Kev cuam tshuam Metabolic hauv qog tiv thaiv kab mob: Tsom ntsoov rau Dual Pathway Inhibitors

Cov ntsiab lus yooj yim:

Metabolic reprogramming yog ib qho ntawm cov qog thiab lub cev tiv thaiv kab mob 'kev hloov pauv tseem ceeb tshaj plaws hauv metabolic. Tsis tas li ntawd, cov kev taw qhia txog metabolic, xws li phosphoinositide 3-kinases (PI3Ks), lub hom phiaj tsiaj ntawm rapamycin (mTOR), tuaj yeem ua rau muaj kev loj hlob, kev loj hlob, thiab kev tsim ntawm cov qog hlwb. Yog li ntawd, inhibiting cov txheej txheem metabolic no tuaj yeem suav tias yog lub peev xwm kho tau zoo hauv tib neeg malignancies. Ntawm qhov tod tes, raws li kev tshawb fawb yav dhau los, pharmacological inhibiting ntawm metabolic txoj kev siv dual-pathway inhibitors tuaj yeem cuam tshuam cov qog loj hlob thiab kev loj hlob, ntau dua li kev txwv txhua txoj hauv kev sib cais. Qhov kev tshuaj xyuas no yog txhawm rau txheeb xyuas cov kev cuam tshuam metabolic tshiab los ntawm ob txoj hauv kev inhibitors thiab sib tham txog kev ua tiav thiab kev txwv ntawm qhov kev siv tshuaj kho mob no.

Cov txiaj ntsig ntawm cistanche tubulosa-Antitumor

Abstract:

Cov metabolism hauv cov qog nqaij hlav thiab lub cev tiv thaiv kab mob hauv cov qog microenvironment (TME) tuaj yeem cuam tshuam rau txoj hmoo ntawm kev mob qog noj ntshav thiab tiv thaiv kab mob. Metabolic reprogramming tuaj yeem tshwm sim tom qab ua kom muaj kev cuam tshuam ntawm metabolic-txog kev taw qhia, xws li phosphoinositide 3-kinases (PI3Ks) thiab cov hom phiaj tsiaj ntawm rapamycin (mTOR). Ntxiv mus, ntau yam qog-derived immunosuppressive metabolites tom qab metabolic reprogramming kuj cuam tshuam rau cov tshuaj tiv thaiv kab mob. Cov ntaub ntawv pov thawj qhia tau hais tias kev cuam tshuam hauv cov txheej txheem metabolic ntawm cov qog lossis lub cev tiv thaiv kab mob tuaj yeem yog qhov kev xaiv zoo nkauj thiab kho tshiab rau mob qog noj ntshav. Piv txwv li, kev tswj hwm cov tshuaj inhibitors ntawm ntau yam kev taw qhia, xws li phosphoinositide 3-kinases (PI3Ks), tuaj yeem txhim kho T cell-mediated antitumor tiv thaiv kab mob. Txawm li cas los xij, ob txoj kev inhibitors tuaj yeem cuam tshuam cov qog loj hlob ntau dua li lawv inhibit txhua txoj hauv kev sib cais. Qhov kev tshuaj xyuas no tham txog qhov kev cuam tshuam metabolic tshiab los ntawm ob txoj hauv kev inhibitors nrog rau qhov zoo thiab qhov tsis zoo ntawm txoj kev kho no.

Ntsiab lus:

kev cuam tshuam metabolic; dual inhibitor; metabolic reprogramming; kho mob qog noj ntshav

1. Taw qhia

Cov txheej txheem metabolic hloov cov as-ham rau hauv cov molecules hu ua metabolites los ntawm kev sib koom ua ke ntawm cov tshuaj lom neeg biochemical, tsim lub zog, redox sib npaug, thiab macromolecules, xws li RNA, DNA, proteins, thiab lipids tseem ceeb rau kev ua haujlwm ntawm tes thiab ciaj sia [1,2]. Cytosolic glycolysis nyob rau hauv anaerobic tej yam kev mob thiab mitochondrial oxidative phosphorylation nyob rau hauv aerobic tej yam kev mob yog lub zog qhov chaw rau ib txwm hlwb, feem [3]. Hauv qhov sib piv, raws li "Warburg effect", cov qog nqaij hlav cancer xav tau lub zog ntawm cytosolic glycolysis dua li oxidative phosphorylation, txawm tias nyob rau hauv aerobic mob [4,5]. Tom qab ua kom cov glycolysis, glycolytic qog hlwb tsim lactate, uas yog suav hais tias yog ib tug muaj zog roj rau oxidative qog hlwb. Monocarboxylate transporters (MCTs) catalyze cov proton-txuas kev thauj mus los ntawm lactate thiab lwm yam monocarboxylates thoob plaws cell membranes [6] (Daim duab 1). Qhov laj thawj rau qhov nyiam ntawm cov qog hlwb yog lawv qhov kev loj hlob tsis tuaj yeem tswj tau thiab xav tau cov khoom siv ATP ceev uas tsuas yog siv tau los ntawm glycolysis [7,8]. Ntawm qhov tod tes, ntau txoj hauv kev tseem ceeb ntawm cov metabolism tuaj yeem ua rau tsis zoo hauv cov qog hlwb [1]. Raws li muaj kev paub, cov lus teb tiv thaiv kab mob cuam tshuam nrog kev hloov pauv tseem ceeb hauv cov ntaub so ntswg metabolism, xws li kev noj zaub mov kom tsawg, noj cov pa oxygen, thiab tsim cov pa oxygen thiab nitrogen intermediates [9-11].

Figure 1. The Warburg effect. Most tumor cells produce energy, principally through glycolysis in the cytosol, producing lactic acid even in the presence of oxygen. MCTs catalyze the proton-linked transport of produced lactate across cell membranes. On the other hand, normal cells use oxidative phosphorylation in the mitochondria to produce energy under aerobic conditions

Daim duab 1. Cov nyhuv Warburg. Feem ntau cov qog hlwb tsim lub zog, feem ntau los ntawm glycolysis hauv cytosol, tsim cov lactic acid txawm tias muaj oxygen. MCTs catalyze cov proton-txuas kev thauj mus los ntawm tsim lactate thoob plaws cell membranes. Ntawm qhov tod tes, cov hlwb ib txwm siv oxidative phosphorylation hauv mitochondria los tsim lub zog nyob rau hauv aerobic mob.

Ntxiv mus, hauv TME, ntau cov metabolites tuaj yeem cuam tshuam rau lub cev tiv thaiv kab mob sib txawv thiab kev ua haujlwm zoo [12]. Txawm li cas los xij, hauv TME, yeej ib txwm muaj kev sib tw hnyav ntawm lub cev tiv thaiv kab mob thiab cov qog hlwb kom noj cov khoom noj, thiab cov qog hlwb feem ntau yeej qhov kev sib tw no vim lawv lub zog loj hlob thiab cov yam ntxwv hnyav [13]. Piv txwv li, kev cuam tshuam metabolic tej zaum yuav yog ib txoj hauv kev kho mob rau kev kho mob malignancies. Nws tau raug qhia tias muaj ntau yam kev taw qhia, xws li mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), hypoxia-inducible factor 1-alpha (HIF{ {6}}), PI3K/AKT, Ras, thiab insulin receptor koom nrog hauv cell metabolism. Interestingly, cov txheej txheem no thiab kev tswj hwm tus ntoo khaub lig tuaj yeem cuam tshuam cov qog loj hlob thiab T cell-mediated tiv thaiv [14,15]. Hauv qhov no, ntau qhov kev tshawb fawb pom tau hais tias kev siv tshuaj kho mob siv ntau yam inhibitors ntawm txoj hauv kev no tuaj yeem txiav txim siab T cell ' metabolic zog thiab persistence ntawm cov kab mob no [16]. Piv txwv li, sirolimus analogs xws li mTOR inhibitors yog tam sim no tau kawm nyob rau hauv theem II thiab III kev sim tshuaj vim hais tias mTOR signaling dysfunction induces cellular proliferation thiab tau txuam nrog ntau yam tib neeg malignancies [17]. Txawm li cas los xij, txawm tias muaj txiaj ntsig ntawm txoj kev kho mob no, kev siv cov tshuaj tiv thaiv no tuaj yeem muaj kev cuam tshuam tsis zoo xws li nephrotoxicity thiab muaj kev pheej hmoo ntawm kev kis kab mob uas yuav tsum tau saib xyuas kev kho mob [18]. PI3K yog ib qho tseem ceeb tus neeg nruab nrab ntawm cov qog cell loj hlob, proliferation, thiab ciaj sia taus vim overactivated PI3K alpha (PI3KA) tom qab qog mutations yog ib qho tseem ceeb rau downstream signals ntawm receptor tyrosine. Cov ntaub ntawv no qhia tau hais tias kev xaiv PI3KA inhibitors tuaj yeem yog cov tshuaj kho mob zoo nkauj hauv kev kho mob qog noj ntshav. mTOR yog PI3K downstream kinase tseem ceeb hauv kev loj hlob ntawm tes thiab cov metabolism. Yog li, inhibition ntawm mTOR yog qhov zoo hauv kev kho mob rau ntau hom qog nqaij hlav [19].

Tsis tas li ntawd, ob txoj hauv kev inhibitors tuaj yeem ua tau zoo dua li kev tswj cov txheej txheem metabolic sib cais. Ib txhij inhibition ntawm glycolysis thiab oxidative phosphorylation, nrog rau PI3K / AKT / mTOR thiab lwm txoj hauv kev thiab koom nrog cov molecules nrog dual inhibitors, pom tias lub tswv yim no muaj txiaj ntsig zoo rau feem ntau thiab pab tiv thaiv kev loj hlob thiab kev loj hlob ntawm cov qog [20-23. ]. Txawm li cas los xij, cov lus teb rau kev kho mob no tuaj yeem sib txawv ntawm cov qog nqaij hlav sib txawv. Qhov kev tshuaj xyuas no tau piav qhia txog cov metabolism hauv cov qog thiab lub cev tiv thaiv kab mob thiab lawv cov kev cuam tshuam rau ib leeg. Tsis tas li ntawd, cov kev taw qhia tseem ceeb cuam tshuam nrog cov qog thiab lub cev tiv thaiv kab mob hauv lub cev metabolism, cuam tshuam txog kev kho mob nrog dual inhibitors tab sis tsis yog ob qho kev cuam tshuam ntawm cov txheej txheem metabolic nrog kev sib xyaw ua ke, thiab qhov zoo thiab qhov tsis zoo ntawm cov tshuaj tiv thaiv dual no tau tham txog.

Desert ginseng-Improve immunity (9)

cistanche cov txiaj ntsig rau txiv neej-ua kom muaj zog tiv thaiv kab mob

2. Metabolism ntawm qog thiab lub cev tiv thaiv kab mob

2.1. Cov qog hlwb

Vim muaj qhov loj ntawm cov qog hlwb, tsis hais seb tus mob puas yog aerobic lossis anaerobic, cytosolic glycolysis yog txoj kev nyiam muab ATP rau lawv txoj kev loj hlob [24]. Cov kws tshawb fawb tau pom tias cov qog hlwb tsim pyruvate nyob rau hauv cov xwm txheej hypoxic ntawm txoj kev glycolysis, tsim cov lactic acid los ntawm pyruvate kinase hom M2 es tsis txhob nkag mus rau mitochondrial oxidative phosphorylation thiab acetyl CoA tsim [25]. Cov qog hlwb kuj tsim cov roj ntsha macromolecules kom rov ua dua lawv tus kheej siv serine metabolism thiab pentose phosphate pathway (PPP) [26,27]. Ib puag ncig tej yam kev mob thiab concentration ntawm cov as-ham rau cov qog hlwb txiav txim seb txoj kev twg thiab cov macromolecules uas lawv siv los nrhiav cov kev pom zoo rau lawv txoj kev loj hlob thiab kev loj hlob. Yog li ntawd, ntxiv rau decomposing qabzib, qog hlwb siv tau lwm yam macromolecules, xws li amino acids, lipids, thiab fatty acids, los tsim lub zog thiab loj hlob [28–30].

Interestingly, thaum lub concentration ntawm qabzib los yog glutamine yog tsawg (tsis muaj zaub mov), qog hlwb induce c-Myc los txhawb lawv txoj kev ciaj sia los ntawm kev tswj cov metabolic enzyme qhia nyob rau hauv lub serine synthesis txoj kev, xws li phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1). ), phosphoserine phosphatase (PSPH), activating de novo serine synthesis thiab preserving redox homeostasis [31]. Ntxiv mus, nyob rau hauv cov khoom noj tsis txaus, cov qog hlwb tuaj yeem siv acetoacetate los tsim acetyl-CoA thiab fatty acids, uas lav lawv txoj sia nyob [32–34]. Ketone lub cev decomposition los ntawm qog hlwb kuj tsim cov metabolites uas tuaj yeem nkag mus rau lub voj voog tricarboxylic acid (TCA), muab ATP rau lawv txoj sia nyob [30]. Lub voj voog ntawm tes raug ntes, autophagy, anoikis, thiab entosis yog plaub hom kev ciaj sia nyob ruaj khov [35]. Tsis ntev los no kev tshawb nrhiav tau tshaj tawm tias cov qog hlwb tseem ceeb tshaj glutamine-derived TCA lub zog metabolism dua glycolysis los txhawb ATP thiab txo qis oxidative kev nyuaj siab los ntawm kev cuam tshuam nrog cysteine, khaws cia ib qho chaw ruaj khov-yooj yim ciaj sia [36]. Cov kev tshawb pom no qhia tau hais tias nyob ntawm cov xwm txheej sib txawv tswj hwm TME, cov qog hlwb tuaj yeem ntse muab lawv lub zog xav tau los ntawm metabolic reprogramming thiab siv ntau txoj hauv kev los ua kom lawv txoj sia nyob ntev.

Desert ginseng-Improve immunity (16)

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

Nyem qhov no mus saib Cistanche Enhance Immunity khoom

【Nug ntxiv】 Email: cindy.xue@wecistanche.com / Whats App: 0086 18599088692 / Wechat: 18599088692

2.2. Immune Cells

Feem ntau, kev siv hluav taws xob hauv lub cev tiv thaiv kab mob sib txawv hauv lub xeev tsis muaj zog thiab tsis muaj zog. Ntxiv mus, zoo li cov qog nqaij hlav cancer, lub cev tiv thaiv kab mob kuj tseem siv cov txheej txheem metabolic uas tau hais hauv ntu dhau los [37]. Cov qauv metabolic sib txawv tuaj yeem cuam tshuam rau lub cev tiv thaiv kab mob sib txawv. Cov kev tshawb fawb yav dhau los tau pom tias M1 macrophages, activated neutrophils, thiab inducible nitric oxide synthase (iNOS) --qhia dendritic hlwb (DCs) feem ntau siv glycolysis rau lawv lub zog mov [38]. Hauv lub xeev so, DCs nyiam siv oxidative phosphorylation rau lub zog, tab sis kev ua kom cov hlwb no cuam tshuam nrog nce glycolysis thiab lipid metabolism hloov pauv, cuam tshuam rau lawv txoj haujlwm [39,40]. Tsis tas li ntawd, neutrophils siv pentose phosphate thiab aerobic glycolysis txoj hauv kev, thiab glycolysis koom nrog hauv kev tswj hwm ntau lub zog neutrophil, xws li chemotaxis thiab ua pa tawg [41].

T hlwb ua lub luag haujlwm tshwj xeeb hauv kev tiv thaiv qog nqaij hlav ntawm lub cev tiv thaiv kab mob, thiab raws li ntau yam microenvironment signals, lawv cov phenotypes yog metabolically sib txawv ntawm lwm lub cev tiv thaiv kab mob. Cov ntaub ntawv pov thawj pom tau tias cov qauv metabolic ntawm naïve thiab nco T hlwb yog nyob rau hauv ib qho yooj yim as-ham noj hom, glycolysis tus nqi yog txo, proliferation yog nyob rau hauv ib tug tsawg kawg nkaus lub xeev, thiab ATP mov tsuas yog nyob ntawm oxidative phosphorylation [42]. Hauv cov kab mob pathologic xws li mob qog noj ntshav, naïve T hlwb yuav tsum sib txawv rau hauv cov nyhuv T hlwb los tiv thaiv qog hlwb, uas yuav tsum tau hloov pauv metabolic thiab nce kev loj hlob. Cov kev hloov pauv hauv metabolic no ua rau muaj kev nqus ntawm cov as-ham thiab glycolysis thiab ua kom cov synthesis ntawm cov macromolecules tseem ceeb, xws li nucleotides, proteins, thiab lipids. Ib txhij nrog cov kev hloov pauv hauv metabolic, mitochondrial oxygen noj yog condensed, inducing ib tug effector T cell proliferation [2].

Hauv qhov sib piv, kev tswj hwm T hlwb (Tregs) thiab M2 macrophages feem ntau siv oxidative phosphorylation los ntawm fatty acid oxidation (FAO) los muab lub zog uas lawv xav tau [43]. B hlwb yog lwm lub cev tiv thaiv kab mob uas koom nrog kev tiv thaiv humeral. Nws tau raug tshaj tawm tias activated B hlwb nyiam siv glycolysis. Txawm li cas los xij, tom qab B cell activation los ntawm lipopolysaccharide (LPS) los yog lwm yam antigens, mitochondrial metabolism thiab glycolysis yog boosted hauv cov hlwb [44,45]. Tsis ntev los no, nws tau raug tshaj tawm tias kev txhim kho ntawm oncogene c-Myc thiab nce glycolysis yog qhov tseem ceeb rau kev tsim cov kev tswj hwm B hlwb (Bregs) [46].

2.3. Kev sib tw noj zaub mov ntawm cov qog hlwb thiab lub cev tiv thaiv kab mob

Ib qho kev sib tw tseem ceeb rau cov tshuaj tiv thaiv kab mob tiv thaiv kab mob yog kev sib tw ntawm cov qog hlwb thiab lub cev tiv thaiv kab mob kom noj qabzib, amino acids, fatty acids, kev loj hlob, thiab lwm yam metabolites hauv TME. Kev nthuav qhia ntawm cov khoom thauj muaj feem xyuam rau ntawm qhov chaw ntawm cov hlwb no tuaj yeem cuam tshuam txoj hmoo ntawm cov qog thiab lub cev tiv thaiv kab mob cov lus teb [13]. Cov khoom noj tseem ceeb tshaj plaws uas tau txais thiab nqus los ntawm cov qog hlwb yog cov piam thaj, uas tseem yog ib qho tseem ceeb ntawm cov khoom siv hluav taws xob rau kev sib txawv, kev ua kom muaj zog, thiab kev ua haujlwm ntawm cov kab mob infiltrated hauv TME, xws li qog-infiltrating lymphocytes (TILs) [47-49. ]. Kev sib tw ntawm cov piam thaj los ntawm cov qog hlwb txhawm rau txhawm rau ua haujlwm ntawm TILs yog ib qho ntawm cov qog khiav tawm thiab kev tiv thaiv kab mob qog noj ntshav [50]. Ntxiv mus, nce glycolytic kev ua ub no ntawm cov qog hlwb, thiab tsim cov metabolites, xws li lactate, tuaj yeem txo cov piam thaj los ntawm TILs, lawv qaug zog, thiab kev puas tsuaj rau lawv txoj haujlwm [51,52]. Tsis tas li ntawd, qog heterogenicity, siab acidity, hypoxia, thiab siab concentrations ntawm lactate thiab ROS nyob rau hauv TME txhawb kev tiv thaiv kab mob thiab kev loj hlob ntawm cancer [52]. Yog li ntawd, kev tsom mus rau ntau yam kev cuam tshuam cov txheej txheem metabolic cuam tshuam rau T cell-mediated antitumor cov lus teb tuaj yeem yog txoj hauv kev los kov yeej cov kev puas tsuaj ntawm kev sib tw metabolic ntawm lub cev tiv thaiv kab mob thiab qog hlwb [53] (Daim duab 2).

Daim duab 2. Kev sib tw metabolic ntawm cov qog nqaij hlav qog noj ntshav thiab lub cev tiv thaiv kab mob hauv TME. Muaj kev sib tw ntawm cov qog hlwb thiab lub cev tiv thaiv kab mob los nqa cov piam thaj, amino acids, fatty acids, kev loj hlob, thiab lwm yam metabolites hauv TME. Cov khoom noj tseem ceeb tshaj plaws uas tau noj thiab nqus los ntawm cov qog hlwb yog cov piam thaj, uas tseem ua haujlwm tseem ceeb ntawm cov khoom siv hluav taws xob rau kev sib txawv, kev ua kom muaj zog, thiab kev ua haujlwm ntawm cov kab mob infiltrated hauv TME, xws li TILs. Kev sib tw ntawm cov piam thaj los ntawm cov qog hlwb kom txo qis kev ua haujlwm ntawm TILs. Ua kom muaj glycolytic kev ua ub no ntawm cov qog hlwb, thiab tsim cov metabolites, xws li lactate, tuaj yeem txo qis kev noj qab haus huv los ntawm TILs, thiab lawv qhov qaug zog.

3. Txoj Kev Metabolic tseem ceeb tshaj plaws hauv kev mob qog noj ntshav thiab kev kho mob

3.1. PI3K/AKT/mTOR Txoj Kev

PI3K yog lub npe hu ua ib pawg ntawm plasma membrane ntsig txog lipid kinases. Cov kinases no suav nrog p55 (kev tswj hwm), p110 (catalytic), thiab p85 (kev tswj hwm) subunits [54]. PI3K tau muab faib ua PI3KI, PI3KII, thiab PI3KIII cov chav kawm raws li ntau yam qauv thiab substrates [55]. Lub p85 kev tswj hwm subunit tuaj yeem khi thiab sib txuas cov cim los ntawm cov protein kinase C (PKC), tyrosine kinase-txuas receptors, hormonal receptors, Src homology 2 domain-muaj protein ntau tyrosine phosphatase 1 (SHP1), Src, mutated Ras, Rac, thiab Rho, activating p110 catalytic subunit thiab lwm yam downstream molecules [56]. Stabilizing lub p110 subunit nyob ntawm nws dimerization nrog p85 subunit. Raws li extracellular stimuli, cov tshuaj hormones, cytokines, thiab kev loj hlob yam ua rau PI3K nyob rau hauv ib txwm thiab physiologic tej yam kev mob [57]. Activated PI3K induces lub phosphorylation ntawm phosphatidylinositol 4, 5-bisphosphate los tsim phosphatidylinositol 3,4, 5-trisphosphate (PIP3), stimulating downstream kinases, xws li AKT thiab {{0} phosphosphate pendinositol. -1 (PDK1), thiab inducing cell loj hlob thiab cell survival txoj kev [58,59]. Nws tau raug tshaj tawm tias phosphatase thiab tensin homolog (PTEN) tswj txoj hauv kev PI3K ntawm dephosphorylation ntawm PIP3 rau PIP2, inhibiting downstream kinase activation [56].

Ib qho ntawm cov thawj coj hauv qab PI3K signaling effectors yog mTOR, serine / threonine protein kinase uas tswj kev loj hlob ntawm tes, kev loj hlob, thiab cov metabolism [60,61]. Raws li kev paub muaj, mTOR complex 1 (mTORC1) thiab mTOR complex 2 (mTORC2) yog ob lub qauv ntawm mTOR. Cov complexes muaj cov haujlwm sib txawv; Piv txwv li, mTORC1 induces cell anabolism los ntawm kev txhawb cov synthesis ntawm nucleic acid thiab protein thaum tiv thaiv cell catabolism-mediated dab xws li autophagy. Ntawm qhov tod tes, mTORC2 induces glutamine uptake ntawm activating AGC kinases, uas ua rau cov kev cai ntawm glutamine cell nto transporters [60]. Tsis tas li ntawd, mTORC1 induces glutamine synthesis los ntawm zoo tswj glutamate dehydrogenase (GDH) thiab suppressing sirtuin 4 (SIRT4), uas yog lub luag hauj lwm rau GDH inhibition [62,63]. Txij li thaum aerobic glycolysis yog ib qho cim ntawm cov qog hlwb, nitrogen thiab carbon tau muab los ntawm glutamine los pab txhawb cov txheej txheem anabolic thiab kev loj hlob ntawm tes [64]. Hauv cov qog nqaij hlav, nws tau pom tias txoj hauv kev mTOR yog lub luag haujlwm rau kev txhawb nqa cov qog nqaij hlav, ua rau cov lus qhia ntawm inhibitory molecules, xws li programmed cell death ligand-1 (PDL-1), thiab suppressing anticancer cov lus teb. [65].

Hauv qee qhov tib neeg malignancies, mTOR noob hloov pauv tau tshaj tawm vim tias cov kab mob no tuaj yeem ua rau mTOR ua haujlwm. Raws li cov qog genome sequencing datasets, peb caug-peb mTOR kev hloov pauv koom nrog hauv kev mob qog noj ntshav tau raug txheeb xyuas. Cov kev hloov pauv tau pom tau muab faib ua rau thaj tsam sib txawv hauv C-terminal ib nrab ntawm mTOR. Lawv yog lub luag haujlwm rau kev cuam tshuam kev cuam tshuam ntawm mTOR thiab DEP domain-muaj mTOR-interacting protein (DEPTOR) (endogenous mTOR inhibitor), hyperactivating mTOR txoj kev [66]. Lwm qhov kev hloov pauv kuj tseem muaj feem xyuam rau mTORC1 thiab mTORC2- cov khoom tshwj xeeb thiab cov ntsiab lus ntws, suav nrog oncogenes thiab qog suppressors [67,68]. Ntxiv mus, ntau qhov kev hloov kho mob qog noj ntshav tau tshaj tawm nyob rau hauv txoj kev PI3K, sab sauv ntawm mTORC1 thiab mTORC2 [69]. Piv txwv li, kev hloov pauv hauv PIK3CA, uas encodes p110 PI3K catalytic subunit, tau tshaj tawm nyob rau hauv ntau tus tib neeg malignancies, xws li prostate, lub mis, endometrium, txoj hnyuv, thiab sab sauv aerodigestive tract cancers [70].

Raws li tau hais los saum no, cov qog nqaij hlav qog noj ntshav xav tau cov txheej txheem metabolic los pab txhawb lawv txoj kev loj hlob, kev loj hlob, kev ua haujlwm lom neeg, thiab muaj sia nyob. Hauv cov ntsiab lus no, mTOR ua lub luag haujlwm tswj hwm hauv cellular metabolism los ntawm kev txhawb nqa kev qhia ntawm ribosomal protein S6 kinase beta-1 (S6K1) thiab eukaryotic translation pib qhov tseem ceeb 4E (eIF4E)-binding protein 1 (4E-BP1) [71 ]. Tsis tas li ntawd, kev loj hlob thiab kev loj hlob ntawm cov qog hlwb tau txais kev txhawb nqa los ntawm mTOR-txhim kho cov piam thaj metabolism los ntawm kev txhim kho cov thauj khoom 1 (GlUT1), HIF1- , thiab c-MYC, ua rau kev txhim kho ntawm glycolytic enzymes, xws li enolase. (ENO), phosphofructokinase (PFK), thiab phosphoglucoisomerase (PGI) [72–74]. Lub teeb liab ntawm mTORC1 thiab mTORC2 induces fatty acid uptake thiab lipogenesis los txhawb cov qog cell proliferation [74]. Cov complexes induce sterol regulatory element-binding protein 1 (SREBP-1) thiab peroxisome proliferator-activated receptor (PPAR), uas koom nrog kev txhawb nqa kev qhia ntawm lipid thiab cholesterol homeostasis-associated enzymes, xws li fatty acid transporter. CD36, acetyl-CoA carboxylase 1 (ACC1), ATP citrate lyase (ACLY), thiab fatty acid synthase (FASN) [75–77]. Nws tau raug tshaj tawm tias inhibiting tus khub rapamycin-insensitive ntawm lub hom phiaj ntawm mammalian rapamycin (RICTOR) raws li mTORC2 tivthaiv, nrog rau inhibition ntawm mTORC1, mTORC2, thiab PI3K, tuaj yeem cuam tshuam qhov kev mob qog noj ntshav ntawm pancreatic thiab ua kom muaj sia nyob ntev. - theem ntawm qog [78]. Tsis tas li ntawd, overexpression ntawm RICTOR yog txuam nrog lymph node metastasis, qog nqaij hlav, thiab tsis zoo prognosis [79]. Kev ua haujlwm kinase inhibitors lossis siv RICTOR knockdown yog lwm txoj hauv kev kho mob hauv mTORC2- hom phiaj kho mob qog noj ntshav, ua rau muaj kev cuam tshuam ntawm cov qog cell loj hlob, tsiv teb tsaws, thiab metastasis [80,81]. Hauv kev mob qog nqaij hlav hauv plab (CRC), RICTOR tsis txaus tuaj yeem txo qis pAktSer473 qib thiab txo qis kev loj hlob thiab kev loj hlob ntawm CRC hlwb [82]. AKT hyperactivation yog lwm qhov txiaj ntsig ntawm RICTOR upregulation, kev loj hlob ntawm cov qog hlwb thiab txo qis kev ciaj sia. Hauv tib neeg epidermal growth factor receptor 2 (EGFR2) zoo mob qog noj ntshav, qhov ua tau zoo ntawm HER2 / EGFR tyrosine kinase inhibitors xws li lapatinib yog nce tom qab lub khob ntawm RICTOR lossis siv kinase inhibitors [68].

cistanche cog-nce kev tiv thaiv kab mob

Raws li cov pov thawj muaj, nws tswj hwm lub cev tiv thaiv kab mob, suav nrog kev tiv thaiv kab mob hauv lub cev, kev sib txawv, kev ua kom muaj zog, kev ua haujlwm, thiab homeostasis hauv innate thiab adaptive tiv thaiv [83]. Ntxiv mus, kev ua kom PI3K/AKT/mTORC1 yog qhov tseem ceeb rau kev tsim cov metabolic reprogramming effector CD4+ thiab CD8+ T cells [84,85]. Tom qab kev sib cuam tshuam ntawm T cell receptor (TCR) thiab cov antigens nthuav tawm, downstream signals xa los ntawm TCR, co-stimulatory molecules hauv immunologic synapses, nrog rau cytokine-mediated signals tau txais los ntawm mTORC1 thiab mTORC2 thiab lawv cov complexes tswj lub cev tiv thaiv kab mob. , transcription yam, migration, thiab metabolic reprogramming. Tsis tas li ntawd, mTOR cov cim qhia tau koom nrog hauv kev txiav txim siab txoj hmoo ntawm T hlwb thiab cov phenotype yuav tsim nyob rau hauv lawv thiab mus rau lub cim xeeb, kev tswj hwm, lossis effector T hlwb [85]. Hauv qhov no, kev tshawb nrhiav pom tias T hlwb nrog Rheb tsis muaj peev xwm tsis tuaj yeem sib txawv rau T tus pab 1 (Th1) thiab Th17 thiab tsim cov tshuaj tiv thaiv kab mob. Hauv qhov sib piv, cov T hlwb no zoo li sib txawv rau Th2 [86]. Interestingly, targeting mTORC2 signals through the knockdown of RICTOR in T cells tiv thaiv lawv qhov sib txawv rau hauv Th2 thiab txhim kho kev sib txawv rau Th1 thiab Th17 hlwb. Tsis tas li ntawd, tiam ntawm Tregs nyob ntawm qhov kev xaiv tshem tawm ntawm mTORC1 thiab mTORC2 cov cim tsis hais txog ntawm lub neej ntawm kev hloov pauv kev loj hlob ntawm exogenous-beta (TGF- ) [86]. Yog li ntawd, rapamycin, raws li ib tug mTOR inhibitor, muaj peev xwm tsub kom lub activation thiab proliferation ntawm T hlwb [87]. Ib txoj kev tshawb nrhiav pom tau hais tias metabolic manipulation ntawm naïve T cells thiab TILs thaum lawv nthuav dav hauv vitro siv Akt inhibitor VIII tuaj yeem ua rau muaj kev sib txawv ntawm T hlwb rau hauv lub cim xeeb T hlwb nrog cov kev ua haujlwm antitumor tsim nyog tom qab rov ua dua ntawm cov T hlwb rau cov nas tsis muaj zog nrog ntau yam. myeloma [88].

Cov kev cuam tshuam metabolic siv cov kws tshuaj tuaj yeem cuam tshuam cov metabolism hauv lub cev thiab T cell persistence [16]. Kev tshawb xyuas ntawm CD33- tshwj xeeb chimeric antigen receptor (CAR)-T hlwb tau pom tias kev kho cov hlwb tsim kho nrog LY294002, PI3K inhibitor, hauv vitro ua rau muaj kev sib txawv ntawm cov hlwb tsawg dua rau hauv cov ntawv luv luv nrog cov tshuaj tiv thaiv zoo. kev ua ub no thiab persistence hauv nas. Inhibition ntawm PI3K / AKT / mTOR kuj tseem cuam tshuam nrog nce glycolytic flux tom qab ua kom lub hlwb CAR-T [89]. Hauv cov hlwb CAR-T no, siv ntau yam co-stimulatory domains xws li CD28 lossis 4-1BB tuaj yeem cuam tshuam rau T cell metabolism thiab persistence. Piv txwv li, 4-1BB tuaj yeem ua rau mitochondrial biogenesis, oxidative phosphorylation, thiab sib txawv rau hauv lub cim xeeb T hlwb, nrog rau ntau dua hauv vivo persistence ntawm T hlwb, thaum ua hauj lwm CD28 yog txuam nrog nce glycolysis thiab effector sib txawv ntawm T hlwb [90 ]. Cov kev tshawb pom no qhia tau hais tias cov kev cuam tshuam hauv metabolic tuaj yeem cuam tshuam nrog kev txhim kho kev ua haujlwm ntawm tes kho mob qog noj ntshav; Txawm li cas los xij, vim qhov hloov pauv ntawm cov metabolism hauv T hlwb, nws tuaj yeem hloov pauv txoj haujlwm thiab phenotype, thiab hom kev cuam tshuam no xav tau kev tshawb fawb ntxiv.

3.2. AMPK Txoj Kev

AMPK yog suav tias yog ib qho tseem ceeb molecule hauv kev tswj cov cell zog homeostasis los ntawm kev saib xyuas AMP, ADP, thiab ATP qib. AMPK suav nrog peb subunits: subunit (catalytic) thiab (kev tswj hwm) subunits thiab ntau cov ntaub so ntswg / kab mob-specific isoforms, suav nrog 1, 2, 1, 2, 1, 2, 3 [91]. Intracellular calcium ions los ntawm calcium / calmodulin-dependent protein kinase kinase 2 (CAMKK2) thiab adenine nucleotides tuaj yeem qhib txoj hauv kev AMPK [92]. Hauv cov xwm txheej kev ntxhov siab, suav nrog hypoxia, cov piam thaj qis, thiab ischemia cuam tshuam nrog ATP depletion, txoj hauv kev AMPK kuj tau qhib. Qhov kev ua kom no yog tswj hwm los ntawm cov xov tooj ntawm tes AMP / ADP / ATP uas sib tw khi rau lub subunit. Cov xwm txheej no tuaj yeem txhawb nqa Thr172 phosphorylation ntawm lub subunit ntawm cov qog nqaij hlav hauv siab kinase B1 (LKB1) lossis suppress Thr172 phosphorylation los ntawm dephosphorylating subunit los ntawm phosphatase [93,94]. AMPK tseem tuaj yeem cuam tshuam los ntawm fructose 1, 6-bisphosphate (FBP), cov piam thaj metabolite [91]. Kev ua kom lub AMPK tuaj yeem ua rau autophagy thiab fatty acid oxidation los muab thiab rov ua kom lub cev ATP [95]. Txij li thaum gluconeogenesis, protein, thiab lipid synthesis yog ATP-siv, AMPK tsis zoo tswj cov txheej txheem biosynthetic kom khaws ATP thiab tswj lub zog metabolism, ua kom lub cev tsis muaj zog [96]. Cov kev tshawb pom no qhia tias txoj hauv kev AMPK tswj qhov sib npaug ntawm lub cev tiv thaiv kab mob thiab lub zog metabolism [2]. Ntawm qhov tod tes, AMPK activation inhibits ntau yam kev tiv thaiv kab mob hauv lub cev muaj feem cuam tshuam nrog kev loj hlob thiab ua kom lub cev tiv thaiv kab mob, xws li myeloid-derived suppressor cells (MDSCs) [96]. Raws li txoj hauv kev, AMPK txoj hauv kev, ua tus tswj hwm cov metabolism, tuaj yeem ua lub luag haujlwm tiv thaiv qog noj ntshav. Hauv qhov sib piv, lwm cov kev tshawb fawb pom tau tias AMPK kev ua kom muaj feem cuam tshuam nrog kev tawm tsam ntawm txoj hauv kev ua rau cov kab mob, xws li NFκB, thiab kev sib txawv ntawm macrophages los ntawm M1 rau hauv M2 phenotype, txhim kho kev qhia ntawm cov tshuaj tiv thaiv cytokines, xws li IL. -10 [97,98]. Kev ua kom lub AMPK txoj hauv kev los ntawm kev tswj lub zog metabolism yog koom nrog kev sib txawv ntawm T hlwb, cuam tshuam rau kev ua haujlwm ntawm cov kab mob tiv thaiv kab mob no [2].

3.3. Adenosine Txoj Kev

Tom qab cov ntaub so ntswg raug mob los yog hypoxic TME, nucleoside adenosine qib tau nthuav dav thiab khi rau adenosine 2A receptor (A2AR) ntawm lub xov tooj ntawm tes, inhibiting cytotoxic T cell / natural killer cells (NK) cell-mediated antitumor immune responses. CD73 thiab CD39 tswj kev tsim cov adenosine ntawm catabolism ntawm ATP. CD39 converts ATP rau AMP, thiab CD73 converts AMP rau adenosine [99]. Immunosuppressive hlwb xws li Tregs tuaj yeem nthuav qhia CD39 thiab ua kom txoj hauv kev A2AR hauv cov kab mob tiv thaiv kab mob no ua rau txo qis ntawm cov kab mob sib kis thiab kev txhim kho ntawm cov tshuaj tiv thaiv kab mob, xws li IL-10, ua rau dephosphorylation ntawm cov teeb liab transducer thiab activator. ntawm transcription 5 (STAT5), inhibiting NFκB txoj hauv kev, thiab txo IL-2R-mediated signals hauv T hlwb. Tregs tsim adenosine los ntawm kev sib tham ntawm CD39 / CD73, ua kom txoj hauv kev adenosine thiab overexpressing prostaglandin E2 (PGE2) receptors, EP2 receptors (EP2R) ntawm qhov chaw ntawm T cells. Tsis tas li ntawd, adenylate cyclase kev ua haujlwm tau nce ntxiv tom qab adenosine txoj kev ua haujlwm, ua rau muaj zog cAMP thiab txhawb kev tiv thaiv kab mob [100].

4. Dual Pathway Inhibitors

Txog tam sim no, ntau cov kev tshawb fawb tau ua tiav ntawm cov txheej txheem metabolic inhibitors hauv kev kho mob qog noj ntshav, thiab cov txiaj ntsig tau zoo tau ua tiav. Txawm li cas los xij, kuj tseem muaj txoj kev xav tias kev siv ob txoj hauv kev inhibitors ua rau muaj txiaj ntsig ntawm kev kho mob qog noj ntshav. Tshooj lus no tham txog cov khoom ntawm cov tshuaj tiv thaiv dual no thiab qhov tshwm sim ntawm lawv siv hauv kev kho mob qog noj ntshav (Table 1). Cov qauv tshuaj thiab cov mis molecular ntawm dual inhibitors kuj pom nyob rau hauv Table 2.

Table 1. Daim ntawv teev cov tseem ceeb tshaj ob txoj kev inhibitors

Table 1. List of the most important dual pathway inhibitors

Table 1. Cont.

Table 2. Cov qauv tshuaj ntawm ob txoj kev inhibitors

Table 2. Chemical structure of dual pathway inhibitors

Table 2. Cont

4.1. Dual PI3K / AKT / mTOR Inhibitors

PI3K thiab mTOR belongs rau tsev neeg ntawm phosphatidylinositol 3-kinase-related kinases (PIKKs). Raws li cov qauv thiab kev ua haujlwm zoo sib xws ntawm PI3K thiab mTOR, nrog rau cov kev tshawb fawb ntawm mTOR inhibitors, cov kws tshawb fawb tau tsim cov inhibitors nrog ob lub zog, suppressing PI3K thiab mTOR [143].

4.1.1. Dactolisib

Dactolisib (BEZ235) yog ib qho imidazoquinoline tsom rau PI3K thiab mTOR, nrog rau kev ua kom muaj zog tiv thaiv kab mob. Dactolisib suppresses PI3K kinase thiab mTOR kinase nyob rau hauv txoj kev PI3K / AKT / mTOR kinase, inducing qog cell apoptosis thiab inhibiting kev loj hlob ntawm PI3K / mTOR heev nthuav cov qog nqaij hlav cancer. Ntxiv rau qhov ua rau cov qog cell loj hlob, kev loj hlob, thiab kev ciaj sia, txoj hauv kev PI3K / mTOR kuj tseem ua lub luag haujlwm tseem ceeb hauv kev ua kom cov qog tiv taus rau cov kev kho mob ib txwm muaj, xws li kev kho hluav taws xob thiab tshuaj khomob [101].

Nws tau tshawb xyuas hauv cov qog nqaij hlav tsis me me (NSCLC) cov hlwb nrog ntau yam EGFR xwm txheej seb puas muaj kev sib koom ua ke PI3K thiab mTOR yuav txhim kho cov txiaj ntsig kho mob. Txoj kev tshawb no tau tshaj tawm tias BEZ235 cuam tshuam cov qog loj hlob hauv vitro thiab hauv vivo los ntawm kev txhawb nqa lub voj voog ntawm tes ntawm G1 theem thiab txo cov cyclin D1 / D3 qhia. Tsis tas li ntawd, BEZ235 synergistically txhawb cisplatin-mediated apoptosis hauv NSCLC hlwb los ntawm kev txhawb nqa lossis ua rau DNA puas tsuaj. Cov ntaub ntawv no qhia tau hais tias dual PI3K / mTOR inhibition los ntawm BEZ235 tuaj yeem yog tus neeg sawv cev tiv thaiv kab mob uas ua rau muaj txiaj ntsig ntawm kev kho mob lossis kws khomob [102].

Kev tshawb xyuas ntawm mantle cell lymphoma (MCL) hlwb tau pom tias piv nrog everolimus (ib qho mTOR inhibitor) lossis NVP-BKM120 (ib qho PI3K inhibitor), BEZ235 tuaj yeem muaj zog ntau dua hauv kev tawm tsam PI3K / Akt / mTOR txoj hauv kev. Tsis tas li ntawd, BEZ235 tuaj yeem cuam tshuam cov kab mob angiogenesis, kev tsiv teb tsaws, thiab kev cuam tshuam ntawm cov qog hlwb. Tsis tas li ntawd, nws tau raug qhia tias interleukin-4 (IL-4) thiab IL-6/sib nqus transducer thiab activator ntawm transcription 3 (STAT3) txoj kev koom nrog chemoresistance. Hais txog lub luag haujlwm ntawm IL-6 hauv inducing chemoresistance, nws tau raug qhia tias IL-6-kho cov qia cell expansion thiab epithelial-mesenchymal hloov (EMT) tuaj yeem koom nrog hauv qhov teeb meem no. Mechanistically, IL -6 induces upregulation ntawm multidrug-resistant txuam nrog cov neeg kho mob, xws li MDR1 thiab glutathione S transferase pi (GSTpi). Ntxiv mus, IL-6 tiv thaiv qog hlwb los ntawm paclitaxel thiab cisplatin-txuas nrog cytotoxic teebmeem los ntawm downregulating caspase3 (Cas3) thiab upregulating antiapoptotic proteins, xws li X-linked inhibitors ntawm apoptosis (XIAP), B-cell lymphoma 2 (Bcl. -2), thiab B-cell lymphoma-extra large (Bcl-xL) hauv cov qog nqaij hlav resistant. Tsis tas li ntawd, IL-6 tuaj yeem ua rau kev ua haujlwm ntawm PI3K / AKT txoj hauv kev tiv thaiv qog hlwb [144]. Tsis muaj qhov qhia meej meej ntawm qhov tseeb mechanism uas IL-4 pab txhawb rau chemoresistance hauv cov qog; Txawm li cas los xij, cov ntaub ntawv pov thawj pom tau tias zoo ib yam li IL-6, IL-4 tuaj yeem tswj hwm qhov tseem ceeb antiapoptotic yam uas yuav muaj txiaj ntsig zoo rau cov tshuaj chemoresistance [145].

Tsis zoo li Everolimus thiab NVP-BKM120, BEZ235 tuaj yeem cuam tshuam cov cim ntawm cov cytokines, txhim kho kev ua haujlwm ntawm cov tshuaj khomob [103]. Cov kev tshawb pom no qhia tias ob txoj hauv kev inhibitors tuaj yeem ua tau zoo dua li ib txoj hauv kev inhibition, inhibiting PI3K / Akt / mTOR txoj hauv kev ntawm ntau theem. Kev sib xyaw BEZ235 nrog dexamethasone hauv cov mob qog ntshav qog ntshav qog ntshav (TSIS TAU) tau pom tias nrog rau inhibiting PI3K / AKT / mTOR txoj hauv kev, cov teebmeem antileukemic ntawm dexamethasone tau txhim kho hauv vitro thiab hauv vivo. AKT1 yog lub luag haujlwm rau kev tawm tsam dexamethasone-induced qog cell apoptosis. Yog li, BEZ235, los ntawm inhibiting AKT thiab downregulating myeloid cell leukemia-1 (MCL{11}}), tuaj yeem ua rau dexamethasone-mediated apoptotic pathways hauv malignant cells [104]. Ib theem Ib koob tshuaj-escalation soj ntsuam kuaj pom tau hais tias combining everolimus thiab BEZ235 (hais lus nyob rau hauv escalating koob tshuaj ntawm 200, 400, thiab 800 mg / hnub ntxiv rau everolimus ntawm 2.5 mg / hnub nyob rau hauv 28- hnub cycles) thiab cov kev kho mob no yog cuam tshuam nrog kev ua haujlwm tsis zoo thiab kev ua siab ntev. Qhov zoo tshaj plaws ntawm BEZ235 kev tswj hwm yog tias nws qhov kev tswj hwm qhov ncauj tsis tuaj yeem yog qhov kev xaiv tsim nyog rau kev kho mob vim tias tsis muaj bioavailability thiab gastrointestinal toxicity. Hauv qhov sib piv, kev tswj hwm kev tswj hwm ntawm qhov inhibitor no tuaj yeem muaj txiaj ntsig zoo dua nyob rau hauv koob tshuaj [146]. Lwm theem I/Ib, multicenter, qhib-daim ntawv lo los ntawm kev tswj cov koob tshuaj sib txawv ntawm BEZ235 rau cov neeg mob HER2+ mob qog noj ntshav tau pom tias cov nyhuv ntawm cov tshuaj no tau pom ib feem ntawm tsuas yog 13% ntawm cov neeg mob. Cov kev mob tshwm sim, suav nrog xeev siab, raws plab, thiab ntuav, tau tshaj tawm hauv cov neeg mob. Ntxiv mus, BEZ235 tau pom ntau qhov sib txawv thiab muaj txiaj ntsig hauv koob tshuaj ntau dua 100 mg, txawm hais tias cov koob tshuaj siab tau cuam tshuam nrog kev mob plab hnyuv [105].

Ntawm qhov tod tes, cov neeg mob uas muaj kab mob pancreatic neuroendocrine siab heev (pNET) tau kho nrog qhov ncauj everolimus 10 mg ib hnub ib zaug lossis qhov ncauj BEZ235 400 mg ob zaug ib hnub ntawm kev noj tshuaj tas li. Cov kev tshawb pom tau pom tias qhov nruab nrab ntawm kev muaj sia nyob tsis muaj sia nyob (PFS) hauv BEZ235- pab pawg kho mob yog 8.2 lub hlis piv rau 10.8 lub hlis hauv cov neeg mob kho mob everolimus. Feem ntau cov teebmeem tshwm sim hauv cov neeg mob BEZ235 yog raws plab, stomatitis, thiab xeev siab. Cov txiaj ntsig no qhia tau tias BEZ235 tsis tuaj yeem ua haujlwm zoo dua li everolimus, yam tsawg kawg ntawm PFS. Ntawm qhov tod tes, qhov no dual inhibitor cov kev mob tshwm sim ntau dua li everolimus. Txawm li cas los xij, cov lus teb rau kev kho mob no tuaj yeem hloov pauv hauv cov qog nqaij hlav thiab cov neeg mob uas muaj mob sib txawv [147].

Desert ginseng-Improve immunity

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

4.1.2. Gedatolisib

Gedatolisib (PKI{0}}) yog ib qho inhibitor dual tsom rau PI3K thiab mTOR kinases hauv PI3K/mTOR kev taw qhia txoj hauv kev, muaj peev xwm tiv thaiv kev ua haujlwm. Cov ntaub ntawv pov thawj pom tau tias tom qab txhaj tshuaj ntawm gedatolisib, nws inhibits mTOR thiab PI3K kinases, inducing apoptosis thiab suppressing kev loj hlob ntawm qog hlwb overexpressing PI3K / mTOR. Ntxiv mus, gedatolisib tuaj yeem txhim kho xov tooj cua thiab chemosensitivity los ntawm inhibiting PI3K / AKT / mTOR txoj hauv kev kom txo tau DNA puas tsuaj kho mechanisms [106]. Tsis ntev los no, kev tshawb nrhiav tau tshaj tawm tias kev sib txuas PKI-587 nrog Cofetuzumab Pelidotin, ib qho protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate nyob rau hauv cov neeg mob uas mob qog noj ntshav metastatic triple-negative mis (TNBC) tau cuam tshuam nrog Kev cog lus kev ua haujlwm kho mob, ob lub hlis nruab nrab PFS, thiab kev mob toxicity (anorexia xeev siab, mucositis, thiab qaug zog) [107]. PKI-587 tuaj yeem ua rau muaj kev hnov mob hauv xov tooj cua. Kev tshawb nrhiav pom tias DNA puas tau nce ntxiv hauv SK-Hep1 xenograft hepatocellular carcinoma (HCC) qauv, sib txuas ionizing hluav taws xob nrog PKI-587, thiab G0/G1 cell-cycle ntes, nrog rau apoptosis, raug ntxias hauv cov qog hlwb. . Raws li, kev tawm tsam PI3K / AKT / mTOR thiab DNA kev puas tsuaj kho txoj hauv kev los ntawm PKI-587 tuaj yeem txhawb nqa cov xov tooj cua ntawm HCC hlwb [108]. Qhov kev tshwm sim hauv T-cell TAG NRHO cov neeg mob (T-ALL) tsis zoo. Kev hloov pauv hauv PI3K / mTOR kev taw qhia txoj hauv kev yog lub luag haujlwm rau kev rov qab los thiab kev kho mob tsis ua haujlwm vim tias txoj kev PI3K / mTOR yog overactivated hauv cov neeg mob T-ALL. Txoj kev tshawb no pom tau hais tias PKI-587 inhibited T-ALL cell kab proliferation thiab colony tsim los ntawm kev xaiv suppression ntawm PI3K/mTOR txoj kev uas tsis cuam tshuam rau mitogen-activated protein kinase (MAPK) txoj hauv vitro thiab hauv vivo. Tsis tas li ntawd, PKI-587 txo cov qog nqaij hlav thiab kev loj hlob, ua kom muaj sia nyob ntev ntawm cov nas tsis muaj zog tiv thaiv kab mob xenograft yam tsis ua rau poob phaus hauv cov nas uas kho nrog tus inhibitor [109]. Nws zoo nkaus li tias PKI-587 tuaj yeem yog qhov kev xaiv tsim nyog rau kev kho tib neeg mob. Txawm li cas los xij, kev sib xyaw ua ke siv PKI-587 tuaj yeem ua rau muaj txiaj ntsig zoo ntawm kev kho mob los ntawm kev tsim cov lus teb ua ke.

4.1.3. Voxtalisib

Voxtalisib (SAR245409) yog ib chav kawm haib-I PI3Ks, mTORC1, thiab mTORC2 inhibitor [148]. Nws tau raug tshaj tawm tias voxtalisib tuaj yeem cuam tshuam cov phosphorylation ntawm PI3K thiab tswj kev koom ua ke ntawm mTOR effector hauv cov qog nqaij hlav cancer [149]. Hauv ib theem Ib qho kev sim tshuaj rau cov neeg mob uas muaj mob qog noj ntshav siab, 90 mg pimasertib (ib qho MEK1/2 inhibitor) thiab 70 mg voxtalisib tau tswj hwm, thiab kev tshawb pom pom tias qhov kev sib xyaw ua ke no tsis zoo zam thiab tsis muaj kev cuam tshuam tseem ceeb ntawm kev kho mob. ciaj sia ntawm cov neeg mob uas muaj mob qog nqaij hlav. Feem ntau pom cov xwm txheej tsis zoo hauv txoj kev tshawb no yog raws plab, xeev siab, thiab qaug zog [110]. Nws zoo nkaus li tias tus neeg mob kam rau tshuaj yog nyob ntawm qhov koob tshuaj voxtalisib thiab lub sijhawm. Ib theem kuv qhov chaw kuaj mob tau tswj hwm kev sib xyaw ntawm voxtalisib nrog temozolomide, nrog lossis tsis muaj kev kho hluav taws xob, rau cov neeg mob uas muaj qib siab glioma. Cov txiaj ntsig tau pom tias cov koob tshuaj siab tshaj plaws (MTDs) rau voxtalisib ua ke nrog temozolomide yog 90 mg ib hnub ib zaug thiab 40 mg ob zaug ib hnub. Feem ntau cov xwm txheej tsis zoo hauv txoj kev tshawb no yog xeev siab, qaug zog, thrombocytopenia, raws plab, thiab lymphopenia. Txoj kev tshawb no tau pom tias voxtalisib, ua ke nrog temozolomide nrog lossis tsis muaj kev kho hluav taws xob, tuaj yeem kho cov qib siab gliomas nrog kev nyab xeeb zoo [111].

4.1.4. Bimiralisib

Bimiralisib (PQR309) yog lub npe hu ua yias-chav kawm I PI3K / mTOR antagonist uas tawm tsam PI3K thiab mTOR. Raws li kev sim biochemical, bimiralisib muaj kev cuam tshuam tsawg dua ntawm PI3K thiab tsis tuaj yeem cuam tshuam lwm cov protein kinases [150]. Nws tau raug tshaj tawm tias txoj kev PI3K / mTOR tau koom nrog ntau hom lymphoma. Yog li ntawd, pharmacological inhibition ntawm txoj kev no yuav pab tau cov neeg mob lymphoma.

Tus qauv lymphoma preclinical pom tau hais tias bimiralisib tau pom cov tshuaj tiv thaiv lymphoma hauv vitro ib leeg lossis ua ke nrog lwm cov tshuaj tiv thaiv kabmob, xws li panobinostat, venetoclax, lenalidomide, ibrutinib, ARV-825, rituximab, thiab marizomib. Txoj kev tshawb no tau pom tias bimiralisib tuaj yeem ua rau muaj kev qhia ntawm HRK, YPEL3, thiab TP63, thaum lub gene qhia ntawm HSPA8 thiab HSPA1B, CCDC86, PAK1IP1, thiab MIR155HG raug txo qis tom qab kev kho mob [112]. Ib koob tshuaj-escalation, qhib-label theem I sim ntsuas cov tshuaj tiv thaiv kab mob thiab kev nyab xeeb ntawm bimiralisib ( koob tshuaj 10 txog 150 mg) hauv cov neeg mob uas muaj cov qog nqaij hlav siab heev. Cov txiaj ntsig tau pom tias cov lus teb ib nrab tau kuaj pom tom qab kev kho bimiralisib hauv tus neeg mob nrog metastatic thymus malignancy.

Ntxiv mus, tus kab mob ntim tau txo mus rau ib feem peb ntawm tus neeg mob uas muaj mob qog noj ntshav sinonasal, thiab tus neeg mob uas muaj cov qog nqaij hlav qog nqaij hlav Bartholin tau ntsib cov kab mob ruaj khov rau ntau tshaj kaum rau lub lis piam. MTD thiab pom zoo theem 2 koob tshuaj bimiralisib tau suav tias yog 80 mg ntawm qhov ncauj ib hnub. Kev soj ntsuam ntawm cov qog nqaij hlav tau qhia tias bimiralisib siv nws cov tshuaj tiv thaiv kab mob los ntawm kev txo qis PI3K txoj hauv kev phosphoprotein. Tsis tas li ntawd, cov xwm txheej tsis zoo, suav nrog hyperglycemia, qaug zog, xeev siab, cem quav, raws plab, ua pob, ntuav, thiab anorexia, tau kuaj pom hauv kwv yees li 30% ntawm cov neeg mob [113]. Interestingly, bimiralisib tuaj yeem ua tau zoo hla lub hlwb-ntshav barrier (BBB) piv nrog BEZ235 thiab voxtalisib [112,114]. Cov yam ntxwv ntawm bimiralisib no tuaj yeem pab txhawb nws txoj kev xa mus rau cov qog nqaij hlav hauv cov qog hlwb thiab txhim kho cov txiaj ntsig ntawm kev kho mob.

4.1.5. Paxalisib

Paxalisib (GDC{0}}) yog lub npe hu ua ib qho kev xaiv thiab muaj zog ntawm qhov ncauj hlwb-penetrant dual inhibitor ntawm PI3K thiab mTOR kinase. Paxalisib tau tsim tshwj xeeb rau kev kho mob qog nqaij hlav hauv hlwb, xws li kev loj hlob lossis rov tshwm sim glioma, vim tias nws tuaj yeem hla BBB tau zoo los txhim kho cov tshuaj xa mus rau lub hlwb. Cov kev tshawb fawb soj ntsuam tau pom tias tuag tes tuag taw tuaj yeem cuam tshuam kev loj hlob ntawm cov qog hlwb nyob rau hauv koob tshuaj [115–117]. Raws li kev paub muaj, PI3K / Akt / mTOR txoj hauv kev yog overactivated vim PIK3CA hloov mus txog li 70% ntawm lub hlwb metastases hauv cov neeg mob qog noj ntshav. Ib txoj kev tshawb fawb ua ntej tau pom tias tuag tes tuag taw txo qis ntawm tes thiab phosphorylation ntawm AKT thiab p70 S6 kinase. Ntxiv mus, apoptosis ntawm PIK3CA-mutant mob cancer mis lub hlwb metastatic hlwb tau nce ntxiv tom qab kev kho mob nyob rau hauv kab nyob rau hauv ib koob tshuaj-dependent zam [118]. Yog li ntawd, kev siv cov tuag tes tuag taw tuaj yeem ua tau zoo hauv cov qog nqaij hlav hlwb thiab cov qog nqaij hlav hauv hlwb. Txawm li cas los xij, qhov tshuaj tiv thaiv dual no tuaj yeem ua haujlwm tau zoo hauv lwm yam kab mob, xws li cutaneous squamous cell carcinoma (cSCC). Hauv cov ntsiab lus no, kev tshawb nrhiav tau tshaj tawm tias kev kho mob tuag tes tuag taw ntawm cov koob tshuaj nanomole muaj peev xwm ua rau muaj kev loj hlob thiab muaj sia nyob ntawm SCC-13, SCL-1, thiab A431 cell kab nrog rau thawj tib neeg cSCC hlwb ntawm induction ntawm apoptosis thiab cell voj voog ntes hauv cSCC hlwb. Interestingly, ntxiv rau nws cov txiaj ntsig ua rau cov qog hlwb ntau dua li lwm cov PI3K-Akt-mTOR txoj kev inhibitors, tuag tes tuag taw tsis muaj tshuaj lom rau cov tawv nqaij li qub, suav nrog keratinocytes thiab fibroblasts [119]. Lub tshuab ua haujlwm ntawm kev tuag tes tuag taw yog inhibiting phosphorylation ntawm cov khoom tseem ceeb ntawm PI3K-Akt-mTOR txoj hauv kev, xws li Akt, S6, p85, thiab S6K1. Tsis tas li ntawd, kev tuag tes tuag taw cuam tshuam kev ua kom DNA-PKcs hauv cSCC hlwb [119].

4.1.6. Omipalisib

Omipalisib (GSK2126458) yog qhov ncauj ob lub qhov ncauj PI3K / mTOR inhibitor uas inhibits kev loj hlob thiab kev loj hlob ntawm cov qog nqaij hlav cancer [151]. Nws tau raug tshaj tawm tias kev kho mob omipalisib tuaj yeem tiv thaiv kev tsim cov kab mob qog noj ntshav thiab ua rau autophagic cell tuag vim clonogenicity nyob ntawm theem pib fibroblast kev loj hlob (bFGF) thiab Insulin-zoo li kev loj hlob 1 (IGF-1) signaling ntawm AKT thiab ERK txoj hauv kev thiab omipalisib ua ke nrog ERK inhibitor, xws li MEK162 tuaj yeem cuam tshuam kev tsim cov colony [121]. Anti-proliferative nyhuv ntawm omipalisib ntawm AML kab ntawm tes tau tshawb nrhiav thiab qhia tias omipalisib tuaj yeem ua rau G0/G1 cell voj voog raug ntes hauv OCI-AML3 HL60 thiab THP1 cell kab. Raws li kev sib tham, omipalisib txo qis phosphorylation ntawm mTOR, AKT, 4E-BP1, thiab S6K. Tsis tas li ntawd, kev txheeb xyuas cov txheej txheem metabolic ntxiv tau pom tias cov metabolites cuam tshuam nrog cov amino acid metabolism tau txo qis heev thaum kho nrog omipalisib. Tsis tas li ntawd, tom qab kev kho mob ntawm OCI-AML3 hlwb nrog omipalisib, kev qhia ntawm ntau lub noob tseem ceeb, suav nrog PHGDH, PSPH, PSAT1, MTHFD1/2, thiab SHMT1/2, hauv glycine thiab serine synthesis pathway, tau txo qis hauv cov hlwb no. . Vim lub zog theem, biosynthesis thiab kev ua haujlwm ntawm mitochondria tej zaum yuav cuam tshuam los ntawm omipalisib [122]. Tsis tas li ntawd, kev tshawb fawb ntawm cov qauv nas pom tau hais tias 0.2 lossis 1 mg / kg qhov ncauj kev tswj hwm ntawm omipalisib tuaj yeem txo cov qog loj hlob yam tsis muaj kev hloov pauv hauv lub cev hnyav ntawm cov tsiaj kho [123].

4.1.7 ib. SIB 1126

SF1126 yog ib qho RGD-conjugated LY294002 pro-tshuaj nrog cov solubility siab thiab antiangiogenic cov khoom uas tuaj yeem khi rau cov integrins tshwj xeeb hauv TME [152]. Yog li, kev tswj hwm ntawm SF1126 txhim kho kev xa mus rau TME thiab qog vasculature. Cov kev tshawb fawb tsis ntev los no tau pom tias qhov sib xyaw no tuaj yeem cuam tshuam PI3K / AKT / mTOR thiab bromodomain-muaj protein ntau 4 (BRD4) txoj hauv kev hauv cov qog nqaij hlav cancer [124,125]. Ib txoj kev tshawb fawb tau kho CRC kab ntawm tes nrog rau cov tib neeg cov kab mob qog noj ntshav uas cais tawm ntawm tib neeg cov qog nrog SF1126, thiab kev tshawb pom pom tias cov tshuaj no tuaj yeem cuam tshuam cov qog cell loj hlob thiab induce apoptosis. SF1126 kuj tuaj yeem ua rau lub voj voog ntawm tes ntes hauv cov qog nqaij hlav cancer [124]. Lwm txoj kev tshawb fawb tau tshaj tawm tias SF1126 kev kho mob tshem tawm HIF-2 stabilization hauv VHL-mutated RCC cell kab nyob rau hauv normoxic thiab hypoxic mob. Tsis tas li ntawd, SF1126 subcutaneously tswj hwm rau RCC-xenografted nas zoo kawg nkaus inhibited angiogenesis, qog loj hlob, thiab kev loj hlob. SF1126 kuj tuaj yeem cuam tshuam cov qog nqaij hlav hauv nruab nrog cev thiab thaiv cov integrin-induced guanosine diphosphate (GDP)-Rac tsev neeg me GTPase 1 (Rac1) hloov mus rau nws lub xeev nquag [126].

4.1.8 ib. PF-04691502

PF-04691502 yog lwm dual PI3K / mTOR inhibitor uas tuaj yeem cuam tshuam cov qog loj hlob thiab kev loj hlob los ntawm kev cuam tshuam ntawm apoptosis. PF-04691502 kuj tseem txhim kho cov xov tooj cua ntawm ntau tus tib neeg malignancies [127]. Nws tau raug tshaj tawm tias PF-04691502 tuaj yeem cuam tshuam kev loj hlob, kev loj hlob, kev tsiv teb tsaws, thiab kev cuam tshuam ntawm cov qog nqaij hlav zais zis. Tsis tas li ntawd, nws tuaj yeem txhim kho apoptosis ntawm cov qog hlwb los ntawm txoj hauv kev hauv nruab nrog. PF-04691502 txo cov kev qhia ntawm PI3K/Akt/mTOR txoj hauv kev thiab myeloid leukemia 1 (MCL-1) hauv cov qog nqaij hlav zais zis. Raws li nrog ob peb ntawm cov tshuaj inhibitors sib tham, PF-04691502 kuj tseem tuaj yeem ua rau muaj txiaj ntsig zoo ntawm kev kho mob thiab ua kom cov qog hlwb rhiab heev rau kev kho hluav taws xob [128]. Advanced-theem gastroenteropancreatic neuroendocrine hlav (GEP-NETs) cuam tshuam nrog kev ua haujlwm tsis zoo txawm hais tias siv xov tooj cua thiab kws khomob. Kev kho mob ntawm NET cell kab (QGP-1 thiab BON) nrog PF-04691502 txo qis kev qhia ntawm pAKT txog li 72 h dua li hauv pawg tswj hwm. Kuj ceeb tias, kev kho mob ib txhij nrog PF-04691502 thiab xov tooj cua kho tsis tau txhim kho apoptosis hauv NET hlwb, thaum ntxiv PF-04691502 48 h raws li kev kho hluav taws xob cuam tshuam rau apoptosis piv rau kev kho hluav taws xob lossis PF{18}} kho ib leeg [129] . Cov txiaj ntsig no qhia tau tias kev sib txuas hluav taws xob thiab PF-04691502 tuaj yeem yog qhov tshiab thiab muaj peev xwm kho tau rau kev kho NETs [153].

Hauv cov neeg mob uas muaj T-cell lymphomas (CTCLs) thiab Sézary syndrome (SS), overactivation ntawm PI3K / AKT / mTOR txoj kev yog pom tau. Yog li, thaiv txoj hauv kev no qhia tau tias muaj peev xwm kho tau los tiv thaiv CTCLs [130]. Kev kho mob nrog PF-04691502 inhibited kev loj hlob ntawm CTCL cell kab thiab muab cov qog hlwb los ntawm cov neeg mob SS. PF-04691502 induced apoptotic cascades thiab G1 cell ntes nyob rau hauv lub cell voj voog ntawm CTCL cell kab, whereas, nyob rau hauv cov neeg mob SS, nws qhov kev txiav txim yog feem ntau yog vim induction ntawm muaj zog apoptosis. Qhov tseem ceeb, PF-04691502 tsuas yog cuam tshuam me ntsis rau cov neeg noj qab haus huv tau txais T cells.

Ntxiv mus, PF{{0}} txwv tsis pub CXCL12-txog kev nrhiav neeg ua haujlwm ntawm tes thiab kev tsiv teb tsaws chaw hauv txhua pawg kawm. Tom qab kev kho mob, nrog rau kev muaj sia nyob ntxiv, nws tau pom tias cov qog nqaij hlav txo los ntawm 936 mm3 hauv pawg tswj mus rau 400 mm3 hauv cov nas kho. Tsis tas li ntawd, qog qhov hnyav tau txo los ntawm 0.56 g hauv kev tswj hwm mus rau 0.2 g hauv cov nas kho [153].

4.1.9 ib. Samotolisib

Samotolisib (LY3023414) yog ib qho kev hais lus muaj dual kinase inhibitor ntawm chav kawm I PI3K thiab mTOR [131]. Cov kev tshawb fawb hauv tsev kho mob tau pom tias kev sib txuas ntawm samotolisib nrog prexasertib, qhov chaw kuaj xyuas kinase 1 inhibitor (samotolisib 200 mg ntawm qhov ncauj ob zaug ib hnub ntxiv rau prexasertib 105 mg / m2 intravenously txhua 14 hnub), tuaj yeem muaj kev tiv thaiv kab mob hauv cov qauv ua ntej thiab tus nqi ua ntej hauv cov neeg mob pretreated tiag; Txawm li cas los xij, kev kho mob sib xyaw ua ke tau nrog cov tshuaj toxicity, uas yuav tsum tau txiav txim siab hauv kev sim yav tom ntej [131]. Ob qhov muag tsis pom kev, cov placebo-tswj theem Ib / II sim ua ke nrog samotolisib nrog enzalutamide (cov tshuaj nonsteroidal antiandrogen siv los kho mob qog noj ntshav) hauv cov neeg mob uas mob qog noj ntshav metastatic castration-resistant prostate cancer. Txoj kev tshawb no qhia tau hais tias kev sib xyaw ntawm samotolisib nrog enzalutamide tau txais txiaj ntsig zoo thiab ua kom pom tseeb PFS hauv cov neeg mob kawm [132]. Cov ntaub ntawv pov thawj tau pom tias qaug zog, xeev siab, ntuav, thiab raws plab yog qhov tshwm sim tsis zoo tom qab kev kho mob nrog samotolisib [133]. Hauv qhov quav dysplasia thiab mob qog noj ntshav hauv qhov quav, inhibition ntawm PI3K / AKT / mTOR txoj hauv kev yog qhov ua tau zoo. Hauv K14E6 / E7 nas kho nrog tshuaj pleev xim samotolisib, squamous cell carcinoma raug txwv tsis pub tom qab 15 lub lis piam ntawm kev pib kho hauv kev sib deev (tsuas yog txiv neej nas) [134].

4.1.10 Nws. PWT 33597

PWT33597 yog lwm dual kinase inhibitor uas, raws li kev soj ntsuam biochemical, represses PI3K alpha thiab mTOR. PWT33597 profiling qhia me me los yog tsis muaj kev sib tshuam nrog cov protein kinases, suav nrog tyrosine kinases lossis serine / threonine [19]. Kev kho mob ntawm kev hloov pauv hloov pauv PI3K alpha hauv HCT116 thiab NCI-H460 qog hlwb nrog PWT33597 pom tias cov tshuaj no tuaj yeem cuam tshuam mTOR txoj hauv kev proteins thiab PI3K. Ntxiv mus, PWT33597 tau nthuav tawm cov khoom muaj txiaj ntsig zoo nyob rau hauv ntau cov qog xenograft qauv los ntawm kev cia siab ntawm PI3K thiab mTOR txoj kev taw qhia [19]. Ntau cov tshuaj uas inhibit mTORC1 (rapalogs) tau pom zoo rau kev kho mob ntawm lub raum cell carcinoma (RCC) [154]. Txawm li cas los xij, qhov ua tau zoo ntawm cov tshuaj no tsuas yog txwv rau qee qhov tshwj xeeb ntawm cov neeg mob thiab tsis tas yuav mus ntev. Nws tau thov kom tswj hwm PWT33597 rau lub raum xenograft qauv uas ob qho tib si mTORC1 thiab mTORC2 inhibitions thiab PI3K inhibition tuaj yeem ua rau muaj txiaj ntsig zoo ntawm kev kho mob los ntawm kev tsom ncaj qha rau ntau qhov kev taw qhia, suav nrog cov vascular endothelial kev loj hlob receptors (VEGFRs). PWT33597 tau sim hauv VHL-/−, PTEN-/- xenografts piv rau rapamycin ua ib qho mTORC1 inhibitor thiab sorafenib, VEGFR / RAF inhibitor. Cov txiaj ntsig tau pom tias txawm tias cov qog loj hlob-inhibitory zog ntawm sorafenib thiab rapamycin (64%), PWT33597 muaj kev loj hlob ntau dua-inhibitory nyhuv (93%). PWT33597 tau ua haujlwm zoo dua li tuag tes tuag taw (ib lub lauj kaub-PI3K inhibitor) hauv inhibiting qog loj hlob, txo cov qog hnyav thiab loj. Tsis tas li ntawd, PWT33597 nce cleaved caspase 3 (qhov taw qhia apoptotic) [135].

4.1.11. Apitolisib

Apitolisib (GDC{0}}) yog ib qho tshiab dual PI3K / mTOR inhibitor. Kev kho Apitolisib tau txo qis cov phosphorylation ntawm AKT thiab mTOR thiab txo qis kev loj hlob hauv ob lub cholangiocarcinoma (CCA) cell kab, SNU1196 thiab SNU478. Apitolisib kuj tau txhim kho cov teebmeem ntawm cov tshuaj chemotherapeutic, xws li cisplatin lossis gemcitabine, hauv vitro thiab txhawb nqa qhov cleavage ntawm PARP. Tsis tas li ntawd, kev sib xyaw apitolisib nrog tshuaj kho mob hauv tus nas xenograft qauv ntawm CCA txo qis kev tsim los ntawm SNU1196 thiab SNU478 hlwb thiab inhibited qog cell loj hlob [136]. Dysregulated PI3K / AKT / mTOR cov teeb liab yog lub luag haujlwm rau cov qog nqaij hlav ntawm inducing qog loj hlob, metastasis, thiab tsis kam mus rau kev kho mob antitumor hauv glioblastoma. Yog li, qhov axis no tuaj yeem yog lub hom phiaj kho mob zoo nkauj rau kev siv tshuaj kho mob. Glioblastoma multiforme (GBM) kab ntawm tes (A-172 thiab U-118-MG) tau kho nrog apitolisib, thiab kev kho mob tau cuam tshuam nrog lub sijhawm- thiab koob tshuaj-nyob ntawm cytotoxicity thiab apoptosis. Qhov kev txiav txim ntawm apitolisib yog tej zaum lub downregulation ntawm protein kinase RNA zoo li endoplasmic reticulum kinase (PERK) qhia, thaiv nws inhibitory nyhuv ntawm protein synthesis, intensifying translation, thiab inducing apoptosis [137]. Hauv qhov sib piv, qhov kev sib tw qhib-label theem II tau tshaj tawm tias vim muaj cov xwm txheej tsis zoo, xws li hyperglycemia thiab pob liab liab, apitolisib tuaj yeem kho tsis tau zoo metastatic RCC, piv nrog everolimus [155]. Tej zaum, cov nyhuv ntawm tus inhibitor no tuaj yeem sib txawv ntawm cov qog nqaij hlav sib txawv.

4.2. Lwm Yam Muaj Peev Xwm Dual Inhibitors

Ib txoj hauv kev kho mob qog noj ntshav yog ob qhov inhibition ntawm cov txheej txheem metabolic tseem ceeb, xws li glycolysis thiab oxidative phosphorylation, uas rhuav tshem cov qog nqaij hlav cancer ' metabolic plasticity thiab txwv cov khoom siv hluav taws xob [156,157]. Hauv qhov no, ib qho aptamer-based dag enzyme tau tsim thiab tsim los ntawm arginine aptamer-modified carbon-dots doped graphitic carbon nitride (AptCCN) kom inhibit glycolysis thiab oxidative phosphorylation ib txhij. Kev hloov pauv tuaj yeem ntes cov arginine hauv lub cev thiab hloov arginine rau nitric oxide (NO) ntawm oxidation hauv qab lub teeb liab irradiation. Cov ntaub ntawv pov thawj pom tias qhov depletion ntawm arginine thiab TSIS muaj kev ntxhov siab suppress glycolysis thiab oxidative phosphorylation, thaiv lub zog mov thiab inducing qog cell apoptosis [138]. Ntau cov qog hlwb tau pom tias yuav ua rau muaj kev nthuav qhia ntawm nicotinamide phosphoribosyltransferase (NAMPT), uas yog qhov tseem ceeb rau NAD + kev cawm dim. Yog li ntawd, kev ntiav NAMPT inhibitors tuaj yeem yog qhov kev xaiv zoo rau kev kho mob qog noj ntshav [158]. KPT-9274 yog dual NAMPT/p21-activated kinase 4 (PAK4)/inhibitor uas txo NAD+/NADH piv hauv cov qog nqaij hlav cancer, inhibiting qog loj hlob hauv sarcoma nas qauv thiab RCC [139,159]. KPT-9274 kuj induces antitumor tiv thaiv kab mob los ntawm kev txhim kho qog antigen nthuav qhia thiab nce interferons (IFN)- thiab IFN- teb [139]. GMX1778 yog lwm NAMPT inhibitor uas tau siv hauv murine GMB los ntawm microparticles. Ib txoj kev tshawb fawb ntawm GBM qauv tau tshaj tawm tias kev sib txuas cov tshuaj tiv thaiv kab mob tiv thaiv kab mob nrog GMX1778 nce kev ciaj sia ntawm cov tsiaj kho [160]. GMX1778 tsub kom qhov kev qhia ntawm cov txheej txheem cell tuag ligan-1 (PD-L1) ntawm NAD + depletion thiab induces recruiting effector immune cells, xws li CD4+ thiab CD{28}} T cells. Qhov zaus ntawm M2-macrophages li immunosuppressive hlwb kuj txo qis tom qab kev kho mob nrog GMX1778.

Raws li kev sib tham, cov qog hlwb muaj peev xwm hloov cov piam thaj hauv metabolic los ntawm oxidative phosphorylation mus rau cytoplasmic glycolysis; pyruvate dehydrogenase kinases (PDKs) thiab lactate dehydrogenase A (LDHA) yog cov enzymes tseem ceeb hauv qhov tshwm sim no. Yog li, inhibiting cov enzymes no yuav yog ib txoj hauv kev zoo hauv kev kho mob qog noj ntshav. Kev tshawb nrhiav tsim ob PDK / LDHA inhibitors (20e thiab 20k) uas tuaj yeem txo qis lactate tsim thiab txhim kho oxygen noj hauv A549 hlwb. Cov ntaub ntawv no qhia tias cov inhibitors tuaj yeem tswj cov piam thaj hauv cov metabolism hauv cov hlwb [140]. Hom II topoisomerases yog lub luag haujlwm rau hloov DNA topology los ntawm kev tsim cov DNA hloov pauv ob-strand thiab tseem ceeb heev rau cov hlwb eukaryotic [161]. Nws tau raug qhia tias dual inhibitors ntawm kinases thiab topoisomerases II tuaj yeem yog txoj hauv kev kho mob qog noj ntshav. Tsim dual inhibitors kuj tseem yog ib qho tseem ceeb thiab zoo siab lub tswv yim los kov yeej cov tshuaj tiv thaiv topoisomerase-targeted vim cov qauv zoo sib xws ntawm topoisomerase II thiab lwm cov proteins, xws li kub poob siab protein 90 (Hsp90), uas koom nrog hauv DNA kho mechanisms [ 162] ib.

Lysine (K)-specific demethylase 1A (KDM1A) yog ib qho flavin-dependent amine oxidase uas koom nrog hauv demethylation ntawm lysine 3 thiab 4 hauv histone 3 tails (H3K4 thiab H3K9) [163]. Cov ntaub ntawv pov thawj pom tias kev tswj hwm ntawm KDM1A yog txuam nrog ntau yam kev mob tib neeg, xws li mob qog noj ntshav, los ntawm kev txo methylation ntawm H3K4 thiab H3K9. Ntxiv mus, lub demethylation ntawm H3K4 thiab H3K9 ua rau lub condensation ntawm chromatin, suppressing transcription ntawm ob peb anticancer gene cheeb tsam, xws li DNA methyltransferase-1 (DNMT-1), p53, p21, GATA-binding yam. (GATA)-1 thiab GATA{27}}. Raws li, KDM1A inhibition tuaj yeem muaj txiaj ntsig zoo hauv kev txo cov qog nqaij hlav [141]. Ntawm qhov tod tes, spermine oxidase (SMOX) yog amine oxidase uas tuaj yeem hloov spermine thiab spermidine rau spermidine thiab putrescine ntawm deaminating aminopropyl [164]. Spermine thiab spermidine koom nrog hauv kev ua haujlwm ntawm tes, xws li kev tswj cov noob caj noob ces, tshem tawm cov pa oxygen reactive (ROS), kev tswj lub voj voog ntawm tes, kev saib xyuas cov qauv DNA, thiab cov protein synthesis [165]. Interestingly, SMOX muaj ntau ntau homology rau KDM1A, uas pab txhawb kev tsim ntawm dual inhibitors rau kev kho mob qog noj ntshav [142]. Hauv cov ntsiab lus no, kev tshawb nrhiav tau tshaj tawm tias 3,{35}}diamino-1,2,4-triazole analogs tuaj yeem siv rau ob qho kev inhibition ntawm KDM1A thiab SMOX los kho mob qog noj ntshav [141].

5. Qhov zoo thiab qhov tsis zoo ntawm Dual Pathway Inhibitors hauv Kev Kho Mob Cancer

Cov ntaub ntawv pov thawj pom tau hais tias multitarget inhibitors yog cov cuab yeej muaj txiaj ntsig zoo rau kev kho cov kab mob nyuaj vim muaj qhov rov ua dua tshiab thiab muaj zog ntawm ntau cov kab mob lom neeg thiab txoj hauv kev. Nyob rau hauv parallel, tsim multitarget inhibitors yog qhov nyuaj rau cov kws kho mob tshuaj [166] (Daim duab 3). Ib qho ntawm txoj hauv kev tseem ceeb hauv metabolic uas tau kawm ntau dua yog txoj hauv kev PI3K / AKT / mTOR, thiab qhov tseem ceeb dual inhibitors tau tsim los inhibit kinases ntawm txoj kev no. Muaj ntau qhov kev tsis txaus ntseeg ntawm PI3K / AKT / mTOR qhia txoj hauv kev ntawm cov qog nqaij hlav cancer [167–169]. Muaj cov chav sib txawv ntawm PI3K / AKT / mTOR inhibitors, suav nrog mTOR inhibitors, PI3K / AKT inhibitors, thiab dual PI3K / AKT / mTOR inhibitors. Qhov laj thawj ntawm PI3K / AKT / mTOR inhibitor txoj kev loj hlob yog qhov muaj qhov tsis zoo ntawm cov lus tawm tswv yim ntawm S6K1 vim tias muaj zog inhibition ntawm mTOR txhawb kev ua kom PI3K / AKT [170].

Figure 3. Advantages and disadvantages of using dual pathway inhibitors in cancer therapy

Daim duab 3. Qhov zoo thiab qhov tsis zoo ntawm kev siv ob txoj hauv kev inhibitors hauv kev kho mob qog noj ntshav

Cov kev sim tshuaj ntsuam xyuas tau tshaj tawm tias cov tshuaj toxicity ntawm kev tswj hwm PI3K / AKT / mTOR inhibitors yog pob khaus, mob plab hnyuv, qaug zog, thiab asthenia. Kev kwv yees ua haujlwm ntawm PI3K / AKT / mTOR inhibitors yog lwm qhov kev txwv hauv kev kho mob ntawm cov tshuaj tiv thaiv dual. Txawm li cas los xij, hauv qee tus neeg mob qog noj ntshav, xws li mob qog noj ntshav mis, PIK3CA kev hloov pauv yog suav tias yog biomarker rau kev kwv yees PI3K / AKT / mTOR txoj hauv kev [171]. Tsis tas li ntawd, WNT / -catenin txoj kev hloov kho PIK3CA tuaj yeem txo qhov rhiab heev ntawm cov qog hlwb mus rau dual PI3K / mTOR inhibitor [172].

Cov kev sim tshuaj ntsuam xyuas tau tshaj tawm tias cov tshuaj toxicity ntawm kev tswj hwm PI3K / AKT / mTOR inhibitors yog pob khaus, mob plab hnyuv, qaug zog, thiab asthenia. Tsis tas li ntawd, vim qhov cuam tshuam ntawm PI3K signaling ntawm cov piam thaj metabolism, hyperglycemia kuj tau hloov pauv [173]. Txawm li cas los xij, lwm yam xwm txheej tsis zoo kuj tuaj yeem raug tshaj tawm tom qab kev tswj hwm ntawm ob txoj hauv kev inhibitors. Qhov induction ntawm RICTOR acetylation los ntawm cov piam thaj yog lwm qhov kev sib tw hauv kev tsom mus rau PI3K / AKT / mTOR txoj hauv kev vim tias nws ua rau kev ua kom mTORC2 thiab kho tsis kam rau PI3K / AKT inhibitors. Hauv glioblastoma hlwb, overactivation ntawm mTORC2 tom qab cov piam thaj-mediated RICTOR acetylation txhawb cov epidermal kev loj hlob receptor vIII (EGFRvIII) signaling [174]. Tsis tas li ntawd, nws tau pom tias monotherapy nrog mTOR inhibitors, xws li rapamycin, suppresses antitumor tiv thaiv kab mob los ntawm inhibiting effector CD8+ T hlwb, nce Tregs zaus, thiab modulating dendritic hlwb thiab antigen nthuav qhia [175]. Yog li, kev txiav txim siab lub luag haujlwm ntawm mTOR txoj hauv kev hauv microenvironment ntawm cov qog nqaij hlav sib txawv ua lub luag haujlwm tseem ceeb hauv kev ua tiav ntawm kev kho mob siv PI3K / AKT / mTOR inhibitors. Piv txwv li, nws tau tsis ntev los no tau hais tias inhibiting mTOR txoj hauv kev ua kom muaj zog tiv thaiv kab mob tiv thaiv kab mob los ntawm kev nce zaus ntawm CD nyob ntev 8+ nco T hlwb thiab txhim kho qog cell eradication [16]. Tsis tas li ntawd, inhibition ntawm PI3K / AKT / mTOR txoj hauv kev tuaj yeem cuam tshuam nrog txo cov qog cell loj hlob, kev loj hlob, kev tsiv teb tsaws, kev ntxeem tau, thiab kev ciaj sia. Ntawm qhov tod tes, PI3K / AKT / mTOR inhibitors tuaj yeem txhim kho qog tiv thaiv kab mob los ntawm kev txo qis txoj hauv kev tiv thaiv kab mob thiab ua kom lub cev tiv thaiv kab mob hauv TME.

ATP-binding cassette (ABC) cov tshuaj thauj tshuaj, suav nrog ABCB1 thiab ABCG2, koom nrog ntau yam tshuaj tiv thaiv [176]. Nws tau raug qhia tias overexpression ntawm cov thauj no txo cov kev ua tau zoo ntawm dual PI3K / AKT / mTOR inhibitors, xws li LY3023414, nyob rau hauv cov qog hlwb. Txij li LY3023414 yog substrate rau ABCB1 thiab ABCG2, cov thauj no, los ntawm lawv cov tshuaj efflux muaj nuj nqi, txo qis intracellular theem ntawm LY3023414 hauv qog hlwb [177]. Tsis tas li ntawd, kev hloov pauv tshuaj pharmacokinetic hauv PI3K / AKT / mTOR inhibitors yuav tsum raug sau tseg hauv cov tshuaj pharmacological thaum cov tshuaj tau sau ua ke. Piv txwv li, kev siv tshuaj yeeb-tshuaj cuam tshuam ntawm cov tshuaj tiv thaiv no, xws li everolimus thiab BEZ235, tuaj yeem cuam tshuam rau lawv cov tshuaj pharmacokinetic tsis tu ncua [146]. Nws pom tau hais tias everolimus yog ib qho substrate ntawm CYP3A4 enzyme nrog rau P-glycoprotein (ib qho tshuaj thauj khoom) enzymes. Cov tshuaj no muaj kev cuam tshuam rau kev hloov pauv hauv qib ntawm enzyme CYP3A [178]. Muaj cov kev tshawb fawb txog metabolic pom tau tias BEZ235 tuaj yeem hloov kho qhov kev qhia thiab ua kom CYP3A4. Nws tau pom tias everolimus thiab BEZ235 tuaj yeem cuam tshuam vim lawv qhov nqus, metabolism (pharmacokinetic zog), thiab txoj hauv kev pharmacodynamic [179]. Yuav ua li cas cov inhibitors metabolized kuj yog ib qho teeb meem tseem ceeb hauv kev ua tau zoo ntawm kev kho mob. Qee qhov PI3K / AKT / mTOR dual inhibitors, xws li PWT33597, yog metabolized qeeb dua hauv vivo thiab cuam tshuam nrog cytochrome P450 enzyme, uas ua rau muaj kev cuam tshuam ntev ntawm PI3K / AKT / mTOR txoj hauv kev xenograft hlav. Txawm li cas los xij, PWT33597 kev tswj hwm hauv cov nas tuaj yeem nrog los ntawm kev nce ntxiv hauv insulin plasma concentrations [19]. Yog li ntawd, xav txog cov tshuaj zoo thiab qhov tsis zoo yog qhov tseem ceeb hauv kev tswj hwm thiab ua kom muaj kev vam meej ntawm kev kho mob qog noj ntshav nrog kev cuam tshuam metabolic.

6. Cov lus xaus

Pharmacological kev cuam tshuam hauv cov txheej txheem metabolic sib txawv tuaj yeem ua rau muaj kev hloov pauv tseem ceeb hauv cov qog cell metabolism thiab kev ua haujlwm pathological, cuam tshuam rau kev tiv thaiv kab mob hauv TME. Ob txoj kev inhibitors ntawm metabolic txoj kev tuaj yeem muaj txiaj ntsig zoo hauv kev tiv thaiv kev loj hlob thiab kev loj hlob ntawm cov qog hlwb vim muaj kev cuam tshuam ib txhij ntawm txoj hauv kev xws li PI3K / AKT / mTOR txoj hauv kev. Txawm li cas los xij, hauv qee cov qog nqaij hlav, xws li cov qog nqaij hlav pancreatic neuroendocrine siab heev (pNET), kev siv cov tshuaj inhibitors ntawm txhua txoj kev sib cais tau muaj txiaj ntsig zoo dua li cov inhibitors dual. Txawm hais tias muaj ntau yam zoo, kev tswj xyuas dual inhibitors muaj ntau yam kev sib tw thiab kev txwv. Piv txwv li, txoj kev mTOR tej zaum yuav ua rau muaj kev tiv thaiv qog nqaij hlav. Hauv cov xwm txheej no, nws qhov inhibition tuaj yeem cuam tshuam nrog kev tiv thaiv ntawm lub cev tiv thaiv kab mob, thiab qhov teeb meem no tuaj yeem nyob ntawm seb hom qog, teeb liab, thiab theem. Piv txwv li, hauv melanoma, PI3K/Akt, MyD88, thiab IKK txoj hauv kev tuaj yeem koom nrog hauv IL-36 -kev sib kho mTORC1 ua kom, txhawb CD8+ T cell activation thiab inducing antitumor tiv thaiv kab mob hauv vitro thiab hauv vivo [180]. Raws li cov kev tshawb fawb muaj, nws pom tau hais tias kev sib txuas cov tshuaj tiv thaiv dual nrog rau lwm cov tshuaj kws khomob (paclitaxel thiab cisplatin) lossis lwm yam kev kho mob, xws li trastuzumab lossis tshuaj tiv thaiv kab mob tiv thaiv kab mob (anti-PD-1 thiab anti-CTLA{{ 12}}), tuaj yeem ua kom muaj txiaj ntsig ntawm kev kho mob [105,181,182]. Txawm li cas los xij, cov tshuaj toxicity, tshwj xeeb tshaj yog nyob rau hauv plab hnyuv toxicity, thiab kev kho tshuaj koob tshuaj, kuj yog ib qho tseem ceeb yam tseem ceeb uas yuav tsum tau txiav txim siab nyob rau hauv tsim ib tug pharmacologic raws tu qauv siv monotherapy nrog dual inhibitors ntawm metabolic txoj kev los yog kev kho mob ua ke.

Cov ntaub ntawv

1. Boroughs, LK; DeBerardinis, RJ Metabolic txoj hauv kev txhawb kev mob qog noj ntshav thiab kev loj hlob. Nat. Cell Bio. 2015, 17, 351–359. [CrossRef]

2. Xia, L.; Yog, L.; Lin, J.; Tan, S.; Han, Y.; Wu, N.; Yim, P.; Tang, L.; Pan, Q.; Rao, S. Cov kab mob qog noj ntshav metabolic reprogramming thiab tiv thaiv kab mob. Mol. Cancer 2021, 20, 28. [CrossRef] [PubMed]

3. Vazquez, A.; Liu, J.; Zhou, Y.; Oltvai, ZN Catabolic efficiency ntawm aerobic glycolysis: Cov nyhuv Warburg rov mus xyuas. BMC Syst. Biol. 2010, 4, 58. [CrossRef] [PubMed]

4. Lapa, B.; Gonçalves, UA; Jorge, J.; Alves, R.; Pires, AS; Abrantes, AM; Caucelo, M.; Abrunhosa, A.; Botelho, MF; Nascimento Costa, JM Mob myeloid leukemia rhiab heev rau metabolic inhibitors: Glycolysis pom tias yog lub hom phiaj kho zoo dua. Med. Oncol. 2020, 37, 72. [CrossRef]

5. Callao, V.; Montoya, E. Toxohormone zoo li qhov tshwm sim los ntawm cov kab mob uas muaj kev ua pa tsis zoo. Science 1961, 134, 2041–2042. [CrossRef]

6. Nyiaj, VL; Mina, E.; Van Hee, VF; Porporato, PE; Sonveaux, P. Monocarboxylate transporters in cancer. Mol. Metab. 2020, 33, 48–66. [CrossRef]

7. Domi ´ski, A.; Krawczyk, M.; Konieczny, T.; Kasprów, M.; Fory's, A.; Pastuch-Gawołek, G.; Kurcok, P. Biodegradable pH-responsive micelles loaded nrog 8-hydroxyquinoline glycoconjugates rau Warburg nyhuv raws li qog hom phiaj. Eur. J. Pharm. Biopharm. 2020, 154, 317–329. [CrossRef] [PubMed]

8. Zhou, J.; Yaj, J.; Lin, C.; Li, W.; Hu, Y.; Yaj, M.; Jiang, S.-H.; Sun, Y.; Hua, R. Endoplasmic Reticulum stress-dependent qhia ntawm ERO1L txhawb nqa aerobic glycolysis hauv Pancreatic Cancer. Theranostics 2020, 10, 8400. [CrossRef]

9. Huang, IB; Nkauj, B.-l.; Xu, C. Cov roj (cholesterol) metabolism hauv mob qog noj ntshav: cov cuab yeej thiab cov hauv kev kho mob. Nat. Metab. 2020, 2, 132–141. [CrossRef]

10. Chen, IB; Gao, UA; Tau, B.; Wang, Y.; yus, X.; Wang, Y.; Xiu, Y.; Wang, IB; Wan, Y.; Huang, Y. Metabolic modulation ntawm mTOR txoj hauv kev thiab tiv thaiv angiogenesis remodels qog microenvironment siv PD-L1-targeting codelivery. Biomaterials 2020, 255, 120187. [CrossRef]

11. Terry, S.; Engelsen, AS; Taub, S.; Elsayed, WS; Venkatesh, GH; Chouaib, S. Hypoxia-driven intratumor heterogeneity and immune evasion. Cancer Lett. 2020, 492, 1–10. [CrossRef] [PubMed]

12. Yan, Y.; Chaw, L.; Tian, H.; Vaj, L.; Zhang, YJ; Yaj, T.; Li, G.; Hu, W.; Shah, K.; Chen, G. 1-Pyrroline-5-carboxylate tso tawm los ntawm prostate Cancer cell inhibit T cell proliferation thiab muaj nuj nqi los ntawm lub hom phiaj SHP1/cytochrome c oxidoreductase/ROS Axis. J. Immunother. Cancer 2018, 6, 148. [CrossRef] [PubMed]

13. Chang, C.-H.; Qiu, J.; O'Sullivan, D.; Koob, M.; Noguchi, T.; Curtis, J.; Chen, Q.; Gindin, M.; ib. Kubin, M.; Tonc, E. Kev sib tw metabolic hauv qog microenvironment yog tus tsav tsheb ntawm kev mob qog noj ntshav. Cell 2015, 162, 1229–1241. [CrossRef] [PubMed]

14. Amirani, E.; Hallajzadeh, J.; Asem, Z.; Mansournia, MA; Yousefi, B. Cov teebmeem ntawm chitosan thiab oligo chitosans ntawm phosphatidylinositol 3-kinase-AKT txoj hauv kev kho mob qog noj ntshav. Int. J. Biol. Macromol. 2020, 164, 456–467. [CrossRef]

15. Kim, J.; Yang, GS; Lyon, D.; Kelly, DL; Stechmiller, J. Metabolomics: Kev cuam tshuam ntawm comorbidities thiab o ntawm tus cwj pwm mob rau cov tib neeg uas muaj mob ntev. Adv. Wound Care 2021, 10, 357–369. [CrossRef]

16. Araki, K.; Turner, AP; Shaffer, VO; Gangappa, S.; Keller, SA; Bachmann, MF; Larsen, CP; Ahmed, R. mTOR tswj kev nco CD8 T-cell sib txawv. Xwm Txheej 2009, 460, 108–112. [CrossRef]

17. Ali, ES; Mitra, K.; Akter, S.; Ramproshad, S.; Mondal, IB; Khan, IN; Islam, MT; Sharifi-Rad, J.; Calina, D.; Cho, WC Kev nce qib tsis ntev los no thiab kev txwv ntawm mTOR inhibitors hauv kev kho mob qog noj ntshav. Cancer Cell Int. 2022, 22, 284. [CrossRef]

18. Viana, SD; Reis, F.; Alves, R. Kev kho mob siv mTOR inhibitors hauv cov kab mob raum: Kev nce qib, qhov tsis zoo, thiab cov nyom. Oxidative Med. Cell. Longev. 2018, 2018, 3693625. [CrossRef]

19. Mathais, DJ; O'Farrell, M.; ib. James, J.; Giddens, AC; Rewcastle, GW; Denny, WA Preclinical characterization ntawm PWT33597, ib tug dual inhibitor ntawm PI3-kinase alpha thiab mTOR. Cancer Res. 2011, 71, 4485. [CrossRef]

20. Herschbein, L.; ib. Liesveld, JL Dueling rau dual inhibition: txhais tau tias txhim khu kev ua tau zoo ntawm PI3K / Akt / mTOR inhibitors hauv AML. Ntshav Rev. 2018, 32, 235–248. [CrossRef]

21. Chen, J.; Zhao, K.-N.; Li, R.; Chaw, R.; Chen, C. Ua kom muaj PI3K/Akt/mTOR txoj hauv kev thiab dual inhibitors ntawm PI3K thiab mTOR hauv kev mob qog noj ntshav endometrial. Curr. Med. Chem. 2014, 21, 3070–3080. [CrossRef]

22. Bhatt, AP; Bhende, PM; Sin, S.-H.; Rau, D.; Dittmer, DP; Damania, B. Dual inhibition ntawm PI3K thiab mTOR inhibits autocrine thiab paracrine proliferative loops hauv PI3K/Akt/mTOR-addicted lymphomas. Ntshav J. Am. Soc. Hematol. 2010, 115, 4455–4463. [CrossRef]

23. Sabbah, DA; Brattain, MG; Zhong, H. Dual inhibitors ntawm PI3K / mTOR lossis mTOR-xaiv inhibitors: Peb yuav mus qhov twg? Curr. Med. Chem. 2011, 18, 5528–5544. [CrossRef]

24. Moreno-Sánchez, R.; Rodríguez-Enríquez, S.; Marín-Hernández, A.; Saavedra, E. Zog metabolism hauv qog hlwb. FEBS J. 2007, 274, 1393–1418. [CrossRef] [PubMed]

25. Mazurek, S. Pyruvate kinase type M2: Ib qho tseem ceeb regulator ntawm cov nyiaj txiag metabolic hauv cov qog hlwb. Int. J. Biochem. Cell Bio. 2011, 43, 969–980. [CrossRef]

26. Jiang, P.; Du, W.; Wu, M. Kev cai ntawm pentose phosphate txoj hauv kev mob qog noj ntshav. Protein Cell 2014, 5, 592–602. [CrossRef] [PubMed]

27. Amelio, I.; Cutruzolá, F.; Antonov, A.; Agostini, M. Melino, G. Serine thiab glycine metabolism hauv mob qog noj ntshav. Trends Biochem. Sci. 2014, 39, 191–198. [CrossRef] [PubMed]

28. Altman, BJ; Stine, ZE; Dang, CV Los ntawm Krebs mus rau tsev kho mob: Glutamine metabolism rau kev kho mob qog noj ntshav. Nat. Rev. Cancer 2016, 16, 619–634. [CrossRef] [PubMed]

29. Liu, Q.; Luo, Q. Halim, A.; Nkauj, G. Targeting lipid metabolism ntawm cov qog nqaij hlav cancer: Kev cog lus kho mob zoo rau mob qog noj ntshav. Cancer Lett. 2017, 401, 39–45. [CrossRef] [PubMed]

30. Chen, Y.; Li, P. Fatty acid metabolism thiab mob qog noj ntshav. Sci. Bull. 2016, 61, 1473–1479. [CrossRef]

31. Tshav, L.; Nkauj, L.; Wan, Q.; Wu, G.; Li, X.; Wang, Y.; Wang, J.; Liu, Z.; Zhou, X.; Nws, X. cMyc-mediated activation ntawm serine biosynthesis txoj hauv kev yog qhov tseem ceeb rau kev mob qog noj ntshav raws li cov khoom noj tsis txaus. Cell Res. 2015, 25, 429–444. [CrossRef] [PubMed]

32. Schug, ZT; Vande Voorde, J.; Gottlieb, E. Txoj hmoo metabolic ntawm acetate hauv kev mob qog noj ntshav. Nat. Rev. Cancer 2016, 16, 708–717. [CrossRef]

33. Schug, ZT; Peb, B.; Jones, DT; Zhang, Q.; Grosskurth, S.; Alam, IS; Goodwin, LWM; Smethurst, E.; Mason, S.; Blyth, K. Acetyl-CoA synthetase 2 txhawb nqa kev siv acetate thiab tswj cov qog nqaij hlav qog noj ntshav raws li kev ntxhov siab hauv metabolic. Cancer Cell 2015, 27, 57–71. [CrossRef] [PubMed]

34. Mashimo, T.; Pichumani, K.; Kev, V.; Hatanpaa, KJ; Singh, DK; Sirasanagandla, S.; Nannepaga, S.; Piccirillo, SG; Kev, Z.; Foong, C. Acetate yog bioenergetic substrate rau tib neeg glioblastoma thiab hlwb metastases. Cell 2014, 159, 1603–1614. [CrossRef] [PubMed]

35. Deng, Z.; Wang, H.; Liu, J.; Deng, Y.; Zhang, N. Kev nkag siab zoo txog kev muaj sia nyob tsis muaj sia nyob thiab nws qhov cuam tshuam hauv kev mob qog noj ntshav. Cell Tuag Dis. 2021, 12, 629. [CrossRef] [PubMed]

36. Endo, H.; Owada, S.; Inagaki, Y.; Shida, Y.; Tatemichi, M. Metabolic reprogramming txhawb nqa cov qog nqaij hlav qog noj ntshav tom qab extracellular matrix detachment. Redox Biol. 2020, 36, 101643. [CrossRef] [PubMed]

37. Ghesquière, B.; Wong, BW; Kev, A.; Carmeliet, P. Metabolism ntawm stromal thiab lub cev tiv thaiv kab mob hauv kev noj qab haus huv thiab kab mob. Xwm Txheej 2014, 511, 167–176. [CrossRef] [PubMed]

38. Thwe, PM; Amiel, E. Lub luag hauj lwm ntawm nitric oxide nyob rau hauv metabolic kev cai ntawm dendritic cell tiv thaiv muaj nuj nqi. Cancer Lett. 2018, 412, 236–242. [CrossRef]

39. Williford, J.-M.; Ishihara, J.; Ishihara, A.; Mansurov, A.; Hosseini, P.; Marchell, TM; Potin, L.; Swartz, MA; Hubbell, JA Recruitment of CD103+ dendritic cells ntawm qog-targeted chemokine xa tuaj yeem txhim kho qhov ua tau zoo ntawm kev kuaj xyuas qhov inhibitor immunotherapy. Sci. Adv. Peb Hlis 2019, 5, 1357. [CrossRef]

40. Vaj, Y.; Hwang, J.-Y.; Park, H.-b.; Yadav, D.; Oda, T.; Jin, J.-O. Porphyran cais los ntawm Pyropia yezoensis inhibits lipopolysaccharide-induced activation ntawm dendritic hlwb hauv nas. Carbohydrate. Polym. 2020, 229, 115457. [CrossRef] [PubMed]

41. Jeon, J.-H.; Hong, C.-W.; Kim, EJ; Lee, JM Tam sim no nkag siab txog cov metabolism ntawm neutrophils. Immune Netw. Peb Hlis 2020, 20, 46. [CrossRef] [PubMed]

42. Pearce, EL; Poffenberger, MC; Chang, C.-H.; Jones, RG Fueling kev tiv thaiv: Kev nkag siab rau cov metabolism thiab lymphocyte muaj nuj nqi. Science 2013, 342, 1242454. [CrossRef] [PubMed]

43. Pearce, E.; Pearce, E. Metabolic txoj hauv kev hauv lub cev tiv thaiv kab mob ua kom lub cev thiab quiescence. Kev tiv thaiv 2013, 38, 633–643. [CrossRef]

44. Kobayashi, T.; Lam, PY; Jiang, H.; Bednarska, K. Hlo, R.; Murigneux, V.; Tau, J.; Jacquelot, N.; Li, R.; Tuong, ZK Ntxiv lipid metabolism cuam tshuam NK cell muaj nuj nqi thiab kho kom haum rau cov lymphoma ib puag ncig. Ntshav 2020, 136, 3004–3017. [CrossRef] [PubMed]

45. Domka, K.; Goral, ib.; Firczuk, M. cROSsing kab: Nruab nrab ntawm cov txiaj ntsig thiab kev phom sij ntawm cov pa oxygen reactive hauv B-cell malignancies. Pem hauv ntej. Immunol. 2020, 11, 1538. [CrossRef]

46. Wang, X.-Y.; Wei, Y.; Hu, B.; Liao, Y.; Wang, X.; Wan, W.-H.; Huang, C.-X.; Mahabati, M.; Liu, Z.-Y.; Qu, J.-R. c-Myc-tsav glycolysis polarizes kev tswj hwm kev ua haujlwm B hlwb uas ua rau cov kab mob inflammatory teb. Teeb liab Transduct. Hom phiaj. Ther. 2022, 7, 105. [CrossRef]

47. Kob, D.; Kolisetti, N.; Surnar, IB; Sarkar, S.; Guin, S.; Shah, AS; Dhar, S. Metabolic modulation ntawm cov qog microenvironment ua rau ntau qhov chaw kuaj xyuas inhibition thiab kev tiv thaiv kab mob hauv lub cev. ACS Nano 2020, 14, 11055–11066. [CrossRef]

48. Palmer, CS; Ostrowski, M.; Balderson, IB; Christian, N.; Crowe, SM Glucose metabolism tswj T cell activation, sib txawv, thiab ua haujlwm. Pem hauv ntej. Immunol. 2015, 6, 1. [CrossRef]

49. Togo, M.; Yokobori, T.; Shimizu, K.; Handa, T.; Cai, K.; Sano, T.; Tsukagoshi, M.; Higuchi, T.; Yog, S.; Shirabe, K. Diagnostic tus nqi ntawm 18F-FDG-PET los kwv yees cov qog tiv thaiv kab mob uas txhais los ntawm qog nqaij hlav PD-L1 thiab CD8+ qog-infiltrating lymphocytes hauv qhov ncauj squamous cell carcinoma. Br. J. Cancer 2020, 122, 1686–1694. [CrossRef]

50. Qiu, J.; Villa, M.; Sanin, DE; Buck, MD; O'Sullivan, D.; Ching, R.; Matsushita, M.; Grzes, KM; Winkler, F.; ib. Chang, C.-H. Acetate txhawb nqa T cell effector ua haujlwm thaum lub sijhawm txwv cov piam thaj. Cell Rep. 2019, 27, 2063–2074.e5. [CrossRef]

51. Sukumar, M.; Roychoudhuri, R.; Restifo, NP Nutrient kev sib tw: Lub axis tshiab ntawm kev tiv thaiv qog noj ntshav. Cell 2015, 162, 1206–1208. [CrossRef] [PubMed]

52. Harmon, C.; O'Farrelly, C.; Robinson, MW Lub cev tiv thaiv qhov tshwm sim ntawm lactate hauv qog microenvironment. Hauv Tumor Microenvironment; Springer: Berlin/Heidelberg, Lub teb chaws Yelemees, 2020; ib., 113–124.

53. Kareva, I. Metabolism thiab plab microbiota hauv kev tiv thaiv kab mob qog noj ntshav, CD8/Treg ratios, immune cell homeostasis, thiab mob qog noj ntshav (immuno) therapy: Kev tshuaj xyuas nruj. Stem Cells 2019, 37, 1273–1280. [CrossRef] [PubMed]

54. Donahue, TR; Tran, LWM; Hill, R.; Li, Y.; Kovochich, A.; Calvopina, JH; Patel, SG; Wu, N.; Hindoyan, UA; Farrell, JJ Integrative Survival-Based Molecular Profiling of Human Pancreatic CancerIntegrative Profile of Human Pancreatic Cancer. Clin. Cancer Res. 2012, 18, 1352–1363. [CrossRef] [PubMed]

55. Kas, R.; Okkenhaug, K.; Ahmad, K.; Dawb, S.; Tim, J.; Waterfield, MD Cellular muaj nuj nqi ntawm phosphoinositide 3-kinases: Kev cuam tshuam rau kev loj hlob, kev tiv thaiv kab mob, homeostasis, thiab mob qog noj ntshav. Annu. Rev. Cell Dev. Biol. 2001, 17, 615–675. [CrossRef]

56. Hennessy, BT; Smith, DL; Ram, PT; Lu, Y.; Mills, GB Siv txoj hauv kev PI3K / AKT rau kev tshawb nrhiav tshuaj mob qog noj ntshav. Nat. Rev. Drug Discov. 2005, 4, 988–1004. [CrossRef]

57. Guo, H.; German, P.; Bai, S.; Barnes, S.; Guo, W.; Qi, X.; Lus, H.; Liang, J.; Jonasch, E.; Mills, GB Txoj kev PI3K/AKT thiab lub raum cell carcinoma. J. Genet. Genom. 2015, 42, 343–353. [CrossRef]

58. Manning, BD; Cantley, LC AKT/PKB signaling: Navigating downstream. Cell 2007, 129, 1261–1274. [CrossRef]

59. Yaj, J.; Neej, J.; Ma, X.; Wei, Y.; Peng, Y.; Wei, X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer 2019, 18, 26. [CrossRef]

60. Masui, K.; Harachi, M.; Cavenee, WK; Mishel, PS; Shibata, N. mTOR complex 2 yog ib qho kev sib koom ua ke ntawm cov kab mob qog noj ntshav thiab epigenetics. Cancer Lett. Xyoo 2020, 478, 1–7. [CrossRef]

61. Huang, K.; Fingar, DC Loj hlob kev paub ntawm mTOR signaling network. Semin. Cell Dev. Biol. 2014, 36, 79–90. [CrossRef]

62. Csib, A.; Li, G.; Yoon, S.-O.; Tong, H.; Ib, D.; Elias, I.; Fendt, S.-M.; Roberts, TM; Blenis, J. Txoj kev mTORC1/S6K1 tswj glutamine metabolism los ntawm eIF4B-nyob tswj ntawm c-Myc txhais lus. Curr. Biol. 2014, 24, 2274–2280. [CrossRef] [PubMed]

63. Csib, A.; Fendt, S.-M.; Li, C.; Poulogiannis, G.; Chaw, AY; Chapski, DJ; Yim, SM; Dempsey, JM; Parkhitko, UA; Morrison, T. Txoj kev mTORC1 txhawb nqa glutamine metabolism thiab cell proliferation los ntawm kev tsuj SIRT4. Cell 2013, 153, 840–854. [CrossRef] [PubMed] 6

4. Vander Heiden, MG; Cantley, LC; Thompson, CB Nkag siab txog cov nyhuv Warburg: Cov kev cai metabolic ntawm cell proliferation. Science 2009, 324, 1029–1033. [CrossRef]

65. Zhang, X.; Liang, T.; Yang, W.; Zhang, L. Wu, S.; Yog, C.; Li, Q. Astragalus membranaceus txhaj tshuaj suppresses zus tau tej cov interleukin -6 los ntawm activating autophagy los ntawm AMPK-mTOR txoj hauv kev lipopolysaccharide-stimulated macrophages. Oxidative Med. Cell. Longev. Xyoo 2020, 2020, 1364147.

66. Grabiner, BC; Nardi, V.; Birsoy, K.; Possemato, R.; Shen, K.; Sinha, S.; Jordan, UA; Beck, AW; Sabatini, DM Ib Ntau Yam Ntawm Cov Kab Mob Cancer-Associated MTOR Mutations Yog Hyperactivating thiab tuaj yeem kwv yees Rapamycin SensitivityCancer-Associated Hyperactivating MTOR Mutations. Cancer Discov. 2014, 4, 554–563. [CrossRef]

67. Pilotto, S.; Simbolo, M.; Sperduti, ib.; Novello, S.; Vicentini, C.; ib. Peretti, UA; Pedron, S.; Ferrara, R. Cais, M.; Millella, M. OA06. 06 kev hloov pauv tshuaj uas cuam tshuam nrog txoj hauv kev tseem ceeb carcinogenesis tsav qhov kev tshwm sim ntawm squamous cell lung carcinoma (SCLC). J. Thorac. Oncol. 2017, 12, S266–S267. [CrossRef]

68. Morrison Joly, M.; Hicks, DJ; Jones, IB; Sanchez, V.; Estrada, MV; Young, C.; Williams, M.; ib. Rexer, IB; Sarbassov, DD; Muller, WJ Rictor/mTORC2 Tsav Kev Txhim Kho thiab Kev Kho Mob ntawm HER2-Amplified Breast CancersHER2-Mediated Tumorigenesis Yuav tsum tau mTORC2. Cancer Res. 2016, 76, 4752–4764. [CrossRef]

69. Mafi, S.; Mansoori, IB; Taub, S.; Sadeghi, H.; Abbasi, R.; Cho, WC; Rostamzadeh, D. mTOR-mediated kev cai ntawm kev tiv thaiv kab mob hauv kev mob qog noj ntshav thiab qog microenvironment. Pem hauv ntej. Immunol. 2022, 12, 5724. [CrossRef] [PubMed] 7

0. Chaw, N.; Baker, SJ PTEN thiab PI3-kinase txoj hauv kev mob qog noj ntshav. Annu. Rev. Pathol. Mech. Dis. 2009, 4, 127–150. [CrossRef]

71. Lien, EC; Lyssiotis, CA; Cantley, LC Metabolic reprogramming los ntawm PI3K-Akt-mTOR txoj hauv kev mob qog noj ntshav. Hauv Metabolism hauv Cancer; Springer: Berlin/Heidelberg, Lub teb chaws Yelemees, 2016; Ib., 39–72.

72. Buller, CL; Loberg, RD; Fan, M.-H.; Zhu, Q.; Park, JL; Vaus, E.; Ib, K.; Guan, K.-L.; Brosius, FC, III. GSK-3/TSC2/mTOR txoj kev tswj cov piam thaj nce siab thiab GLUT1 cov piam thaj thauj khoom. Am. J. Physiol. Cell Physiol. 2008, 295, C836–C843. [CrossRef]

73. Gordan, JD; Thompson, IB; Simon, MC HIF, thiab c-Myc: Sibling sib tw rau kev tswj cov qog noj ntshav cell metabolism thiab kev loj hlob. Cancer Cell 2007, 12, 108–113. [CrossRef]

74. Mossmann, D.; Park, S.; Hall, MN mTOR signaling thiab cellular metabolism yog kev sib nrig sib txiav txim nyob rau hauv mob cancer. Nat. Rev. Cancer 2018, 18, 744–757. [CrossRef]

75. Yecies, JL; Zhang, HH; Menon, S.; Liu, S.; Yees, D.; Lipovsky, AI; Gorgun, C.; Kwiatkowski, DJ; Hotamisligil, GS; Li, C.-H. Akt stimulates hepatic SREBP1c thiab lipogenesis los ntawm kev sib npaug ntawm mTORC1- txoj hauv kev nyob thiab ywj pheej. Cell Metab. 2011, 14, 21–32. [CrossRef]

76. Hagiwara, A.; Cornu, M.; Cybulski, N.; Polak, P.; Betz, C.; Trapani, F.; Terracciano, L.; Heim, MH; Rüegg, MA; Hall, MN Hepatic mTORC2 activates glycolysis thiab lipogenesis los ntawm Akt, glucokinase, thiab SREBP1c. Cell Metab. 2012, 15, 725–738. [CrossRef]

77. Laplante, M.; Sabatini, DM mTOR signaling ntawm ib nrais muag. J. Cell Sci. 2009, 122, 3589–3594. [CrossRef]

78. Driscoll, DR; Karim, SA; Sano, M.; Gay, DM; Jacob, W.; Yog, J.; Mizukami, Y.; Gopinathan, UA; Jodrell, DI; Evans, TRJ; ua al. mTORC2 Kev Tshaj Tawm Tsav Kev Loj Hlob thiab Kev Loj Hlob ntawm Pancreatic Cancer. Cancer Res. 2016, 76, 6911–6923. [CrossRef] 7

9. Ib., Y.; Wang, Z.; Xu, J.; Zhao, W.; Cai, H.; Zhang, Z. Elevated Rictor qhia yog txuam nrog cov qog nqaij hlav thiab cov tsos mob tsis zoo rau cov neeg mob qog noj ntshav. Biochem. Biophys. Res. Pawg. 2015, 464, 534–540. [CrossRef]

80. Zhou, F.; Zhang, X.; Li, M.; Chen, P.; Zhang, IB; Guo, H.; Cai, W.; Wei, X.; Cai, X.; Hao, X.; ua al. mTOR Complex Component Rictor Interacts nrog PKCζ thiab tswj cov qog nqaij hlav qog noj ntshav. Cancer Res. Xyoo 2010, 70, 9360–9370. [CrossRef]

81. Li, H.; Lin, J.; Wang, X.; Yao, G.; Vaj, L.; Zheng, H.; Yaj, C.; Jia, C.; Liu, A.; Bai, X. Targeting ntawm mTORC2 tiv thaiv cell migration thiab txhawb apoptosis hauv qog noj ntshav. Lub mis Cancer Res. Kho. 2012, 134, 1057–1066. [CrossRef]

82. Gulhati, P.; Cai, Q.; Li, J.; Liu, J.; Rychahou, PG; Qias, S.; Li, EY; Silva, SR; Bowen, KA; Gao, T.; ua al. Targeted Inhibition of Mammalian Target of Rapamycin Signaling Inhibits Tumorigenesis of Colorectal Cancer. Clin. Cancer Res. 2009, 15, 7207–7216. [CrossRef]

83. Xie, S.; Chen, M.; ib. Yog, B.; Nws, X.; Chen, X.; Li, D. Kev txheeb xyuas lub luag haujlwm rau PI3K/AKT/mTOR Txoj Kev Teeb Meem hauv Innate Immune Cells. PLoS IB 2014, 9, e94496. [CrossRef] [PubMed]

84. Kim, EH; Suresh, M. Lub luag haujlwm ntawm PI3K/Akt signaling hauv nco CD8 T cell sib txawv. Pem hauv ntej. Immunol. 2013, 4, 20. [CrossRef] [PubMed]

85. Chi, H. Kev tswj hwm thiab kev ua haujlwm ntawm mTOR signaling hauv T cell txoj hmoo kev txiav txim siab. Nat. Rev. Immunol. 2012, 12, 325–338. [CrossRef] [PubMed]

86. Delgoffe, GM; ib. Pollizzi, KN; Waickman, AW; Heikamp, E.; Meyers, DJ; Horton, MR. Xiao, B.; Worley, PF; Powell, JD Lub kinase mTOR tswj qhov sib txawv ntawm tus pab T hlwb los ntawm kev xaiv ua kom pom tseeb los ntawm mTORC1 thiab mTORC2. Nat. Immunol. 2011, 12, 295–303. [CrossRef]

87. Guri, Y.; Nordmann, TM. Roszik, J. mTOR ntawm Kev Tshaj Tawm thiab Tau Txais Qhov Kawg Hauv Kev Tiv Thaiv Kab Mob. Pem hauv ntej. Immunol. 2018, 9, 578. [CrossRef]

88. Crompton, JG; Sukumar, M.; ib. Roychoudhuri, R.; Clever, D.; Gros, UA; Eil, RL; Tran, E.; Hanada, K.-i.; yus, Z.; Palmer, DC; ua al. Akt Inhibition pab txhawb kev nthuav dav ntawm cov qog nqaij hlav tshwj xeeb Lymphocytes nrog cov yam ntxwv ntawm lub cim xeeb. Cancer Res. 2015, 75, 296–305. [CrossRef]

89. Zheng, W.; O'Hear, CE; Li, R.; Basham, JH; Abdelsamed, HA; Palmer, LE; Jones, LL. Youngblood, B.; Geiger, TL PI3K orchestration ntawm lub vivo persistence ntawm chimeric antigen receptor-hloov T hlwb. Leukemia 2018, 32, 1157–1167. [CrossRef]

90. Kawalekar, OU; O'Connor, NWS; Fraietta, JA; Guo, L.; McGettigan, SE; Posey, AD; Patel, PR; Guedan, S.; Scholler, J.; ib. Keith, IB; ua al. Cov cim qhia tshwj xeeb ntawm Coreceptors tswj cov txheej txheem metabolism tshwj xeeb thiab cuam tshuam kev nco txog kev loj hlob hauv CAR T Cells. Kev tiv thaiv 2016, 44, 380–390. [CrossRef]

91. Yuan, J.; Dong, X.; Yog, J.; Hu, J. The MAPK thiab AMPK signalings: Interplay and implicit in targeted cancer therapy. J. Hematol. Oncol. 2020, 13, 113. [CrossRef]

92. Hawley, SA; Pan, DA; Mas, KJ; Rau, L.; Bab, J.; Edelman, AM; Frenguelli, BG; Hardie, DG Calmodulin-dependent protein kinase kinase- yog lwm txoj hauv kev kinase rau AMP-activated protein kinase. Cell Metab. 2005, 2, 9–19. [CrossRef]

93. Shaw, RJ; Kosmatka, M. Bardeesy, N.; Hurley, RL; Witters, LA; DePinho, RA; Cantley, LC Lub qog suppressor LKB1 kinase ncaj qha activates AMP-activated kinase thiab tswj apoptosis nyob rau hauv teb rau lub zog kev nyuaj siab. Proc. Natl. Acad. Sci. USA 2004, 101, 3329–3335. [CrossRef] [PubMed]

94. Ntoo, A.; Johnstone, SR; Dickerson, K.; Leiper, FC; Fryer, LGD; Neeb, D.; Schlattner, UA; Wallimann, T.; Carlson, M.; ib. Carling, D. LKB1 Yog Upstream Kinase hauv AMP-Activated Protein Kinase Cascade. Curr. Biol. 2003, 13, 2004–2008. [CrossRef] [PubMed]

95. Kim, YK; Chaw, SC; Yang, HJ; Ib, DE; Li, S.; Yog, MG; Lee, KJ Cereblon Deletion Ameliorates Lipopolysaccharide-induced Proinflammatory Cytokines los ntawm 5'-Adenosine Monophosphate-Activated Protein Kinase/Heme Oxygenase-1 Ua kom muaj zog hauv ARPE-19 Cells. Immune Netw. 2020, 20, 26 Peb. [CrossRef]

96. Salminen, ib.; Kauppinen, A.; Kaarniranta, K. AMPK activation inhibits lub zog ntawm myeloid-derived suppressor cells (MDSC): Kev cuam tshuam rau kev mob qog noj ntshav thiab kev laus. J. Mol. Med. Xyoo 2019, 97, 1049–1064. [CrossRef] [PubMed]

7. Vang, S.; Lin, Y.; Xiong, X.; Vaj, L.; Guo, Y.; Chen, Y.; Chen, S.; Wang, G.; Lin, P.; Chen, H.; ua al. Tsawg-Dose Metformin Reprograms cov qog tiv thaiv kab mob Microenvironment hauv tib neeg Esophageal Cancer: Cov txiaj ntsig ntawm Phase II Clinical Trial. Clin. Cancer Res. 2020, 26, 4921–4932. [CrossRef]

98. Zhou, YP; Brown, JR; Sag, D.; Zhang, L. Suttles, J. Adenosine 50 -Monophosphate–Activated Protein Kinase Regulates IL-10- Kev Kho Mob Los Tiv Thaiv Kab Mob Teeb Meem Hauv Macrophages. J. Immunol. Xyoo 2015, 194, 584–594. [CrossRef]

99. Antonioli, L.; Pacher, P.; Vizi, ES; Haskó, G. CD39 thiab CD73 hauv kev tiv thaiv kab mob thiab mob. Trends Mol. Med. 2013, 19, 355–367. [CrossRef]

100. Whiteside, T.; Jackson, E. Adenosine thiab Prostaglandin E2 Production los ntawm Human Inducible Regulatory T Cells hauv Kev Noj Qab Haus Huv thiab Kab Mob. Pem hauv ntej. Immunol. 2013, 4, 212. [CrossRef]

Intimate Communications Nyob rau hauv Cov Tumor Microenvironment: Stromal Factors Function As Orchestra

Senescence Rewires Microenvironment Sensing Kom Yooj Yim Antitumor Immunity

Kev cuam tshuam Metabolic hauv qog tiv thaiv kab mob: Tsom ntsoov rau Dual Pathway Inhibitors

Koj Tseem Yuav Zoo Li

Xa kev nug

Kev paub

Kev cuam tshuam Metabolic hauv qog tiv thaiv kab mob: Tsom ntsoov rau Dual Pathway Inhibitors

Koj Tseem Yuav Zoo Li

Xa kev nug