Summary
In the 1920s, Dr Otto Warburg first suggested the significant difference in energy metabolism between malignant cancer cells and adjacent normal cells. Tumor cells mainly adopt the glycolysis as energy source to maintain tumor cell growth and biosynthesis under aerobic conditions. Investigation on energy metabolism pathway in cancer cells has aroused the interest of cancer researchers all around the world. In recent years, plentiful studies suggest that targeting the peculiar cancer energy metabolic pathways, including glycolysis, mitochondrial respiration, amino acid metabolism, and fatty acid oxidation may be an effective strategy to starve cancer cells by blocking essential nutrients. Natural products (NPs) are considered as the “treasure trove of small molecules drugs” and have played an extremely remarkable role in the discovery and development of anticancer drugs. And numerous NPs have been reported to act on cancer energy metabolism targets. Herein, a comprehensive overview about cancer energy metabolism targets and their natural-occurring inhibitors is prepared.
Similar content being viewed by others
References
Baker DD, Chu M, Oza U, et al. The value of natural products to future pharmaceutical discovery. Nat Prod Rep, 2007,24(6):1225–1244
Harvey AL. Natural products in drug discovery. Drug Discov Today, 2008,13(19–20):894
Amin AR, Kucuk O, Khuri FR, et al. Perspectives for cancer prevention with natural compounds. J Clin Oncol, 2009,27(16):2712–2725
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 2009,324(5930):1029–1033
Ganapathy V, Thangaraju M, Prasad PD. Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. Pharmacol Therapeut, 2009,121(1):29–40
Godoy A, Ulloa V, Rodriguez F, et al. Differential subcellular distribution of glucose transporters GLUT1-6 and GLUT9 in human cancer: ultrastructural localization of GLUT1 and GLUT5 in breast tumor tissues. J Cell Physiol, 2006,207(3):614–627
Macheda ML, Rogers S, Best JD. Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol, 2005,202(3):654–662
Deng D, Xu C, Sun P, et al. Crystal structure of the human glucose transporter GLUT1. Nature, 2014,510(7503):121–125
Ho YY, Yang H, Klepper J, et al. Glucose transporter type 1 deficiency syndrome (Glut1DS): mthylxanthines potentiate GLUT1 haploinsufficiency in vitro. Pediatr Res, 2001,50(2):254–260
Steinfelder HJ, Pethö-Schramm S. Methylxanthines inhibit glucose transport in rat adipocytes by two independent mechanisms. Biochem Pharmacol, 1990,40(5):1154–1157
Ojeda P, Pérez A, Ojeda L, et al. Noncompetitive blocking of human GLUT1 hexose transporter by methylxanthines reveals an exofacial regulatory binding site. Am J Physiol Cell Physiol, 2012,303(5):C530
Krasnov GS, Dmitriev AA, Lakunina VA, et al. Targeting VDAC-bound hexokinase II: a promising approach for concomitant anti-cancer therapy. Expert Opin Ther Targets, 2013,17(10):1221–1233
Patra KC, Wang Q, Bhaskar PT, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell, 2013,24(3):399
Bao F, Yang K, Wu C, et al. New natural inhibitors of hexokinase 2 (HK2): steroids from ganoderma sinense. Fitoterapia, 2018,125:123–129
Jacquin MA, Chiche J, Zunino B, et al. GAPDH binds to active Akt, leading to Bcl-XL increase and escape from caspase-independent cell death. Cell Death Differ, 2013,20(8):1043
Ganapathy-Kanniappan S, Kunjithapatham R, Geschwind JF. Glyceraldehyde-3-phosphate dehydrogenase: a promising target for molecular therapy in hepatocellular carcinoma. Oncotarget, 2012,3(9):940
Krasnov GS, Dmitriev AA, Snezhkina AV, et al. Deregulation of glycolysis in cancer: glyceraldehyde-3-phosphate dehydrogenase as a therapeutic target. Expert Opin Ther Targets, 2013,17(6):681–693
Itoh Y, Kodama K, Furuya K, et al. A new sesquiterpene antibiotic, heptelidic acid. Producing organisms, fermentation, isolation and characterization. J Antibiot, 1980,33(5):468
Rahier NJ, Molinier N, Long C, et al. Anticancer activity of koningic acid and semisynthetic derivatives. Bioorg Med Chem Lett, 2015,23(13):3712–3721
Everse J, Kaplan NO. Lactate dehydrogenases: structure and function. Adv Enzymol Relat Areas Mol Biol, 1973,37:61–133
Manerba M, Vettraino M, Fiume L, et al. Galloflavin (CAS 568-80-9): a novel inhibitor of lactate dehydrogenase. Chemmedchem, 2012,7(2):311–317
Farabegoli F, Vettraino M, Manerba M, et al. 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, 2012,47(4):729
Takada M, Nakamura Y, Koizumi T, et al. Suppression of human pancreatic carcinoma cell growth and invasion by epigallocatechin-3-gallate. Pancreas, 2002,25(1):45–48
Zhang L, Pang E, Loo R, et al. Concomitant inhibition of HSP90, its mitochondrial localized homologue TRAP1 and HSP27 by green tea in pancreatic cancer HPAF-II cells. Proteomics, 2011,11(24):4638
Lu QY, Zhang L, Yee JK, et al. Metabolic consequences of LDHA inhibition by epigallocatechin gallate and oxamate in MIA PaCa-2 pancreatic cancer cells. Metabolomics, 2015,11(1):71–80
Sonveaux P, Copetti T, De Saedeleer CJ, et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One, 2012,7(3):e33418
Sonveaux P, Vegran F, Schroeder T, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest, 2008,118(12):3930–3942
Morris ME, Zhang S. Flavonoid–drug interactions: effects of flavonoids on ABC transporters. Life Sci, 2006,78(18):2116–2130
Wang Q, Morris ME. Flavonoids modulate monocarboxylate transporter-1-mediated transport of gamma-hydroxybutyrate in vitro and in vivo. Drug Metab Dispos, 2007,35(2):201–208
Zhang S, Morris ME. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport. J Pharmacol Exp Ther, 2003,304(3):1258–1267
Shim CK, Cheon EP, Kang KW, et al. Inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells. J. Pharm. Pharmacol, 2007,59(11):1515–1519
Jolad SD, Hoffmann JJ, Schram KH, et al. Structures of zeylenol and zeylena, constituents of Uvaria zeylanica (annonaceae). J Org Chem, 1982,46:4267–4272
Motoyama T, Yabunaka H, Miyoshi H. Essential structural factors of acetogenins, potent inhibitors of mitochondrial complex I. ACS Med Chem Lett, 2002,12(16):2089–2092
Schlie-Guzmán MA, García-Carrancá A, González-Esquinca AR. In vitro and in vivo antiproliferative activity of laherradurin and cherimolin-2 of Annona diversifolia Saff. Phytother Res, 2010,23(8):1128–1133
Yuan SS, Chang HL, Chen HW, et al. Annonacin, a mono-tetrahydrofuran acetogenin, arrests cancer cells at the G1 phase and causes cytotoxicity in a Bax- and caspase-3-related pathway. Life Sci, 2003,72(25):2853–2861
De PN, Cautain B, Melguizo A, et al. Mitochondrial complex I inhibitors, acetogenins, induce HepG2 cell death through the induction of the complete apoptotic mitochondrial pathway. J Bioenerg Biomembr, 2013,45(1–2):153–164
Hui YH, Rupprecht JK, Liu YM, et al. Bullatacin and bullatacinone: two highly potent bioactive acetogenins from Annona bullata. J Nat Prod, 1989,52(3):463–477
Morré DJ, De CR, Farley C, et al. Mode of action of bullatacin, a potent antitumor acetogenin: Inhibition of NADH oxidase activity of HELA and HL-60, but not liver, plasma membranes. Life Sci, 1995,56(5):343–348
Wolvetang EJ, Johnson KL, Krauer K, et al. Mitochondrial respiratory chain inhibitors induce apoptosis. FEBS Lett, 1994,339(1–2):40
Chiu HF, Chih TT, Hsian YM, et al. Bullatacin, a potent antitumor Annonaceous acetogenin, induces apoptosis through a reduction of intracellular cAMP and cGMP levels in human hepatoma 2.2.15 cells. Biochem. Pharmacol, 2003,65(3):319–327
Meyer KJ, Singh AJ, Cameron A, et al. Mitochondrial genome-knockout cells demonstrate a dual mechanism of cction for the electron transport Complex I inhibitor mycothiazole. Mar Drugs, 2012,10(4):900–917
Crews P, Kakou Y, Quinoa E. Mycothiazole, a polyketide heterocycle from a marine sponge. J Am Chem Soc, 1988,110(13):4365–4368
Liu Q, Shu X, Sun A, et al. Plant-derived small molecule albaconol suppresses LPS-triggered proinflammatory cytokine production and antigen presentation of dendritic cells by impairing NF-kappaB activation. Int Immunopharmacol, 2008,8(8):1103–1111
Deng Q, Yu X, Xiao L, et al. Neoalbaconol induces energy depletion and multiple cell death in cancer cells by targeting PDK1-PI3-K/Akt signaling pathway. Cell Death Dis, 2013,19(4):e804
Schulte ML, Fu A, Zhao P, et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med, 2018,24(2):194–202
Schulte ML, Hight MR, Ayers GD, et al. Non-invasive glutamine pet reflects pharmacological inhibition of BRAF(V600E) in vivo. Mol Imaging Biol, 2017,19(3):421–428
Mates JM, Segura JA, Martin-Rufian M, et al. Glutaminase isoenzymes as key regulators in metabolic and oxidative stress against cancer. Curr Mol Med, 2013,13(4):514–534
Hartwick EW, Curthoys NP. BPTES inhibition of hGA(124-551), a truncated form of human kidney-type glutaminase. J Enzym Inhib Med Ch, 2012,27(6):861
Wang JB, Erickson JW, Fuji R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell, 2010,18(3):207
Wu C, Zheng M, Gao S, et al. A natural inhibitor of kidney-type glutaminase: a withanolide from with potent anti-tumor activity. Oncotarget, 2017,8(69): 113 516–113 530
Cheng L, Wu CR, Zhu LH, et al. Physapubescin, a natural withanolide as a kidney-type glutaminase (KGA) inhibitor. ACS Med Chem Lett, 2017,27(5):1243
Li C, Allen A, Kwagh J, et al. Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. J Biol Chem, 2006,281(15):10 214–10 221
Li C, Li M, Chen P, et al. Green tea polyphenols control dysregulated glutamate dehydrogenase in transgenic mice by hijacking the ADP activation site. J Biol Chem, 2011,286(39):34 164–34 174
Li M, Li C, Allen A, et al. Glutamate dehydrogenase: structure, allosteric regulation, and role in insulin homeostasis. Neurochem Res, 2014,39(3):433–445
Anglin J, Zavareh RB, Sander PN, et al. Discovery and optimization of aspartate aminotransferase 1 inhibitors to target redox balance in pancreatic ductal adenocarcinoma. ACS Med Chem Lett, 2018,28(16):2675–2678
Holt MC, Assar Z, Beheshti Zavareh R, et al. Biochemical characterization and structure-based mutational analysis provide insight into the binding and mechanism of action of novel aspartate aminotransferase Inhibitors. Biochemistry, 2018,57(47):6604–6614
Thornburg JM, Nelson KK, Clem BF, et al. Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res, 2008,10(5):R84
Sun W, Luan S, Qi C, et al. Aspulvinone O, a natural inhibitor of GOT1 suppresses pancreatic ductal adenocarcinoma cells growth by interfering glutamine metabolism. Cell Commun Signal, 2019,17(1):111
Guo J, Gu X, Zheng M, et al. Azacoccone E inhibits cancer cell growth by targeting 3-phosphoglycerate dehydrogenase. CS Med Chem Lett, 2019,87:16–22
Xu Y, Barringer S. Comparison of volatile release in tomatillo and different varieties of tomato during chewing. J Food Sci, 2010,75(4):C352–358
Zheng M, Guo J, Xu J, et al. Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH. Food Funct, 2019,10(6):3386–3395
Donner J, Reck M, Bergmann S, et al. The biofilm inhibitor Carolacton inhibits planktonic growth of virulent pneumococci via a conserved target. Sci Rep, 2016,6:29677
Kunze B, Reck M, Dotsch A, et al. Damage of Streptococcus mutans biofilms by carolacton, a secondary metabolite from the myxobacterium Sorangium cellulosum. BMC Microbiol, 2010,10:199
Jansen R, Irschik H, Huch V, et al. Carolacton-a macrolide ketocarbonic acid that reduces biofilm formation by the caries-and endocarditis-associated bacterium streptococcus mutans. European J Org Chem, 2010,7:1284–1289
Fu C, Sikandar A, Donner J, et al. The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. Nat Commun, 2017,8(1):1529
Sanchez-Macedo N, Feng J, Faubert B, et al. Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model. Cell Death Differ, 2013,20(4):659–668
Ricciardi MR, Mirabilii S, Allegretti M, et al. Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias. Blood, 2015, 126(16):1925–1929
Tseng CC, Noordali H, Sani M, et al. Development of fluorinated analogues of perhexiline with improved pharmacokinetic properties and retained efficacy. J Med Chem, 2017,60(7):2780–2789
Khwairakpam AD, Shyamananda MS, Sailo BL, et al. ATP citrate lyase (ACLY): a promising target for cancer prevention and treatment. Curr Cancer Drug Targets, 2015,16(2):156–163
Fassina P, Scherer Adami F, Terezinha Zani V, et al. The effect of garcinia cambogia as coadjuvant in the weight loss process. Nutr Hosp, 2015,32(6):2400–2408
Watson JA, Fang M, Lowenstein JM. Tricarballylate and hydroxycitrate: substrate and inhibitor of ATP: citrate oxaloacetate lyase. Arch Biochem Biophys, 1969,135(1):209–217
Liu Y, Ji H, Dong J, et al. Antioxidant alkaloid from the South China Sea marine sponge Iotrochota sp. Z Naturforsch C J Biosci, 2008,63(9–10):636–63
Oleynek JJ, Barrow CJ, Burns MP, et al. Anthrones, naturally occurring competitive inhibitors of adenosine-triphosphate-citrate lyase. Drug Dev Res, 2010,36(1):35–42
Yamamoto Y, Kiriyama N, Arahata S. Studies on the metabolic products of Aspergillus fumigatus (J-4). Chemical structure of metabolic products. Chem Pharm Bull, 1968,16(2):304
Barrow CJ, Oleynek JJ, Marinelli V, et al. Antimycins, inhibitors of ATP-citrate lyase, from a streptomyces sp. J Antibiot, 2010,50(9):729–733
Gao Y, Islam MS, Tian J, et al. Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth. Cancer Lett, 2014,349(1):15–25
Koerner SK, Hanai JI, Bai S, et al. Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase. Eur J Med Chem, 2017,126:920–928
Deng Z, Wong NK, Guo Z, et al. Dehydrocurvularin is a potent antineoplastic agent irreversibly blocking ATP-citrate lyase: evidence from chemoproteomics. Chem Commun, 2019,55(29):4194–4197
Chajes V, Cambot M, Moreau K, et al. Acetyl-CoA carboxylase alpha is essential to breast cancer cell survival. Cancer Res, 2006,66(10):5287–5294
Koen B, Ellen DS, Guido V, et al. RNA interference-mediated silencing of the acetyl-CoA-carboxylase-alpha gene induces growth inhibition and apoptosis of prostate cancer cells. Cancer Res, 2005,65(15):6719–6725
Svensson RU, Shaw RJ. Lipid synthesis is a metabolic liability of non-small cell lung cancer. Cold Spring Harb Symp Quant Biol, 2016,81:93–103
Gerth K, Pradella S, Perlova O, et al. Myxobacteria: proficient producers of novel natural products with various biological activities-past and future biotechnological aspects with the focus on the genus Sorangium. J Biotechnol, 2003,106(2–3):233–253
Beckers A, Organe S, Timmermans L, et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res, 2007,67(17):8180–8187
Omura S. The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. Bacteriol Rev, 1976,40(3):681–697
Kuhajda FP. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition, 2000,16(3):202–208
Pizer ES, Chrest FJ, DiGiuseppe JA, et al. Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Cancer Res, 1998,58(20):4611–4615
Menendez JA, Vellon L, Lupu R. Antitumoral actions of the anti-obesity drug orlistat (XenicalTM) in breast cancer cells: blockade of cell cycle progression, promotion of apoptotic cell death and PEA3-mediated transcriptional repression of Her2/neu (erbB-2) oncogene. Ann Oncol, 2005,16(8):1253–1267
Wang X, Tian W. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. Biochem Biophys Res Commun, 2001,288(5):1200–1206
Wang X, Song KS, Guo QX, et al. The galloyl moiety of green tea catechins is the critical structural feature to inhibit fatty-acid synthase. Biochem Pharmacol, 2003,66(10):2039
Wang X, Tian W. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. Biochem Bioph Res Co, 2001,288(5):1200–1206
Brusselmans K, Vrolix R, Verhoeven G, et al. Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity. J Biol Chem, 2005,280(7):5636–5645
Lv ZD, Liu XP, Zhao WJ, et al. Curcumin induces apoptosis in breast cancer cells and inhibits tumor growth in vitro and in vivo. Int J Clin Exp Patho, 2014,7(6):2818–2824
Guan F, Ding Y, Zhang Y, et al. Curcumin suppresses proliferation and migration of MDA-MB-231 breast cancer cells through autophagy-dependent Akt degradation. PLoS One, 2016,11(1):e0146553
Younesian O, Kazerouni F, Omrani D, et al. Effect of curcumin on fatty acid synthase expression and enzyme activity in breast cancer cell line SKBR3. Int J Cancer Manag, 2017, In Press(In Press)
Lee KH, Lee MS, Cha E Y, et al. Inhibitory effect of emodin on fatty acid synthase, colon cancer proliferation and apoptosis. Mol Med Rep, 2017,15(4):2163
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
None.
Additional information
This work was financially supported by grants from the National Natural Science Foundation of China (No. 81773594, U1703111, 81473254 and 81773637, 31270399), Liaoning Revitalization Talents Program (No. XLYC1807182), Program for Liaoning Innovation Talents in University (No. LR2016002), Liaoning Province Natural Science Foundation (No. 2019-MS-299), and Shenyang Planning Project of Science and Technology (No. 18-013-0-46).
Rights and permissions
About this article
Cite this article
Wang, Qq., Li, Mx., Li, C. et al. Natural Products and Derivatives Targeting at Cancer Energy Metabolism: A Potential Treatment Strategy. CURR MED SCI 40, 205–217 (2020). https://doi.org/10.1007/s11596-020-2165-5
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11596-020-2165-5