ntev los no qhia tau hais tias cov tshuaj tiv thaiv ntawm qog rau trastuzumab feem ntau cuam tshuam nrog kev nce cov piam thaj kom tsawg thiab lactic acid ntau lawm.
Nws tau pom tias 2- deoxy -D- qabzib tuaj yeem txhim kho qhov rhiab heev ntawm cov hlwb tiv taus trastuzumab rau trastuzumab, uas qhia tau tias kev sib xyaw ua ke yuav yog ib qho kev kho mob zoo rau kev mob qog noj ntshav. Tam sim no, 2- deoxy -D- qabzib tau nkag mus rau theem kuv qhov kev sim tshuaj, uas yog qhov ua tau zoo thiab tsis muaj tshuaj lom.
3- bromopyruvate (3-BP) yog ib qho analogue ntawm pyruvate, thiab nws yog ib qho inhibitor ntawm hexokinase thiab 3- glyceraldehyde phosphate dehydrogenase, uas ua lub luag haujlwm tseem ceeb hauv glycolysis. Cov kev tshawb fawb ua ntej tau pom tias 3-BrPA muaj cov txiaj ntsig zoo ntawm cov qog nqaij hlav intrahepatic thiab extrahepatic thaum siv los ntawm cov hlab ntsha hauv siab, thiab nws tsis muaj qhov pom tseeb toxicity.
Cardaci thiab lwm yam kev tshawb fawb tau pom tias 3-BP tuaj yeem ua lub luag haujlwm tshuaj lom los ntawm inhibiting glutamine metabolism, uas yog lwm qhov uas tsis yog-mitochondrial ATP lub zog rau cov qog hlwb. Txawm hais tias glutamine tuaj yeem hloov cov piam thaj hauv cov qog hlwb, 3-BP tseem muaj zog cytotoxicity hauv vitro yam tsis muaj glutamine.
2.4 pyruvate kinase M2 (PKM2) inhibition
Cov kauj ruam kawg ntawm glycolysis yog catalyzed los ntawm pyruvate kinase, thiab phosphoenolpyruvate (PEP) hloov mus rau hauv pyruvate. Muaj plaub subtypes ntawm pyruvate kinase: L, R, M1 thiab M2, ntawm cov uas M2 yog lub ntsiab subtype ntawm pyruvate kinase nyob rau hauv cov qog hlwb. Interestingly, piv nrog rau lwm yam subtypes ntawm pyruvate kinase, cov kev ua ntawm PKM2 (pyruvate kinase M2) yog tsawg heev, uas yuav ua rau cov tsub zuj zuj ntawm upstream intermediates nyob rau hauv glycolysis.
Cov intermediates no tuaj yeem hloov mus rau hauv substrates rau macromolecular synthesis xws li ribose -5- phosphate los ntawm pentose phosphate txoj kev. Txawm hais tias qhov inhibition ntawm PKM2 yuav inhibit qhov kev loj hlob ntawm cov qog, catalysis ntawm PKM2 rau phosphoenolpyruvate rau pyruvate yog ib qho tseem ceeb hauv ATP ntau lawm thiab tseem ceeb rau lub zog homeostasis tu.
Shikonin yog ib qho naphthoquinone derivative ntawm cov tshuaj suav tshuaj suav nrog kev tiv thaiv qog nqaij hlav. Shikonin inhibits qhov kev qhia ntawm PKM2 hauv cov qog hlwb los ntawm kev tsim cov pa oxygen reactive (ROS), thiab cov txheej txheem tshwj xeeb yuav cuam tshuam rau oxidation ntawm cystine residue ntawm txoj hauj lwm 358. Kev tshawb fawb ntawm shikonin hauv kev kho mob qog noj ntshav tau nkag mus rau qhov chaw kho mob thib ob. theem, tab sis tsis muaj ntaub ntawv qhia txog tam sim no.
Vim tias M2 subtype pyruvate kinase muaj ntau dua hauv cov qog hlwb dua li cov ntaub so ntswg, PKM2 tau dhau los ua lub hom phiaj ntawm kev kho tshuaj. Qualcomm kev tshuaj xyuas ntawm cov tshuaj me me raws li MTT txoj kev qhia tias qhov inhibition tus nqi yog 50%, thiab tus nqi ntawm cov tshuaj molecules yog kwv yees li 7%. Txawm hais tias PKM2 inhibitor tau pom, nws qhov kev xaiv rau M1 subtype pyruvate kinase tsis zoo.
Raws li kev xav, PKM2 inhibitors muaj txiaj ntsig zoo tuaj yeem cuam tshuam glycolytic metabolism thiab ATP ntau lawm. Txawm li cas los xij, cov kev xaiv tsis zoo no PKM2 inhibitors yuav muaj lub hom phiaj zoo rau lwm yam subtypes ntawm pyruvate kinase, lossis lawv tuaj yeem siv ua ke nrog lwm cov tshuaj cytotoxic.
Shikonin thiab nws cov analogues (xws li alkannin Lithospermum Liab) yog ntuj dyes thiab khoom noj khoom haus additives, uas tau siv nyob rau hauv lub teb ntawm tsoos suav tshuaj nyob rau hauv Tuam Tshoj rau ntau xyoo. Nws tau pom tias shikonin thiab shikonin tuaj yeem cuam tshuam PKM2, tab sis tsis muaj qhov cuam tshuam rau PKM1 lossis pyruvate kinase -L (PKL), yog li txwv glycolysis thiab ATP ntau lawm. Ob cov tshuaj molecular no muaj cov tshuaj tiv thaiv kab mob rau tib neeg cov qog nqaij hlav qog noj ntshav. Txawm li cas los xij, tsis muaj kev sim tshuaj ntawm shikonin thiab shikonin hauv Tebchaws Meskas.
Muaj ib qho piv txwv zoo txog kev siv cov tshuaj qub qub. Orlistat yog ib qho inhibitor ntawm gastrointestinal lipase thiab fatty acid synthase (FASN), uas yog siv los txo qhov hnyav. Txawm li cas los xij, cov kev tshawb fawb tau pom tias Orlistat kuj muaj kev tiv thaiv qog nqaij hlav. Tsis ntev los no, nws tau pom tias orlistat tuaj yeem cuam tshuam cov kev ua ntawm zes qe menyuam qog noj ntshav (SKOV3)PKM2, uas qhia tau hais tias nws muaj peev xwm siv tus nqi hauv kev kho mob qog noj ntshav ntawm zes qe menyuam.
3. pentose phosphate txoj kev
3.1 Glucose -6- phosphate dehydrogenase inhibitor
Glucose -6- phosphate dehydrogenase (G6PD) yog lub ntsiab antioxidant enzyme hauv cov qog hlwb, uas tuaj yeem tswj hwm qib glutathione (GSH) los tiv thaiv cov hlwb los ntawm ROS. Kev rov tsim dua tshiab ntawm glutathione kev ua si hauv pas dej ua ke yog nyob ntawm kev txo lub zog ntawm NADPH, thiab cov qog hlwb yuav tsum tswj hwm qib siab ntawm kev txo glutathione txhawm rau tiv thaiv cov hlwb los ntawm cov tshuaj lom ntawm ROS.
Yog li ntawd, qhov inhibition ntawm qabzib -6- phosphate dehydrogenase tej zaum yuav muaj kev puas tsuaj loj, thiab qib ntawm ROS tsis tswj, yog li txhawb kev tuag ntawm tes. Txawm hais tias nws tau tshaj tawm thaum ntxov li xyoo 1960 tias cov tshuaj steroids tuaj yeem cuam tshuam cov piam thaj -6- phosphate dehydrogenase, cov piam thaj -6- phosphate dehydrogenase inhibitors hauv kev tshawb fawb los tiv thaiv qog tsis muaj ntau.
Txog tam sim no, feem ntau cov piam thaj -6- phosphate dehydrogenase inhibitors yog cov tshuaj steroids, suav nrog endogenous dehydroepiandrosterone (DHEA) thiab catechin gallates. 6- aminonicotinamide thiab bromophenols, natural products of seaweed, kuj yog xaiv thiab thim rov qab inhibitors ntawm qabzib -6- phosphate dehydrogenase.
Nrog rau qhov tseem ceeb ntawm cov piam thaj ntau ntxiv -6- phosphate dehydrogenase hauv kev kho mob qog noj ntshav, lub hom phiaj ntawm kev tshawb fawb tau hloov mus rau yuav ua li cas thiaj nrhiav tau DHEA analogues zoo dua. Kev tsim ntawm multidrug resistance (MDR) nyob rau hauv cov qog hlwb muaj feem xyuam rau kev ua kom cov tshuaj efflux twj tso kua mis.
Nws tau pom tias qhov kev tswj hwm ntawm cov tshuaj efflux twj MRP1 thiab MRP2 hauv doxorubicin-resistant colorectal cancer hlwb muaj feem xyuam rau kev nce cov piam thaj -6- phosphate dehydrogenase kev ua, pentose phosphate txoj kev theem thiab intracellular glutathione qib. Cov ntaub ntawv no qhia tau hais tias inhibition ntawm qabzib -6- phosphate dehydrogenase tuaj yeem ua rau cov tshuaj efflux twj tso kua mis ntawm cov qog hlwb, yog li ua rau muaj qhov rhiab heev ntawm HT-29DX hlwb rau doxorubicin.
RRx-001 tuaj yeem cuam tshuam cov haujlwm ntawm histone deacetylase (HDACs) thiab DNA methyltransferase, thiab nws yog ib qho tshiab los tiv thaiv qog nqaij hlav, uas tau nkag mus rau thawj theem ntawm kev sim tshuaj. RRx-001 yog ib qho electrophile uas tuaj yeem khi rau nucleophilic thiol pawg ntawm glutathione thiab deoxyhemoglobin.
Cov txheej txheem tiv thaiv qog nqaij hlav ntawm RRx-001 tuaj yeem cuam tshuam nrog kev nce ntawm cov pa oxygen reactive thiab reactive nitrogen hom (RONS) hauv cov qog hlwb. Cysteine-dependent enzyme yog tshwj xeeb tshaj yog rhiab heev rau oxidative hloov / puas, thiab cysteine residue nyob rau hauv nws active site yog xav tau rau catalytic cov tshuaj tiv thaiv, yog li nws muaj peev xwm inhibit qabzib -6- phosphate dehydrogenase (G6PD) los ntawm kev tswj ntawm active oxygen.
RRx-001 yog ib qho muaj zog thiab xaiv ntau yam inhibitor ntawm qabzib -6- phosphate dehydrogenase nyob rau hauv cov qog hlwb, thiab cov qog hlwb muaj rhiab heev nyob rau hauv cov xwm txheej ntawm tsim oxide tsim los ntawm RRx-001. Ib yam li ntawd, RRx-001 kuj tuaj yeem cuam tshuam cov haujlwm ntawm pyruvate kinase M2 los ntawm cov pa oxygen reactive.
Hauv thawj theem ntawm kev sim tshuaj, 25 tus neeg mob uas muaj cov qog metastatic siab heev tau txhim kho zoo tom qab tau txais RRx-001 pretreatment, thiab tsis muaj qhov cuam tshuam loj heev, uas qhia tau tias RRx-001 muaj tshuaj lom ntau rau cov qog hlwb. . Qib ATP yog qhov tseem ceeb ntawm kev txiav txim siab ntawm cov tshuaj tiv thaiv hauv kev kho mob. Nws tau pom tias RRx-001 tuaj yeem txhim kho qhov ua tau zoo ntawm cov tshuaj kho mob tom ntej, suav nrog 4 tus neeg mob qog noj ntshav thiab 1 tus neeg mob uas tsis yog mob qog noj ntshav me me.
Cov txiaj ntsig kev tshawb fawb no tuaj yeem cuam tshuam rau qhov kev xav yav dhau los uas "kev kho tshuaj tiv thaiv tsis tuaj yeem rov qab los", thiab kev hloov pauv hloov pauv yuav yog txoj kev kho mob qog noj ntshav tshiab.
4. Glutamine metabolism
4.1 Glutamine Transporter
Cov qog hlwb tshwj xeeb tshwj xeeb rau ob qho khoom noj, uas yog qabzib thiab glutamine. Glutamine yog qhov ntau tshaj cov amino acid nyob rau hauv tib neeg lub cev. Glutamine tuaj yeem hloov mus rau hauv -ketoglutaric acid tom qab cov metabolism, thiab -ketoglutaric acid yog cov khoom nruab nrab ntawm Krebs cycle. Krebs lub voj voog tsis tsuas yog muab ATP rau cov hlwb, tab sis kuj muab cov precursors rau macromolecular synthesis, xws li malic acid rau gluconeogenesis, NADH rau oxidative phosphorylation thiab succinyl CoA rau heme synthesis.
Ntawm lawv, cov tshuaj tiv thaiv anapleurotic yog qhov tsim nyog rau kev ua haujlwm ntawm lub voj voog Krebs. Txawm hais tias cov hlwb ib txwm tsis tshua siv glutamine rau cov metabolism, cov qog tuaj yeem ua rau cov khoom nruab nrab cuam tshuam nrog glutamine metabolism hauv Krebs lub voj voog. Tsis tas li ntawd, glutamine yog qhov ua ntej ntawm txo glutathione (GSH).
Tamoxifen thiab Raloxifene tuaj yeem thaiv cov cellular uptake ntawm glutamine los ntawm inhibiting glutamine transporter (ASCT2), yog li txo qis glutathione qib intracellular thiab ua rau qee yam cytotoxicity. Txawm li cas los xij, los ntawm kev ntxiv exogenous N- acetyl -L- cysteine (N-acetyl L-cysteine) thiab estradiol (17 beta-estradiol), cov qib glutathione intracellular tuaj yeem nce ntxiv, uas tuaj yeem txo cov cytotoxicity ntawm ob cov tshuaj saum toj no. Glutamine analogues acivicin thiab 6-DIAZO-5-OXO-L-NORLEUCINE (DON) tuaj yeem inhibit glutamine metabolism, yog li inhibiting qog hlwb hauv vitro thiab hauv vivo. Txawm li cas los xij, vim lawv qhov kev xaiv qis thiab muaj tshuaj lom, lawv tseem tsis tau nkag mus rau theem kev sim tshuaj. 5. Autophagy inhibition Raws li qhov tsis muaj cov as-ham, cov qog hlwb siv thiab faib qee cov macromolecules lom rau cov tshuaj metabolic. Autophagy yog ib txoj hauv kev ntxiv rau nws tus kheej kom tswj tau qib ib txwm ntawm ATP, yog li txo qis kev siv hluav taws xob mus rau qib qis tshaj.
Qhov zoo tshaj plaws autophagy inhibitors hauv kev tshawb fawb soj ntsuam yog cov tshuaj tiv thaiv kab mob, xws li chloroquine (CQ) thiab hydroxychloroquine (HCQ), uas tuaj yeem cuam tshuam lysosomal protease kev ua. Zoo li lwm yam ERMAs, chloroquine tuaj yeem kho qhov rhiab heev ntawm Nws 2- cov qog nqaij hlav cancer mis zoo rau trastuzumab.
Interestingly, chloroquine kuj yog lub substrate ntawm P- glycoprotein twj tso kua mis thiab multidrug resistance twj tso kua mis, uas yuav txo tau cov ATP theem nyob rau hauv hlwb (saib hauv qab). chloroquine thiab hydroxychloroquine tab tom ua ntau yam kev sim tshuaj ntsuam xyuas ntsig txog qog autophagy inhibition. Apigenin, flavonoid, tuaj yeem xaiv ua rau apoptosis ntawm cov qog hlwb thiab inhibit qhov kev qhia ntawm GLUT-1.
Cov kev tshawb fawb tau pom tias apigenin tuaj yeem ua rau autophagy hauv hlwb. Interestingly, piv nrog apigenin ib leeg, kev sib xyaw ntawm apigenin thiab autophagy inhibitor 3- methyl adenine tuaj yeem txhim kho qib apoptosis ntawm cov qog hlwb, uas qhia tau hais tias kev sib xyaw ntawm apigenin thiab autophagy inhibitor yuav yog ib qho kev cog lus los tiv thaiv qog noj ntshav. .
6. Ua kom ATP noj cov hlwb
Txhawm rau tiv thaiv ib puag ncig kev cuam tshuam xws li kev kho hluav taws xob thiab tshuaj tua kab mob, cov qog hlwb yuav tsum nce lawv cov ATP ntau lawm kom ua tau raws li qhov xav tau ntawm lub zog ntawm cov kev hloov pauv phenotypic, tab sis qhov no yuav txo tau lawv txoj kev vam meej. Piv txwv li, qee cov qog yuav nce qib ntawm cov tshuaj efflux twj tso kua mis hauv cell membrane, tab sis thaum verapamil ua haujlwm ua ke, nws yuav ua rau ATP noj cov qog hlwb.
Verapamil yog ib qho uas tsis yog-chemotherapeutic substrate ntawm P-glycoprotein twj tso kua mis, uas tuaj yeem ua kom muaj kev ua haujlwm ATPase, uas yuav siv ntau lub zog. Thaum cov concentration qis dua cov tshuaj lom, verapamil tuaj yeem kho cov tshuaj tiv thaiv ntau yam twj tso kua mis phenotype ntawm P-glycoprotein overexpression hlwb. Gatenby thiab lwm tus xav tias qhov kev kho mob zoo ntawm "txo cov khoom siv thiab kev xav tau ntau ntxiv" tuaj yeem tsim cov nyhuv desensitization hauv txoj kev xav, yog li txhim kho cov ciaj sia ntawm cov qog nqaij hlav nas.
7. Tswj cov zaub mov muaj zog
Lub hauv paus rau cov neeg mob qog noj ntshav kom tswj cov khoom noj muaj zog yog txo cov piam thaj kom tsawg thiab ua rau lub xeev ketotic. Nyob rau hauv cov xwm txheej ntawm lub zog txwv lossis kev tawm dag zog lub cev, fatty acid metabolism yuav tsim ketones, uas yuav hloov mus rau hauv acetyl-CoA thiab nkag mus rau tricarboxylic acid voj voog thiab electron hloov saw hlau.
Cov hlwb ib txwm tuaj yeem siv ketones, tab sis cov qog hlwb tsis tuaj yeem siv ketones vim yog oxidative phosphorylation tsis ua haujlwm. Yog li ntawd, kev tswj cov khoom noj muaj zog yuav ua rau cov qog ua rau muaj kev ntxhov siab: (1) glycolysis yuav txo qis; (2) Cov qog nqaij hlav tshaib plab tsis tuaj yeem hloov cov piam thaj nrog ketone lub cev.
Seyfried et al. pom tias kev loj hlob qeeb ntawm glioma hloov pauv hauv situ hauv nas yog cuam tshuam nrog kev txo qis ntawm cov piam thaj thiab nce qib ntawm ketone lub cev hauv vivo. Maurer et al. pom tias cov piam thaj-dependent glioma hlwb, tsis zoo li cov hlwb benign neuron, tsis tuaj yeem siv cov tshuaj ketone - hydroxybutyrate.
Txog tam sim no, tseem tsis tau muaj kev sim tshuaj ntsuam randomized ntawm kev txwv tsis pub noj zaub mov. Txawm li cas los xij, ob daim ntawv tshaj tawm tau coj cov txiaj ntsig zoo rau txhua tus. Xyoo 1995, Nebeling thiab lwm tus tau tshaj tawm tias lub sijhawm tsis muaj kab mob ntawm cov menyuam yaus uas muaj cov kab mob malignant astrocytoma uas tau txais kev kho mob ketogenic mus sij hawm ntev (uas yog, noj zaub mov muaj roj ntau) yog 12 lub hlis.
Seyfried et al. tau tshaj tawm tias tus poj niam muaj hnub nyoog 65- tus neeg mob uas muaj glioblastoma multiforme tau txais kev kho mob niaj hnub, thiab 600 calories ntawm ketogenic noj zaub mov yuav tsum tau ua txhua hnub. Txawm hais tias tus neeg mob poob 20% qhov hnyav tom qab 2 lub hlis ntawm kev kho mob, cov qog tsis rov zoo li ntawm 10 lub lis piam tom qab kev noj zaub mov tas. Txawm hais tias cov txiaj ntsig zoo ntawm qhov kev sim no thiab lub hauv paus theoretical muaj zog, tam sim no tsis muaj cov qauv kev kho mob.
Xav txog qhov poob phaus ntawm cov neeg mob qog noj ntshav nrog cachexia, nws zoo li nyuaj rau kev noj zaub mov txwv calorie, noj zaub mov hypoglycemia lossis ketogenic noj zaub mov. Txawm li cas los xij, los ntawm kev tshawb nrhiav lub vev xaib raug cai ntawm kev sim tshuaj, nws tuaj yeem pom tias qhov kev sim tshuaj ntsuam xyuas randomized hu ua "calorie restriction diet, ketogenic diet and transient fasting (ERGO2)) rau cov neeg mob uas muaj glioblastoma rov tshwm sim thaum siv tshuaj khomob" tau ua, thiab tsawg kawg. plaub qhov kev tshawb fawb txog kev noj zaub mov ketogenic rau cov neeg mob uas muaj ntau hom qog nqaij hlav yog nyob rau thawj theem ntawm kev sim tshuaj.
Nyob rau yav tom ntej, yuav tsum muaj cov ntaub ntawv ntau ntxiv los ua pov thawj qhov ua tau zoo ntawm qhov kev tswj hwm kev noj zaub mov no, ib leeg lossis ua ke nrog lwm cov kev kho mob.
8. Daim ntawv thov kev yees duab
Muaj ob lub biomarkers uas tuaj yeem qhia txog ATP tsim cov qog, lawv yog 2-[18F] fluoro-2-deoxy-glucose (FDG) thiab Tc-technetium-methoxyisobutyl (Tc-Sestamibi). PET scanning tau ntev yog lub ntsiab lus tseem ceeb ntawm kev kuaj qog rau cov qog nqaij hlav malignant.
Tc-MIBI yog lub substrate ntawm P-glycoprotein twj tso kua mis system (P-gp) thiab multidrug resistance protein (MRP). Nws tuaj yeem tsis tsuas yog tso saib lub xeev kev ua haujlwm ntawm cov tshuaj efflux twj tso kua mis (qhov nrawm dua qhov kev tshem tawm ntawm Tc-MIBI, qhov siab dua qhov concentration ntawm cov tshuaj efflux twj tso kua mis, thiab lwm yam), tab sis kuj nce ATP turnover tus nqi ntawm cov twj, uas. ua kom muaj kev kho mob thiab kuaj tau. Qhov kev kuaj mob thiab kev kho mob zoo no tau nkag mus rau theem ob ntawm kev kho mob. Raws li txoj cai, ATP xwm txheej ntawm cov qog hlwb tuaj yeem saib xyuas lub sijhawm tiag tiag los ntawm PET thiab Tc-MIBI crosslinking.
9. xaus
Ob lub koom haum ua txhaum cai thiab cov neeg phem yuav tsum tau tso siab rau kev txhawb nqa nyiaj txiag los ua kev ua txhaum cai, thiab cov peev txheej yog qhov pib rau cov tub ceev xwm los tawm tsam thiab rhuav tshem cov koom haum txhaum cai no. Ib yam li ntawd, ATP thiab NADH, raws li lub zog ntawm tes thiab redox txiaj, ua lub luag haujlwm tseem ceeb hauv qhov tshwm sim, kev loj hlob, kev ntxeem tau thiab cov qog nqaij hlav, uas yog qhov tsis muaj zog ntawm cov qog.
Cov koom haum ua phem txhaum cai muaj peev xwm ua tau ntau yam kev nqis peev. Thaum ib tus account khov lawm, lawv tuaj yeem qhib cov nyiaj ntawm lwm tus account. Sib txawv ntawm cov koom haum ua txhaum cai, "tus tsim tawm" ntawm cov qog ATP tsis muaj txiaj ntsig zoo hauv glycolysis / glutamine metabolism; Tsis tas li ntawd, lub inhospitable hypoxia thiab acidic microenvironment cia li endow hlwb hlwb nrog chemotherapy tsis kam, thiab yuam kom lawv txhim kho qib glycolysis los ua rau lub zog poob los ntawm oxidative phosphorylation.
Mob qog noj ntshav zoo li raug foom los ntawm lub zog, uas ua rau cov qog nqaij hlav metabolism tsis yooj yim. Txhawm rau kom tau txais cov tshuaj tiv thaiv ntev ntev, nws yog ib qho tsim nyog yuav tsum ua kom haum rau cov khoom siv thiab kev xav tau ib puag ncig. Thaum ATP cov khoom siv hauv cov qog hlwb tsis txaus, cov khoom tsim tau qis dhau los ua qhov ua tiav qhov tuag taus, uas yuav ua rau qhov "dhuav" ib puag ncig hauv hlwb ntxiv.
Zoo li lwm yam kab mob, kev kho mob qog noj ntshav yog nyob ntawm qhov sib txawv ntawm cov noob caj noob ces. Txawm li cas los xij, thaum ua kev kho tus kheej, peb tsis tuaj yeem tsis quav ntsej txog kev kho lub tswv yim ntawm kev txwv lub zog. Raws li txoj kev xav ntawm teleological, vim li cas rau lub neej ntawm cov qog hlwb yog kev ciaj sia, uas yuav tsum muaj ATP ntau npaum li cas sai sai kom tau raws li lub zog xav tau ntawm cov hlwb, biosynthesis xav tau, thiab tswj lub xeev redox ntawm cov hlwb.
Classical tumorigenic signaling pathways feem ntau cuam tshuam nrog txoj hauv kev metabolic, xws li PI3K / AKT thiab mTOR txoj hauv kev, uas ncaj qha lossis ncaj qha txhawb nqa biosynthesis thiab cell proliferation, thiab thaum kawg tsim ib lub tswv yim tshiab: teeb liab txoj hauv kev inhibition thiab lub zog txwv kev sib koom ua ke txoj kev kho mob.
Microeconomics ntseeg hais tias yog tias tag nrho cov kev xav tau ntawm ib qho peev txheej tshwj xeeb tshaj qhov khoom siv, qhov tsis txaus yuav ua raws li, thiab yog tias qhov tsis txaus yog thoob ntiaj teb thiab ntev, kev sib koom ua ke yuav kis thoob plaws hauv kev lag luam. Ib yam li ntawd, yog tias qib ATP hauv cov hlwb tsis txaus vim yog kev siv tshuaj yeeb lossis kev tswj xyuas zaub mov, lub zog siab tsim ua rau cov qog hlwb kom rov faib ATP mus rau qhov chaw uas nws xav tau tshaj plaws, xws li kev ciaj sia.
Qhov kev faib tawm tshiab no yuav ua rau muaj kev cuam tshuam ntawm lwm yam kev ua haujlwm ntawm lub zog, xws li ATP-tsav tshuaj efflux twj tso kua mis lossis epigenetic silencing ntawm qog suppressor noob. Inhibition ntawm cov kev ua haujlwm ntawm lub zog-intensive ntawm tes tuaj yeem txhim kho qhov rhiab heev ntawm cov qog hlwb rau kev siv tshuaj khomob thiab kev kho hluav taws xob. Vim li no, uas yog qhov kev sib cav tseem ceeb ntawm daim ntawv no, kev txwv lub zog yog ib lub tswv yim ua tau hauv kev kho mob, tshwj xeeb tshaj yog thaum nws ua ke nrog lwm txoj kev kho mob.
Muab cov tshuaj tiv thaiv qog noj ntshav yav dhau los tshiab chemosensitivity tuaj yeem ua rau muaj kev hloov pauv hauv cov qog nqaij hlav, los ntawm kev kho mob txuas ntxiv mus rau lub voj xov tooj cua / tshuaj kho mob rov ua haujlwm, uas tuaj yeem txhim kho tag nrho cov ciaj sia ntawm cov neeg mob qog thiab tig qog noj ntshav mus rau ib qho mob ntev. kab mob.
Qhov zoo tshaj plaws, kev sib xyaw ua ke thiab kev kho tsis sib tshooj yuav suav nrog cov tshuaj tiv thaiv glycolysis, pentose phosphate txoj hauv kev, glutamine metabolism, autophagy thiab non-chemotherapy cov tswv yim (xws li verapamil, uas tuaj yeem ua rau lub zog hnyav MDR- mediated ATP turnover), thiab cov no. Cov tswv yim yog tsom ncaj qha rau ntawm ATP ntau lawm, uas yuav tsim cov txiaj ntsig kev kho mob zoo tshaj plaws thiab zoo tshaj plaws.
ATP yog lub fulcrum nyob ib ncig ntawm uas tag nrho cov qog "economic system" khiav. Raws li lub zog, lub tswv yim los tiv thaiv kev siv hluav taws xob tuaj yeem ua rau "kev lag luam" ntawm cov qog thiab normalize cov qog kho tam sim no.