Abstract
Background
Abnormal metabolism is the main hallmark of cancer, and cancer metabolism plays an important role in tumorigenesis, metastasis, and drug resistance. Therefore, studying the changes of tumor metabolic pathways is beneficial to find targets for the treatment of cancer diseases. The success of metabolism-targeted chemotherapy suggests that cancer metabolism research will provide potential new targets for the treatment of malignant tumors.
Purpose
The aim of this study was to systemically review recent research findings on targeted inhibitors of tumor metabolism. In addition, we summarized new insights into tumor metabolic reprogramming and discussed how to guide the exploration of new strategies for cancer-targeted therapy.
Conclusion
Cancer cells have shown various altered metabolic pathways, providing sufficient fuel for their survival. The combination of these pathways is considered to be a more useful method for screening multilateral pathways. Better understanding of the clinical research progress of small molecule inhibitors of potential targets of tumor metabolism will help to explore more effective cancer treatment strategies.
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Data availability
All data generated or analyzed during this study are included in this published article.
References
Abdel-Wahab AF, Mahmoud W, Al-Harizy RM (2019) Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 150:104511. https://doi.org/10.1016/j.phrs.2019.104511
Adams DJ, Ito D, Rees MG, Seashore-Ludlow B, Puyang X, Ramos AH et al (2014) NAMPT is the cellular target of STF-31-like small-molecule probes. ACS Chem Biol 9(10):2247–2254. https://doi.org/10.1021/cb500347p
Ahluwalia MS, Patton C, Stevens G, Tekautz T, Angelov L, Vogelbaum MA et al (2011) Phase II trial of ritonavir/lopinavir in patients with progressive or recurrent high-grade gliomas. J Neurooncol 102(2):317–321. https://doi.org/10.1007/s11060-010-0325-3
Ancey PB, Contat C, Meylan E (2018) Glucose transporters in cancer - from tumor cells to the tumor microenvironment. FEBS J 285(16):2926–2943. https://doi.org/10.1111/febs.14577
Ashrafian H, Horowitz JD, Frenneaux MP (2007) Perhexiline. Cardiovasc Drug Rev 25:76–97. https://doi.org/10.1111/j.1527-3466.2007.00006.x
Backus KM, Correia BE, Lum KM, Forli S, Horning BD, González-Páez GE et al (2016) Proteome-wide covalent ligand discovery in native biological systems. Nature 534(7608):570–574. https://doi.org/10.1038/nature18002
Bar-Peled L, Kemper EK, Suciu RM, Vinogradova EV, Backus KM, Horning BD et al (2017) Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer. Cell 171(3):696-709.e23. https://doi.org/10.1016/j.cell.2017.08.051
Benjamin D, Robay D, Hindupur SK, Pohlmann J, Colombi M, El-Shemerly MY et al (2018) Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells. Cell Rep 25(11):3047-3058.e4. https://doi.org/10.1016/j.celrep.2018.11.043
Bergman A, Carvajal-Gonzalez S, Tarabar S, Saxena AR, Esler WP, Amin NB (2020) Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study. Clin Pharmacol Drug Dev 9(4):514–526. https://doi.org/10.1002/cpdd.782
Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z (2021) Lipid metabolism and cancer. J Exp Med 218(1):e20201606. https://doi.org/10.1084/jem.20201606
Bose S, Ramesh V, Locasale JW (2019) Acetate Metabolism in Physiology, Cancer, and Beyond. Trends Cell Biol 29(9):695–703. https://doi.org/10.1016/j.tcb.2019.05.005
Bose S, Zhang C, Le A (2021) Glucose Metabolism in Cancer: The Warburg Effect and Beyond. Adv Exp Med Biol 1311:3–15. https://doi.org/10.1007/978-3-030-65768-0_1
Brenner AJ, Von Hoff DD, Infante JR, Patel MR, Jones SF, Burris HA et al (2015) First-in-Human Investigation of the Oral First-in-Class Fatty Acid Synthase (FASN) Inhibitor, TVB-2640. JCO 33:615. https://doi.org/10.1200/jco.2015.33.15_suppl.tps2615
Broadfield LA, Pane AA, Talebi A, Swinnen JV, Fendt SM (2021) Lipid metabolism in cancer: New perspectives and emerging mechanisms. Dev Cell 56(10):1363–1393. https://doi.org/10.1016/j.devcel.2021.04.013
Butler LM, Mah CY, Machiels J, Vincent AD, Irani S, Mutuku SM et al (2021) Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition. Cancer Res 81(19):4981–4993. https://doi.org/10.1158/0008-5472.CAN-20-3863
Buyse C, Joudiou N, Warscotte A, Richiardone E, Mignion L, Corbet C et al (2022) Evaluation of Syrosingopine, an MCT Inhibitor, as Potential Modulator of Tumor Metabolism and Extracellular Acidification. Metabolites 12(6):557. https://doi.org/10.3390/metabo12060557
Cai S, Gao Z (2021) Atorvastatin inhibits proliferation and promotes apoptosis of colon cancer cells via COX-2/PGE2/β-Catenin Pathway. J BUON 26(4):1219–1225
Camici M, Garcia-Gil M, Pesi R, Allegrini S, Tozzi MG (2019) Purine-Metabolising Enzymes and Apoptosis in Cancer. Cancers (basel) 11(9):1354. https://doi.org/10.3390/cancers11091354
Cao W, Chen HD, Yu YW, Li N, Chen WQ (2021) Changing profiles of cancer burden worldwide and in China: a secondary analysis of the global cancer statistics 2020. Chin Med J (engl) 134(7):783–791
Caylioglu D, Meyer RJ, Hellmold D, Kubelt C, Synowitz M, Held-Feindt J (2021) Effects of the Anti-Tumorigenic Agent AT101 on human glioblastoma cells in the microenvironmental glioma stem cell niche. Int J Mol Sci 22(7):3606. https://doi.org/10.3390/ijms22073606
Chandel NS (2021) Nucleotide Metabolism. Cold Spring Harb Perspect Biol 13(7):a040592. https://doi.org/10.1101/cshperspect.a040592
Chang HW, Lee M, Lee YS, Kim SH, Lee JC, Park JJ et al (2021) p53-dependent glutamine usage determines susceptibility to oxidative stress in radioresistant head and neck cancer cells. Cell Signal 77:109820. https://doi.org/10.1016/j.cellsig.2020.109820
Chen L, Zhao J, Tang Q, Li H, Zhang C, Yu R et al (2016) PFKFB3 control of cancer growth by responding to circadian clock outputs. Sci Rep 6:24324. https://doi.org/10.1038/srep24324
Chi F, Sharpley MS, Nagaraj R, Roy SS, Banerjee U (2020) Glycolysis-independent glucose metabolism distinguishes te from icm fate during mammalian embryogenesis. Dev Cell 53(1):9-26.e4. https://doi.org/10.1016/j.devcel.2020.02.015
Ciscato F, Ferrone L, Masgras I, Laquatra C, Rasola A (2021) Hexokinase 2 in Cancer: a prima donna playing multiple characters. Int J Mol Sci 22(9):4716. https://doi.org/10.3390/ijms22094716
Clem BF, Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA et al (2013) Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther 12(8):1461–1470. https://doi.org/10.1158/1535-7163.MCT-13-0097
Cormerais Y, Massard PA, Vucetic M, Giuliano S, Tambutté E, Durivault J et al (2018) The glutamine transporter ASCT2 (SLC1A5) promotes tumor growth independently of the amino acid transporter LAT1 (SLC7A5). J Biol Chem 293(8):2877–2887. https://doi.org/10.1074/jbc.RA117.001342
Counillon L, Bouret Y, Marchiq I, Pouyssegur J (2016) Na(+)/H(+) antiporter (NHE1) and lactate/H(+) symporters (MCTs) in pH homeostasis and cancer metabolism. Biochim Biophys Acta 1863:2465–2480. https://doi.org/10.1016/j.bbamcr.2016.02.018
Cui R, Bai H, Cao G, Zhang Z (2020) The Role of Lysophosphatidic Acid Receptors in Ovarian Cancer: A Minireview. Crit Rev Eukaryot Gene Expr 30(3):265–272. https://doi.org/10.1615/CritRevEukaryotGeneExpr.2020031091
Curtis NJ, Mooney L, Hopcroft L, Michopoulos F, Whalley N, Zhong H et al (2017) Pre-clinical pharmacology of AZD3965, a selective inhibitor of MCT1: DLBCL, NHL and Burkitt’s lymphoma anti-tumour activity. Oncotarget 8:69219–69236. https://doi.org/10.18632/oncotarget.18215
De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR et al (2013) Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154(3):651–663. https://doi.org/10.1016/j.cell.2013.06.037
De Oliveira T, Goldhardt T, Edelmann M, Rogge T, Rauch K, Kyuchukov ND et al (2021) Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo. Cancers (basel). 13(5):1011. https://doi.org/10.3390/cancers13051011
De Paz Linares GA, Opperman RM, Majumder M, Lala PK (2021) Prostaglandin E2 Receptor 4 (EP4) as a Therapeutic Target to Impede Breast Cancer-Associated Angiogenesis and Lymphangiogenesis. Cancers (basel) 13(5):942. https://doi.org/10.3390/cancers13050942
de Carvalho CCCR, Caramujo MJ (2018) The Various Roles of Fatty Acids. Molecules 23(10):2583. https://doi.org/10.3390/molecules23102583
de la Cruz-López KG, Castro-Muñoz LJ, Reyes-Hernández DO, García-Carrancá A, Manzo-Merino J (2019) Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches. Front Oncol 9:1143. https://doi.org/10.3389/fonc.2019.01143
Deskeuvre M, Lan J, Dierge E, Messens J, Riant O, Corbet C et al (2022) Targeting cancer cells in acidosis with conjugates between the carnitine palmitoyltransferase 1 inhibitor etomoxir and pH (low) insertion peptides. Int J Pharm 624:122041. https://doi.org/10.1016/j.ijpharm.2022.122041
Ding X, Gu Y, Jin M, Guo X, Xue S, Tan C et al (2020) The deubiquitinating enzyme UCHL1 promotes resistance to pemetrexed in non-small cell lung cancer by upregulating thymidylate synthase. Theranostics 10(13):6048–6060. https://doi.org/10.7150/thno.42096
Doherty JR, Yang C, Scott KEN, Cameron MD, Fallahi M, Li W et al (2014) Blocking lactate export by inhibiting the Myc target MCT1 disables glycolysis and glutathione synthesis. Cancer Res 74:908–920. https://doi.org/10.1158/0008-5472.CAN-13-2034
Doménech E, Maestre C, Esteban-Martínez L, Partida D, Pascual R, Fernández-Miranda G et al (2015) AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest. Nat Cell Biol 17(10):1304–1316. https://doi.org/10.1038/ncb3231
Draoui N, Schicke O, Seront E, Bouzin C, Sonveaux P, Riant O et al (2014) Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux. Mol Cancer Ther 13(6):1410–1418. https://doi.org/10.1158/1535-7163.MCT-13-0653
Ducker GS, Chen L, Morscher RJ, Ghergurovich JM, Esposito M, Teng X et al (2016) Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway. Cell Metab 23(6):1140–1153. https://doi.org/10.1016/j.cmet.2016.04.016
Duman C, Yaqubi K, Hoffmann A, Acikgöz AA, Korshunov A, Bendszus M et al (2019) Acyl-CoA-Binding Protein Drives Glioblastoma Tumorigenesis by Sustaining Fatty Acid Oxidation. Cell Metab 30(2):274-289.e5. https://doi.org/10.1016/j.cmet.2019.04.004
Edwards DN, Ngwa VM, Raybuck AL, Wang S, Hwang Y, Kim LC et al (2021) Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest 131(4):e140100. https://doi.org/10.1172/JCI140100
El Sayed SM, Mohamed WG, Seddik MA, Ahmed AS, Mahmoud AG, Amer WH et al (2014) Safety and outcome of treatment of metastatic melanoma using 3-bromopyruvate: a concise literature review and case study. Chin J Cancer 33(7):356–364. https://doi.org/10.5732/cjc.013.10111
Enomoto K, Sato F, Tamagawa S, Gunduz M, Onoda N, Uchino S et al (2019) A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1. Sci Rep 9(1):14616. https://doi.org/10.1038/s41598-019-51144-6
Fan TWM, Bruntz RC, Yang Y, Song H, Chernyavskaya Y, Deng P et al (2019) De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues. J Biol Chem 294(36):13464–13477. https://doi.org/10.1074/jbc.RA119.008743
Farabegoli F, Vettraino M, Manerba M, Fiume L, Roberti M, Di Stefano G (2012) Galloflavin, a new lactate dehydrogenase inhibitor, induces the death of human breast cancer cells with different glycolytic attitude by affecting distinct signaling pathways. Eur J Pharm Sci 47(4):729–738. https://doi.org/10.1016/j.ejps.2012.08.012
Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y (2018) Lactate dehydrogenase A: A key player in carcinogenesis and potential target in cancer therapy. Cancer Med 7(12):6124–6136. https://doi.org/10.1002/cam4.1820
Fhu CW, Ali A (2020) Fatty Acid Synthase: An Emerging Target in Cancer. Molecules 25(17):3935. https://doi.org/10.3390/molecules25173935
Ganapathy-Kanniappan S (2018) Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol 53(6):667–682. https://doi.org/10.1080/10409238.2018.1556578
Gao CL, Hou GG, Liu J, Ru T, Xu YZ, Zhao SY et al (2020) Synthesis and Target Identification of Benzoxepane Derivatives as Potential Anti-Neuroinflammatory Agents for Ischemic Stroke. Angew Chem Int Ed Engl 259(6):2429–2439. https://doi.org/10.1002/anie.201912489
Geeraerts SL, Heylen E, De Keersmaecker K, Kampen KR (2021) The ins and outs of serine and glycine metabolism in cancer. Nat Metab 3(2):131–141. https://doi.org/10.1038/s42255-020-00329-9
Ghanem N, El-Baba C, Araji K, El-Khoury R, Usta J, Darwiche N (2021) The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities. Chemotherapy 66(5–6):179–191. https://doi.org/10.1159/000519784
Goncalves MD, Hopkins BD, Cantley LC (2018) Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer. N Engl J Med 379(21):2052–2062. https://doi.org/10.1056/NEJMra1704560
Gozzelino L, De Santis MC, Gulluni F, Hirsch E, Martini M (2020) PI(3,4)P2 Signaling in Cancer and Metabolism. Front Oncol 10:360. https://doi.org/10.3389/fonc.2020.00360
Granchi C (2018) ATP citrate lyase (ACLY) inhibitors: An anti-cancer strategy at the crossroads of glucose and lipid metabolism. Eur J Med Chem 157:1276–1291. https://doi.org/10.1016/j.ejmech.2018.09.001
Guo XP, Zhang XY, Zhang SD (1991) Clinical trial on the effects of shikonin mixture on later stage lung cancer. Zhong Xi Yi Jie He Za Zhi 11(10):598–599
Häfliger P, Charles RP (2019) The L-Type Amino Acid Transporter LAT1-An Emerging Target in Cancer. Int J Mol Sci 20(10):2428. https://doi.org/10.3390/ijms20102428
Hager S, Fittler FJ, Wagner E, Bros M (2020) Nucleic Acid-Based Approaches for Tumor Therapy. Cells 9(9):2061. https://doi.org/10.3390/cells9092061
Hamada S, Matsumoto R, Tanaka Y, Taguchi K, Yamamoto M, Masamune A (2021) Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition. Int J Mol Sci 22(4):1870. https://doi.org/10.3390/ijms22041870
Han X, Sheng X, Jones HM, Jackson AL, Kilgore J, Stine JE et al (2015) Evaluation of the anti-tumor effects of lactate dehydrogenase inhibitor galloflavin in endometrial cancer cells. J Hematol Oncol 8:2. https://doi.org/10.1186/s13045-014-0097-x
Han S, Wei R, Zhang X, Jiang N, Fan M, Huang JH et al (2019) CPT1A/2-Mediated FAO Enhancement-A Metabolic Target in Radioresistant Breast Cancer. Front Oncol 9:1201. https://doi.org/10.3389/fonc.2019.01201
Hayes JD, Dinkova-Kostova AT, Tew KD (2020) Oxidative Stress in Cancer. Cancer Cell 38(2):167–197. https://doi.org/10.1016/j.ccell.2020.06.001 (Epub 2020 Jul 9)
He ST, Lee DY, Tung CY, Li CY, Wang HC (2019) Glutamine Metabolism in Both the Oxidative and Reductive Directions Is Triggered in Shrimp Immune Cells (Hemocytes) at the WSSV Genome Replication Stage to Benefit Virus Replication. Front Immunol 10:2102. https://doi.org/10.3389/fimmu.2019.02102
He F, Antonucci L, Karin M (2020) NRF2 as a regulator of cell metabolism and inflammation in cancer. Carcinogenesis 41(4):405–416. https://doi.org/10.1093/carcin/bgaa039
He Y, He Z, Zhang X, Liu S (2021) Platelet-activating factor acetyl hydrolase IB2 dysregulated cell proliferation in ovarian cancer. Cancer Cell Int 21(1):697. https://doi.org/10.1186/s12935-021-02406-9
Hochster H (2002) The role of pemetrexed in the treatment of colorectal cancer. Semin Oncol 29(6 Suppl 18):54–56. https://doi.org/10.1053/sonc.2002.37473
Holman GD (2020) Structure, function and regulation of mammalian glucose transporters of the SLC2 family. Pflugers Arch 472(9):1155–1175. https://doi.org/10.1007/s00424-020-02411-3
Hong B, van den Heuvel AP, Prabhu VV, Zhang S, El-Deiry WS (2014) Targeting tumor suppressor p53 for cancer therapy: strategies, challenges and opportunities. Curr Drug Targets 15(1):80–89. https://doi.org/10.2174/1389450114666140106101412
Hresko RC, Hruz PW (2011) HIV protease inhibitors act as competitive inhibitors of the cytoplasmic glucose binding site of GLUTs with differing affinities for GLUT1 and GLUT4. PLoS ONE 6(9):e25237. https://doi.org/10.1371/journal.pone.0025237
Hu X, Jin H, Zhu L (2021) Effect of glutamine metabolism on chemoresistance and its mechanism in tumors. Zhejiang Da Xue Xue Bao Yi Xue Ban 50(1):32–40. https://doi.org/10.3724/zdxbyxb-2021-0040
İlhan M (2022) Non-metabolic functions of pyruvate kinase M2: PKM2 in tumorigenesis and therapy resistance. Neoplasma 69(4):747–754. https://doi.org/10.4149/neo_2022_220119N77
Ishimoto K, Minami A, Minami K, Ueda N, Tsujiuchi T (2021) Different effects of lysophosphatidic acid receptor-2 (LPA2) and LPA5 on the regulation of chemoresistance in colon cancer cells. J Recept Signal Transduct Res 41(1):93–98. https://doi.org/10.1080/10799893.2020.1794002
Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X et al (2018) Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell 172(3):578-589.e17. https://doi.org/10.1016/j.cell.2018.01.006
Jang M, Kim SS, Lee J (2013) Cancer cell metabolism: implications for therapeutic targets. Exp Mol Med 45(10):e45. https://doi.org/10.1038/emm.2013.85
Jara-Gutiérrez Á, Baladrón V (2021) The Role of Prostaglandins in Different Types of Cancer. Cells 10(6):1487. https://doi.org/10.3390/cells10061487
Jelic MD, Mandic AD, Maricic SM, Srdjenovic BU (2021) Oxidative stress and its role in cancer. J Cancer Res Ther 17(1):22–28. https://doi.org/10.4103/jcrt.JCRT_862_16
Jiang M, Liu S, Lin J, Hao W, Wei B, Gao Y et al (2021) A pan-cancer analysis of molecular characteristics and oncogenic role of hexokinase family genes in human tumors. Life Sci 264:118669. https://doi.org/10.1016/j.lfs.2020.118669
Jin L, Chun J, Pan C, Alesi GN, Li D, Magliocca KR et al (2017) Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis. Oncogene 36(27):3797–3806. https://doi.org/10.1038/onc.2017.6
Jin Z, Chai YD, Hu S (2021) Fatty Acid Metabolism and Cancer. Adv Exp Med Biol 1280:231–241. https://doi.org/10.1007/978-3-030-51652-9_16
Jones SF, Infante JR (2015) Molecular Pathways: Fatty Acid Synthase. Clin Cancer Res 21(24):5434–5438. https://doi.org/10.1158/1078-0432.CCR-15-0126
Kanai Y (2022) Amino acid transporter LAT1 (SLC7A5) as a molecular target for cancer diagnosis and therapeutics. Pharmacol Ther 230:107964. https://doi.org/10.1016/j.pharmthera.2021.107964
Kenmotsu H, Yamamoto N, Yamanaka T, Yoshiya K, Takahashi T, Ueno T et al (2020) Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 38(19):2187–2196
Keung W, Ussher JR, Jaswal JS, Raubenheimer M, Lam VHM, Wagg CS et al (2013) Inhibition of Carnitine Palmitoyltransferase-1 Activity Alleviates Insulin Resistance in Diet-Induced Obese Mice. Diabetes 62:711–720. https://doi.org/10.2337/db12-0259
Kim J, Hu Z, Cai L, Li K, Choi E, Faubert B et al (2017) CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546(7656):168–172. https://doi.org/10.1038/nature22359
Ko YH, Verhoeven HA, Lee MJ, Corbin DJ, Vogl TJ, Pedersen PL (2012) A translational study “case report” on the small molecule “energy blocker” 3-bromopyruvate (3BP) as a potent anticancer agent: from bench side to bedside. J Bioenerg Biomembr 44(1):163–170. https://doi.org/10.1007/s10863-012-9417-4
Koppula P, Zhang Y, Zhuang L, Gan B (2018) Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. Cancer Commun (lond) 38(1):12. https://doi.org/10.1186/s40880-018-0288-x
Koundouros N, Poulogiannis G (2020) Reprogramming of fatty acid metabolism in cancer. Br J Cancer 122(1):4–22. https://doi.org/10.1038/s41416-019-0650-z
Lane AN, Fan TW (2015) Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res 43(4):2466–2485. https://doi.org/10.1093/nar/gkv047
Lee EA, Angka L, Rota SG, Hanlon T, Mitchell A, Hurren R et al (2015) Targeting Mitochondria with Avocatin B Induces Selective Leukemia Cell Death. Cancer Res 75(12):2478–2488. https://doi.org/10.1158/0008-5472.CAN-14-2676
Lemberg KM, Vornov JJ, Rais R, Slusher BS (2018) We’re Not “DON” Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-Oxo-L-Norleucine. Mol Cancer 17:1824–1832. https://doi.org/10.1158/1535-7163.MCT-17-1148
Li T, Le A (2018) Glutamine Metabolism in Cancer. Adv Exp Med Biol 1063:13–32. https://doi.org/10.1007/978-3-319-77736-8_2
Li HM, Yang JG, Liu ZJ, Wang WM, Yu ZL, Ren JG et al (2017a) Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma. J Exp Clin Cancer Res 36(1):7. https://doi.org/10.1186/s13046-016-0481-1
Li W, Zheng M, Wu S, Gao S, Yang M, Li Z et al (2017b) Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2. J Exp Clin Cancer Res 36(1):58. https://doi.org/10.1186/s13046-017-0530-4
Li EQ, Zhao W, Zhang C, Qin LZ, Liu SJ, Feng ZQ et al (2019) Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors. Eur J Pharm Sci 137:105010. https://doi.org/10.1016/j.ejps.2019.105010
Ling G, Lamprecht S, Shubinsky G, Osyntsov L, Yerushalmi B, Pinsk I et al (2018) Mycophenolate Mofetil Alone and in Combination with Tacrolimus Inhibits the Proliferation of HT-29 Human Colonic Adenocarcinoma Cell Line and Might Interfere with Colonic Tumorigenesis. Anticancer Res 38(6):3333–3339. https://doi.org/10.21873/anticanres.12599
Ling R, Chen G, Tang X, Liu N, Zhou Y, Chen D (2022) Acetyl-CoA synthetase 2(ACSS2): a review with a focus on metabolism and tumor development. Discov Oncol 13(1):58. https://doi.org/10.1007/s12672-022-00521-1
Liu J, Zhang C, Lin M, Zhu W, Liang Y, Hong X et al (2014) Glutaminase 2 negatively regulates the PI3K/AKT signaling and shows tumor suppression activity in human hepatocellular carcinoma. Oncotarget 5(9):2635–2647. https://doi.org/10.18632/oncotarget.1862
Liu P, Liu J, Jiang W, Carew JS, Ogasawara MA, Pelicano H et al (2016) Elimination of Chronic Lymphocytic Leukemia Cells in Stromal Microenvironment by Targeting CPT with an Anti-Angina Drug Perhexiline. Oncogene 35:5663–5673. https://doi.org/10.1038/onc.2016.103
Long Y, Qiu J, Zhang B, He P, Shi X, He Q et al (2021) Pharmacological Vitamin C Treatment Impedes the Growth of Endogenous Glutamine-Dependent Cancers by Targeting Glutamine Synthetase. Front Pharmacol 12:671902. https://doi.org/10.3389/fphar.2021.671902
Lopes C, Pereira C, Medeiros R (2021) ASCT2 and LAT1 Contribution to the Hallmarks of Cancer: From a Molecular Perspective to Clinical Translation. Cancers (basel) 13(2):203. https://doi.org/10.3390/cancers13020203
Lordan R, Tsoupras A, Zabetakis I (2019) The Potential Role of Dietary Platelet-Activating Factor Inhibitors in Cancer Prevention and Treatment. Adv Nutr 10(1):148–164. https://doi.org/10.1093/advances/nmy090
Lu X (2019) The Role of Large Neutral Amino Acid Transporter (LAT1) in Cancer. Curr Cancer Drug Targets 19(11):863–876. https://doi.org/10.2174/1568009619666190802135714
Lu L, Chen Y, Zhu Y (2017) The molecular basis of targeting PFKFB3 as a therapeutic strategy against cancer. Oncotarget 8(37):62793–62802. https://doi.org/10.18632/oncotarget.19513
Ma Y, Temkin SM, Hawkridge AM, Guo C, Wang W, Wang XY et al (2018) Fatty acid oxidation: An emerging facet of metabolic transformation in cancer. Cancer Lett 435:92–100. https://doi.org/10.1016/j.canlet.2018.08.006
Ma Y, Zhu Q, Wang X, Liu M, Chen Q, Jiang L et al (2022) Synthetic lethal screening identifies DHODH as a target for MEN1-mutated tumor cells. Cell Res 32(6):596–599. https://doi.org/10.1038/s41422-022-00613-1
Maher JC, Krishan A, Lampidis TJ (2004) Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol 53(2):116–122. https://doi.org/10.1007/s00280-003-0724-7
Manerba M, Vettraino M, Fiume L, Di Stefano G, Sartini A, Giacomini E et al (2012) Galloflavin (CAS 568–80-9): a novel inhibitor of lactate dehydrogenase. ChemMedChem 7(2):311–317. https://doi.org/10.1002/cmdc.201100471
Manerba M, Di Ianni L, Govoni M, Roberti M, Recanatini M, Di Stefano G (2017) LDH inhibition impacts on heat shock response and induces senescence of hepatocellular carcinoma cells. Eur J Pharm Sci 105:91–98. https://doi.org/10.1016/j.ejps.2017.05.015
Mao S, Ling Q, Pan J, Li F, Huang S, Ye W et al (2021) Inhibition of CPT1a as a prognostic marker can synergistically enhance the antileukemic activity of ABT199. J Transl Med 19(1):181. https://doi.org/10.1186/s12967-021-02848-9
Martelli MP, Martino G, Cardinali V, Falini B, Martinelli G, Cerchione C (2020) Enasidenib and ivosidenib in AML. Minerva Med 111(5):411–426. https://doi.org/10.23736/S0026-4806.20.07024-X
Martinez RS, Salji MJ, Rushworth L, Ntala C, Rodriguez Blanco G, Hedley A et al (2021) SLFN5 Regulates LAT1-Mediated mTOR Activation in Castration-Resistant Prostate Cancer. Cancer Res 81(13):3664–3678. https://doi.org/10.1158/0008-5472.CAN-20-3694
Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP (2017) Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol 14(1):11–31. https://doi.org/10.1038/nrclinonc.2016.60
Mascagna D, Ghanem G, Morandini R, d’Ischia M, Misuraca G, Lejeune F et al (1992) Synthesis and cytotoxic properties of new N-substituted 4-aminophenol derivatives with a potential as antimelanoma agents. Melanoma Res 2(1):25–32. https://doi.org/10.1097/00008390-199205000-00004
Matés JM, Di Paola FJ, Campos-Sandoval JA, Mazurek S, Márquez J (2020) Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer. Semin Cell Dev Biol 98:34–43. https://doi.org/10.1016/j.semcdb.2019.05.012
Mathur D, Stratikopoulos E, Ozturk S, Steinbach N, Pegno S, Schoenfeld S et al (2017) PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition. Cancer Discov 7(4):380–390. https://doi.org/10.1158/2159-8290.CD-16-0612
McAnulty J, DiFeo A (2020) The Molecular “Myc-anisms” Behind Myc-Driven Tumorigenesis and the Relevant Myc-Directed Therapeutics. Int J Mol Sci 21(24):9486. https://doi.org/10.3390/ijms21249486
McDonald PC, Chafe SC, Brown WS, Saberi S, Swayampakula M, Venkateswaran G et al (2019) Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia. Gastroenterology 157(3):823–837. https://doi.org/10.1053/j.gastro.2019.05.004
McDonald G, Chubukov V, Coco J, Truskowski K, Narayanaswamy R, Choe S et al (2020) Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase. Mol Cancer Ther 19(12):2502–2515. https://doi.org/10.1158/1535-7163.MCT-20-0550
Mikalayeva V, Ceslevičienė I, Sarapinienė I, Žvikas V, Skeberdis VA, Jakštas V et al (2019) Fatty Acid Synthesis and Degradation Interplay to Regulate the Oxidative Stress in Cancer Cells. Int J Mol Sci 20(6):1348. https://doi.org/10.3390/ijms20061348
Mizuno R, Kawada K, Sakai Y (2019) Prostaglandin E2/EP Signaling in the Tumor Microenvironment of Colorectal Cancer. Int J Mol Sci 20(24):6254. https://doi.org/10.3390/ijms20246254
Moloney JN, Cotter TG (2018) ROS signalling in the biology of cancer. Semin Cell Dev Biol 80:50–64. https://doi.org/10.1016/j.semcdb.2017.05.023
Mondal S, Roy D, Sarkar Bhattacharya S, Jin L, Jung D, Zhang S et al (2019) Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers. Int J Cancer 144(1):178–189. https://doi.org/10.1002/ijc.31868
Mukha A, Kahya U, Linge A, Chen O, Löck S, Lukiyanchuk V et al (2021) GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy. Theranostics 11(16):7844–7868. https://doi.org/10.7150/thno.58655
Muto Y, Furihata T, Kaneko M, Higuchi K, Okunushi K, Morio H, Reien Y, Uesato M, Matsubara H, Anzai N (2019) Different Response Profiles of Gastrointestinal Cancer Cells to an L-Type Amino Acid Transporter Inhibitor, JPH203. Anticancer Res 39(1):159–165. https://doi.org/10.21873/anticanres.13092 (PMID: 30591453)
Nagana Gowda GA, Barding GA Jr, Dai J, Gu H, Margineantu DH, Hockenbery DM et al (2018) A Metabolomics Study of BPTES Altered Metabolism in Human Breast Cancer Cell Lines. Front Mol Biosci 5:49. https://doi.org/10.3389/fmolb.2018.00049
Nam JS, Sharma AR, Nguyen LT, Jagga S, Lee YH, Sharma G et al (2018) Lysophosphatidic acid enhances breast cancer cells-mediated osteoclastogenesis. Korean J Physiol Pharmacol 22(5):503–511. https://doi.org/10.4196/kjpp.2018.22.5.503
Ning X, Qi H, Li R, Li Y, Jin Y, McNutt MA et al (2017) Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase. Eur J Med Chem 138:343–352. https://doi.org/10.1016/j.ejmech.2017.06.064
Nishikubo K, Ohgaki R, Okanishi H, Okuda S, Xu M, Endou H et al (2022) Pharmacologic inhibition of LAT1 predominantly suppresses transport of large neutral amino acids and downregulates global translation in cancer cells. J Cell Mol Med 26(20):5246–5256. https://doi.org/10.1111/jcmm.17553
Oda K, Hosoda N, Endo H, Saito K, Tsujihara K, Yamamura M et al (2010) L-type amino acid transporter 1 inhibitors inhibit tumor cell growth. Cancer Sci 101(1):173–179. https://doi.org/10.1111/j.1349-7006.2009.01386.x
Okano N, Naruge D, Kawai K, Kobayashi T, Nagashima F, Endou H, Furuse J (2020) First-in-human phase I study of JPH203, an L-type amino acid transporter 1 inhibitor, in patients with advanced solid tumors. Invest New Drugs 38(5):1495–1506. https://doi.org/10.1007/s10637-020-00924-3
Okesli A, Khosla C, Bassik MC (2017) Human pyrimidine nucleotide biosynthesis as a target for antiviral chemotherapy. Curr Opin Biotechnol 48:127–134. https://doi.org/10.1016/j.copbio.2017.03.010
Pacilli A, Calienni M, Margarucci S, D’Apolito M, Petillo O, Rocchi L et al (2013) Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of myc-induced lymphomagenesis. J Natl Cancer Inst 105(7):489–498. https://doi.org/10.1093/jnci/djt030
Pajak B, Siwiak E, Sołtyka M, Priebe A, Zieliński R, Fokt I et al (2019) 2-Deoxy-d-Glucose and Its Analogs From Diagnostic to Therapeutic Agents. Int J Mol Sci 21(1):234
Park JH, Kundu A, Lee SH, Jiang C, Lee SH, Kim YS et al (2021) Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces Autophagic Cell Death through Disruption of the Glycolysis Pathway in Ovarian Cancer Cells. Int J Biol Sci 17(8):1895–1908. https://doi.org/10.7150/ijbs.59855
Park JH, Lee JS, Oh Y, Lee JS, Park HE, Lee H et al (2022) PKM2 Is Overexpressed in Glioma Tissues, and Its Inhibition Highly Increases Late Apoptosis in U87MG Cells With Low-density Specificity. In Vivo 36(2):694–703. https://doi.org/10.21873/invivo.12755
Pavlova NN, Zhu J, Thompson CB (2022) The hallmarks of cancer metabolism: Still emerging. Cell Metab 34(3):355–377. https://doi.org/10.1016/j.cmet.2022.01.007
Pezzuto A, Carico E (2018) Role of HIF-1 in Cancer Progression: Novel Insights. A Review Curr Mol Med 18(6):343–351. https://doi.org/10.2174/1566524018666181109121849
Pinheiro C, Longatto-Filho A, Azevedo-Silva J, Casal M, Schmitt FC, Baltazar F (2012) Role of monocarboxylate transporters in human cancers: State of the art. J Bioenerg Biomembr 44:127–139. https://doi.org/10.1007/s10863-012-9428-1
Prochownik EV, Wang H (2021) The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells. Cells 10(4):762. https://doi.org/10.3390/cells10040762
Rais R, Jančařík A, Tenora L, Nedelcovych M, Alt J, Englert J et al (2016) Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma. J Med Chem 59(18):8621–8633. https://doi.org/10.1021/acs.jmedchem.6b01069
Rais R, Lemberg KM, Tenora L, Arwood ML, Pal A, Alt J et al (2022) Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv 8(46):5925. https://doi.org/10.1126/sciadv.abq5925
Rani R, Kumar V (2016) Recent Update on Human Lactate Dehydrogenase Enzyme 5 (hLDH5) Inhibitors: A Promising Approach for Cancer Chemotherapy. J Med Chem 59(2):487–496. https://doi.org/10.1021/acs.jmedchem.5b00168
Reis LMD, Adamoski D, Ornitz Oliveira Souza R, Rodrigues Ascenção CF, Sousa de Oliveira KR, Corrêa-da-Silva F et al (2019) Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. J Biol Chem 294(24):9342–9357. https://doi.org/10.1074/jbc.RA119.008180
Renner O, Mayer M, Leischner C, Burkard M, Berger A, Lauer UM et al (2022) Systematic Review of Gossypol/AT-101 in Cancer Clinical Trials. Pharmaceuticals (basel) 15(2):144. https://doi.org/10.3390/ph15020144
Ribera Santasusana JM (2020) Acute lymphoblastic leukemia: From aminopterin to CAR T cells. Med Clin (barc) 154(7):269–274. https://doi.org/10.1016/j.medcli.2019.09.011
Roca Suarez AA, Testoni B, Baumert TF, Lupberger J (2021) Nucleic Acid-Induced Signaling in Chronic Viral Liver Disease. Front Immunol 11:624034. https://doi.org/10.3389/fimmu.2020.624034
Rodríguez-Nogales C, Sebastián V, Irusta S, Desmaële D, Couvreur P, Blanco-Prieto MJ (2019) A unique multidrug nanomedicine made of squalenoyl-gemcitabine and alkyl-lysophospholipid edelfosine. Eur J Pharm Biopharm 144:165–173. https://doi.org/10.1016/j.ejpb.2019.09.017
Romer E, Thyagarajan A, Krishnamurthy S, Rapp CM, Liu L, Fahy K et al (2018) Systemic Platelet-Activating Factor-Receptor Agonism Enhances Non-Melanoma Skin Cancer Growth. Int J Mol Sci 19(10):3109. https://doi.org/10.3390/ijms19103109
Rosilio C, Nebout M, Imbert V, Griessinger E, Neffati Z, Benadiba J et al (2015) L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia. Leukemia 29(6):1253–1266. https://doi.org/10.1038/leu.2014.338 (Epub 2014 Dec 8)
Sajadimajd S, Khazaei M (2018) Oxidative Stress and Cancer: The Role of Nrf2. Curr Cancer Drug Targets 18(6):538–557. https://doi.org/10.2174/1568009617666171002144228
Sarkar Bhattacharya S, Thirusangu P, Jin L, Roy D, Jung D, Xiao Y et al (2019) PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses. Cell Death Dis 10(10):725. https://doi.org/10.1038/s41419-019-1916-3
Sarniak A, Lipińska J, Tytman K, Lipińska S (2016) Endogenous mechanisms of reactive oxygen species (ROS) generation. Postepy Hig Med Dosw (online) 70:1150–1165. https://doi.org/10.5604/17322693.1224259
Schlaepfer IR, Joshi M (2020) CPT1A-mediated Fat Oxidation, Mechanisms, and Therapeutic Potential. Endocrinology 161(2):046. https://doi.org/10.1210/endocr/bqz046
Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquière B, Cauwenberghs S et al (2014) Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab 19(1):37–48. https://doi.org/10.1016/j.cmet.2013.11.008
Schulte ML, Fu A, Zhao P, Li J, Geng L, Smith ST et al (2018) Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24(2):194–202. https://doi.org/10.1038/nm.4464
Serganova I, Cohen IJ, Vemuri K, Shindo M, Maeda M, Mane M et al (2018) LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response. PLoS ONE 13(9):e0203965. https://doi.org/10.1371/journal.pone.0203965
Sharma NS, Gupta VK, Garrido VT, Hadad R, Durden BC, Kesh K et al (2020) Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J Clin Invest 130(1):451–465. https://doi.org/10.1172/JCI127515
Shi L, Pan H, Liu Z, Xie J, Han W (2017) Roles of PFKFB3 in cancer. Signal Transduct Target Ther 2:17044. https://doi.org/10.1038/sigtrans.2017.44
Shima T, Taniguchi K, Tokumaru Y, Inomata Y, Arima J, Lee SW et al (2022) Glucose transporter-1 inhibition overcomes imatinib resistance in gastrointestinal stromal tumor cells. Oncol Rep 47(1):7. https://doi.org/10.3892/or.2021.8218
Siebeneicher H, Cleve A, Rehwinkel H, Neuhaus R, Heisler I, Müller T et al (2016) Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY-876. ChemMedChem 11(20):2261–2271. https://doi.org/10.1002/cmdc.201600276
Siebert A, Deptuła M, Cichorek M, Ronowska A, Cholewiński G, Rachon J (2021) Anticancer Properties of Amino Acid and Peptide Derivatives of Mycophenolic Acid. Anticancer Agents Med Chem 21(4):462–467. https://doi.org/10.2174/1871520620666200516151456
Siegel RL, Miller KD, Jemal A (2020) Cancer statistics. CA. Cancer J Clin 70:7–30. https://doi.org/10.3322/caac.21590
Sies H, Jones DP (2020) Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol 21(7):363–383. https://doi.org/10.1038/s41580-020-0230-3 (Epub 2020 Mar 30)
Singleton DC, Dechaume AL, Murray PM, Katt WP, Baguley BC, Leung EY (2020) Pyruvate anaplerosis is a mechanism of resistance to pharmacological glutaminase inhibition in triple-receptor negative breast cancer. BMC Cancer 20(1):470. https://doi.org/10.1186/s12885-020-06885-3
Sipos A, Ujlaki G, Mikó E, Maka E, Szabó J, Uray K et al (2021) The role of the microbiome in ovarian cancer: mechanistic insights into oncobiosis and to bacterial metabolite signaling. Mol Med 27(1):33. https://doi.org/10.1186/s10020-021-00295-2
Snaebjornsson MT, Janaki-Raman S, Schulze A (2020) Greasing the Wheels of the Cancer Machine: The Role of Lipid Metabolism in Cancer. Cell Metab 31(1):62–76. https://doi.org/10.1016/j.cmet.2019.11.010
Song S, Chen Q, Li Y, Lei G, Scott A, Huo L et al (2021) Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma. Gut 70(12):2238–2248. https://doi.org/10.1136/gutjnl-2020-321175
Soth MJ, Le K, Di Francesco ME, Hamilton MM, Liu G, Burke JP et al (2020) Discovery of IPN60090, a Clinical Stage Selective Glutaminase-1 (GLS-1) Inhibitor with Excellent Pharmacokinetic and Physicochemical Properties. J Med Chem 63(21):12957–12977. https://doi.org/10.1021/acs.jmedchem.0c01398
Still ER, Yuneva MO (2017) Hopefully devoted to Q: targeting glutamine addiction in cancer. Br Cancer. 116(11):1375–1381. https://doi.org/10.1038/bjc.2017.113
Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG (2015) Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell 162(3):552–563. https://doi.org/10.1016/j.cell.2015.07.017
Sun S, Li H, Chen J, Qian Q (2017) Lactic Acid: No Longer an Inert and End-Product of Glycolysis. Physiology (bethesda) 32(6):453–463. https://doi.org/10.1152/physiol.00016.2017
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660
Suzuki K, Miura Y, Mochida Y, Miyazaki T, Toh K, Anraku Y et al (2019) Glucose transporter 1-mediated vascular translocation of nanomedicines enhances accumulation and efficacy in solid tumors. J Control Release 301:28–41. https://doi.org/10.1016/j.jconrel.2019.02.021
Svensson RU, Shaw RJ (2016) Lipid Synthesis Is a Metabolic Liability of Non-Small Cell Lung Cancer. Cold Spring Harb Symp Quant Biol 81:93–103. https://doi.org/10.1101/sqb.2016.81.030874 (Epub 2017 Jan 6)
Syed-Abdul MM, Parks EJ, Gaballah AH, Bingham K, Hammoud GM, Kemble G et al (2020) Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities. Hepatology 72(1):103–118. https://doi.org/10.1002/hep.31000
Tambay V, Raymond VA, Bilodeau M (2021) MYC Rules: Leading Glutamine Metabolism toward a Distinct Cancer Cell Phenotype. Cancers (basel) 13(17):4484. https://doi.org/10.3390/cancers13174484
Tang Z, Xu Z, Zhu X, Zhang J (2021) New insights into molecules and pathways of cancer metabolism and therapeutic implications. Cancer Commun 41(1):16–36
Tang M, Dong X, Xiao L, Tan Z, Luo X, Yang L et al (2022) CPT1A-mediated fatty acid oxidation promotes cell proliferation via nucleoside metabolism in nasopharyngeal carcinoma. Cell Death Dis 13(4):331. https://doi.org/10.1038/s41419-022-04730-y
Tannir NM et al (2021) CANTATA: Primary analysis of a global, randomized, placebo (Pbo)-controlled, double-blind trial of telaglenastat (CB-839) + cabozantinib versus Pbo + cabozantinib in advanced/metastatic renal cell carcinoma (mRCC) patients (pts) who progressed on immune checkpoint inhibitor (ICI) or anti-angiogenic therapies. J Clin Oncol 39:4501–4501
Tao L, Wei L, Liu Y, Ding Y, Liu X, Zhang X et al (2017) Gen-27, a newly synthesized flavonoid, inhibits glycolysis and induces cell apoptosis via suppression of hexokinase II in human breast cancer cells. Biochem Pharmacol 125:12–25. https://doi.org/10.1016/j.bcp.2016.11.001
Tao T, Su Q, Xu S, Deng J, Zhou S, Zhuang Y et al (2019) Down-regulation of PKM2 decreases FASN expression in bladder cancer cells through AKT/mTOR/SREBP-1c axis. J Cell Physiol 234(3):3088–3104. https://doi.org/10.1002/jcp.27129
Teixeira E, Silva C, Martel F (2021) The role of the glutamine transporter ASCT2 in antineoplastic therapy. Cancer Chemother Pharmacol 87(4):447–464. https://doi.org/10.1007/s00280-020-04218-6
Valvona CJ, Fillmore HL, Nunn PB, Pilkington GJ (2016) The regulation and function of lactate dehydrogenase a: therapeutic potential in brain tumor. Brain Pathol 26(1):3–17. https://doi.org/10.1111/bpa.12299
Vaupel P, Multhoff G (2021) Revisiting the Warburg effect: historical dogma versus current understanding. J Physiol 599(6):1745–1757. https://doi.org/10.1113/JP278810
Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M et al (2015) Inhibition of de novo Palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine 2(8):808–824. https://doi.org/10.1016/j.ebiom.2015.06.020
Wahlström T, Henriksson MA (2015) Impact of MYC in regulation of tumor cell metabolism. Biochim Biophys Acta 1849(5):563–569. https://doi.org/10.1016/j.bbagrm.2014.07.004
Wang Z, Wang N, Chen J, Shen J (2012) Emerging glycolysis targeting and drug discovery from chinese medicine in cancer therapy. Evid Based CompL Alternat Med 2012:873175. https://doi.org/10.1155/2012/873175
Wang X, Jung YS, Jun S, Lee S, Wang W, Schneider A et al (2016) PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness. Nat Commun 7:10633. https://doi.org/10.1038/ncomms10633
Wang Y, Hao F, Nan Y, Qu L, Na W, Jia C et al (2018a) PKM2 Inhibitor shikonin overcomes the cisplatin resistance in bladder cancer by inducing necroptosis. Int J Biol Sci 14(13):1883–1891. https://doi.org/10.7150/ijbs.27854
Wang Y, Branicky R, Noë A, Hekimi S (2018b) Superoxide dismutases: dual roles in controlling ros damage and regulating ros signaling. J Cell Biol 217(6):1915–1928. https://doi.org/10.1083/jcb.201708007
Wang K, Jiang J, Lei Y, Zhou S, Wei Y, Huang C (2019) Targeting metabolic-redox circuits for cancer therapy. Trends Biochem Sci 44(5):401–414. https://doi.org/10.1016/j.tibs.2019.01.001
Wang Y, Qu C, Liu T, Wang C (2020a) PFKFB3 inhibitors as potential anticancer agents: Mechanisms of action, current developments, and structure-activity relationships. Eur J Med Chem 203:112612. https://doi.org/10.1016/j.ejmech.2020.112612
Wang JX, Choi SYC, Niu X, Kang N, Xue H, Killam J et al (2020b) Lactic acid and an acidic tumor microenvironment suppress anticancer immunity. Int J Mol Sci 21(21):8363. https://doi.org/10.3390/ijms21218363
Wang J, Liu R, Zhao Y, Ma Z, Sang Z, Wen Z et al (2021a) Novel microcrystal formulations of sorafenib facilitate a long-acting antitumor effect and relieve treatment side effects as observed with fundus microcirculation imaging. Front Oncol 11:743055. https://doi.org/10.3389/fonc.2021.743055
Wang Y, Qin L, Chen W, Chen Q, Sun J, Wang G (2021b) Novel strategies to improve tumour therapy by targeting the proteins MCT1, MCT4 and LAT1. Eur J Med Chem 226:113806. https://doi.org/10.1016/j.ejmech.2021.113806
Wang JJ, Siu MK, Jiang YX, Leung TH, Chan DW, Wang HG et al (2021c) A Combination of Glutaminase Inhibitor 968 and PD-L1 Blockade Boosts the Immune Response against Ovarian Cancer. Biomolecules 11(12):1749. https://doi.org/10.3390/biom11121749
Wang W, Pan H, Ren F, Chen H, Ren P (2022a) Targeting ASCT2-mediated glutamine metabolism inhibits proliferation and promotes apoptosis of pancreatic cancer cells. Biosci Rep 42(3):B20212171. https://doi.org/10.1042/BSR20212171
Wang Q, Morris RJ, Bode AM, Zhang T (2022b) Prostaglandin pathways: opportunities for cancer prevention and therapy. Cancer Res 82(6):949–965. https://doi.org/10.1158/0008-5472.CAN-21-2297
Wendt EHU, Schoenrogge M, Vollmar B, Zechner D (2020) Galloflavin plus metformin treatment impairs pancreatic cancer cells. Anticancer Res 40(1):153–160. https://doi.org/10.21873/anticanres.13936
Yamashita AS, da Costa RM, Stumpo V, Rais R, Slusher BS, Riggins GJ (2020) The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling. Neurooncol Adv. 3(1):149. https://doi.org/10.1093/noajnl/vdaa149
Yang H, Zhang MZ, Sun HW, Chai YT, Li X, Jiang Q et al (2021a) A novel microcrystalline bay-876 formulation achieves long-acting antitumor activity against aerobic glycolysis and proliferation of hepatocellular carcinoma. Front Oncol 11:783194. https://doi.org/10.3389/fonc.2021.783194
Yang Z, Zhang L, Zhu H, Zhou K, Wang H, Wang Y et al (2021b) Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast. J Cell Mol Med 25(7):3511–3523. https://doi.org/10.1111/jcmm.16434
Ye J, Huang Q, Xu J, Huang J, Wang J, Zhong W et al (2018) Targeting of glutamine transporter ASCT2 and glutamine synthetase suppresses gastric cancer cell growth. J Cancer Res Clin Oncol 144(5):821–833. https://doi.org/10.1007/s00432-018-2605-9
Yokoyama Y, Estok TM, Wild R (2022) Sirpiglenastat (DRP-104) induces antitumor efficacy through direct, broad antagonism of glutamine metabolism and stimulation of the innate and adaptive immune systems. Mol Cancer Ther 21(10):1561–1572. https://doi.org/10.1158/1535-7163.MCT-22-0282
Yoo HC, Yu YC, Sung Y, Han JM (2020) Glutamine reliance in cell metabolism. Exp Mol Med 52(9):1496–1516. https://doi.org/10.1038/s12276-020-00504-8
Yothaisong S, Dokduang H, Anzai N, Hayashi K, Namwat N, Yongvanit P, Sangkhamanon S, Jutabha P, Endou H, Loilome W (2017) Inhibition of l-type amino acid transporter 1 activity as a new therapeutic target for cholangiocarcinoma treatment. Tumour Biol 39(3):1010428317694545. https://doi.org/10.1177/1010428317694545
Yu W, Huang J, Dong Q, Li W, Jiang L, Zhang Q et al (2022) Ag120-Mediated Inhibition of ASCT2-dependent glutamine transport has an anti-tumor effect on colorectal cancer cells. Front Pharmacol 13:871392. https://doi.org/10.3389/fphar.2022.871392
Yuan L, Sheng X, Clark LH, Zhang L, Guo H, Jones HM et al (2016) Glutaminase inhibitor compound 968 inhibits cell proliferation and sensitizes paclitaxel in ovarian cancer. Am J Transl Res 8(10):4265–4277
Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K et al (2015) Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science 350(6266):1391–1396. https://doi.org/10.1126/science.aaa5004
Zahra K, Dey T, Ashish MSP, Pandey U (2020) Pyruvate Kinase M2 and Cancer: The Role of PKM2 in promoting tumorigenesis. Front Oncol 10:159. https://doi.org/10.3389/fonc.2020.00159
Zauri M, Berridge G, Thézénas ML, Pugh KM, Goldin R, Kessler BM et al (2015) CDA directs metabolism of epigenetic nucleosides revealing a therapeutic window in cancer. Nature 524(7563):114–118. https://doi.org/10.1038/nature14948
Zaytseva YY, Rychahou PG, Le AT, Scott TL, Flight RM, Kim JT et al (2018) Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer. Oncotarget 9(37):24787–24800. https://doi.org/10.18632/oncotarget.25361
Ždralević M, Vučetić M, Daher B, Marchiq I, Parks SK, Pouysségur J (2018) Disrupting the “Warburg effect” re-routes cancer cells to OXPHOS offering a vulnerability point via ’ferroptosis’-induced cell death. Adv Biol Regul 68:55–63. https://doi.org/10.1016/j.jbior.2017.12.002
Zeng Y (2018) Advances in mechanism and treatment strategy of cancer. Cell Mol Biol 64(6):1–3
Zhang XD, Deslandes E, Villedieu M, Poulain L, Duval M, Gauduchon P et al (2006) Effect of 2-deoxy-D-glucose on various malignant cell lines in vitro. Anticancer Res 26(5):3561–3566
Zhang D, Li J, Wang F, Hu J, Wang S, Sun Y (2014) 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett 355(2):176–183. https://doi.org/10.1016/j.canlet.2014.09.003
Zhang Z, Liu R, Shuai Y, Huang Y, Jin R, Wang X et al (2020) ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma. Br J Cancer 122(1):82–93. https://doi.org/10.1038/s41416-019-0637-9
Zhao S, Jang C, Liu J, Uehara K, Gilbert M, Izzo L et al (2020) Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature 579(7800):586–591. https://doi.org/10.1038/s41586-020-2101-7
Zhelev Z, Aoki I, Lazarova D, Vlaykova T, Higashi T, Bakalova R (2022) A “Weird” mitochondrial fatty acid oxidation as a metabolic “secret” of cancer. Oxid Med Cell Longev. https://doi.org/10.1155/2022/2339584
Zheng M, Wu C, Yang K, Yang Y, Liu Y, Gao S et al (2021) Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis. Pharmacol Res 164:105367. https://doi.org/10.1016/j.phrs.2020.105367
Zhou Y, Huang Z, Su J, Li J, Zhao S, Wu L et al (2020) Benserazide is a novel inhibitor targeting PKM2 for melanoma treatment. Int J Cancer 147(1):139–151. https://doi.org/10.1002/ijc.32756
Zhou Y, Tao L, Zhou X, Zuo Z, Gong J, Liu X et al (2021) DHODH and cancer: promising prospects to be explored. Cancer Metab 9(1):22. https://doi.org/10.1186/s40170-021-00250-z
Zhu W, Ye L, Zhang J, Yu P, Wang H, Ye Z et al (2016) PFK15, a small molecule inhibitor of pfkfb3, induces cell cycle arrest, apoptosis and inhibits invasion in gastric cancer. PLoS ONE 2611(9):e0163768
Zhu S, Guo Y, Zhang X, Liu H, Yin M, Chen X et al (2021) Pyruvate kinase M2 (PKM2) in cancer and cancer therapeutics. Cancer Lett 503:240–248. https://doi.org/10.1016/j.canlet.2020.11.018
Zhu L, Li K, Liu M, Liu K, Ma S, Cai W (2022) Anti-cancer research on arnebiae radix-derived naphthoquinone in recent five years. Recent Pat Anticancer Drug Discov 17(3):218–230. https://doi.org/10.2174/1574892816666211209164745
Zou J, Du K, Li S, Lu L, Mei J, Lin W et al (2021) Glutamine metabolism regulators associated with cancer development and the tumor microenvironment: a pan-cancer multi-omics analysis. Genes (basel). 12(9):1305. https://doi.org/10.3390/genes12091305
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Liu, D., Wang, H., Li, X. et al. Small molecule inhibitors for cancer metabolism: promising prospects to be explored. J Cancer Res Clin Oncol 149, 8051–8076 (2023). https://doi.org/10.1007/s00432-022-04501-4
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DOI: https://doi.org/10.1007/s00432-022-04501-4