Targeting Tumor Metabolism with Plant-Derived Natural Products

Review Cite This: J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Targeting Tumor Metabolism with Plant-Derived Natural Products: Emerging Trends in Cancer Therapy Angela R. Guerra,†,‡ Maria F. Duarte,*,†,§ and Iola F. Duarte*,‡

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†

Centro de Biotecnologia Agrícola e Agro-Alimentar do Alentejo (CEBAL), Instituto Politécnico de Beja, Apartado 6158, 7801-908 Beja, Portugal ‡ CICECO - Instituto de Materiais de Aveiro, Departamento de Quı ́mica, Universidade de Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal § ICAAM - Instituto de Ciências Agrárias e Ambientais Mediterrânicas, Universidade de É vora, Pólo da Mitra, 7006-554 É vora, Portugal ABSTRACT: Recognition of neoplastic metabolic reprogramming as one of cancer’s hallmarks has paved the way for developing novel metabolism-targeted therapeutic approaches. The use of plant-derived natural bioactive compounds for this endeavor is especially promising, due to their diverse structures and multiple targets. Hence, over the past decade, a growing number of studies have assessed the impact of phytochemicals on tumor cell metabolism, aiming at improving current knowledge on their mechanisms of action and, at the same time, evaluating their potential as anti-cancer metabolic modulators. In this Review, we focus on three classes of plant-derived compounds with promising anti-cancer activityphenolic compounds, isoprenoids, and alkaloidsto describe their effects on major energetic and biosynthetic pathways of human tumor cells. Such a comprehensive and integrated account of the ability of these compounds to hit different metabolic targets is expected to contribute to the rational design and critical assessment of novel anti-cancer therapies based on natural-productmediated metabolic reprogramming. KEYWORDS: cancer, metabolism, energetic and biosynthetic pathways, tumor cells, phenolics, isoprenoids, alkaloids

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INTRODUCTION The continuous evolution of cell biology research has expanded our understanding of cancer as a complex and diverse set of diseases. Nevertheless, a number of common traits that support tumor formation, growth, and metastasis have been described, as thoroughly revisited by Hanahan and Weinberg.1,2 Particularly, it has become evident that tumor initiation and progression strongly rely on the reprogramming of cell metabolism, mainly to support increased needs for ATP generation and macromolecules biosynthesis, as well as to maintain a tight control of redox balance. The initial observation by Otto Warburg describing the ability of cancer cells to carry out aerobic glycolysis, a phenomenon known as the “Warburg effect”,3 is currently recognized as a small part of all metabolic rearrangements undertaken by cells in oncogenesis. Indeed, tumor cells have been found to display a range of alterations in intracellular metabolic pathways and in metabolic interactions with the microenvironment, to opportunistically modulate nutrient uptake, and to drive changes in gene regulation.4 Hence, targeting tumor cell metabolism to achieve therapeutic benefit in cancer treatment has been continuously harnessing increased interest. From the discovery and clinical success of anti-folate drugs in the early twentieth century, to the nucleoside analogues a few years later, anti-metabolites have been used for decades in the treatment of several types of cancer.5,6 Their considerable success offered the proof-ofconcept for this type of therapies. Currently, diverse metabolic targets are being exploited for their therapeutic potential, and © XXXX American Chemical Society

several metabolism-targeted drugs are being tested, both in preclinical cancer models and in clinical studies.7,8 Although natural products have historically driven pharmaceutical industry in the discovery of new drugs, their use as lead compounds has declined in the past two decades, mainly due to limited compatibility with the high-throughput screening and fragment-based approaches used in pharmaceutical companies.9 Indeed, isolation of suitable quantities of pure compounds from complex natural mixtures is often a major problem, and laboratory synthesis can include a series of laborious and time-consuming steps. In recent years, the interest in these compounds has however re-emerged, partially due to the disappointing results of large screening collections of synthetic molecules, but most of all, due to the broad range of pharmacophores in plant-derived compounds and their high degree of stereochemistry. Such high structural diversity, together with remarkable biological activities and reported bioavailability and tolerability (as many are dietary components), makes plant-derived compounds exquisitely suitable candidates for the development of novel therapeutic agents. This endeavor is further facilitated by novel bioinformatics approaches, which provide new tools to predict the molecular targets of natural products, thus simplifying the discovery phase.10 Moreover, the establishment of natural productsinspired libraries may allow the transposition of significant Received: Revised: Accepted: Published: A

August 1, 2018 September 18, 2018 September 18, 2018 September 19, 2018 DOI: 10.1021/acs.jafc.8b04104 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry

Figure 1. Schematic overview of main metabolic targets of plant-derived natural compounds (as listed in Tables 1−3). The three compound classes are highlighted in blue (phenolics), yellow (isoprenoids) and purple (alkaloids).

pathways involved in carcinogenic processes, hitting multiple targets and offering increased chances of success. A particularly interesting feature is the recognizably strong interconnection between tumor-specific signaling pathways and metabolic adaptations.14 Hence, significant efforts have been recently conducted to elucidate how plant-derived natural compounds may act as modulators of tumor cell metabolism and, in this way, exert anti-cancer activity. In this Review, we will address the opportunities and challenges regarding the use of plant-derived natural compounds as modulators of tumor cell metabolism. First, a

characteristics to more adaptable synthetic molecules. In the field of cancer chemotherapy, natural product-inspired drugs represent a considerable number of anti-tumor agents on the market.11 Several plant-derived compounds are being extensively studied for their anti-cancer activity in a broad range of cancer models, of which some have reached clinical trials.12,13 One promising advantage is that such compounds could be used not only on their own, but also combined with standard therapies, potentially promoting synergistic effects and reducing undesired secondary effects. Additionally, many plant-derived molecules have been shown to modulate diverse B

DOI: 10.1021/acs.jafc.8b04104 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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deoxy-D-glucose (2-DG) or by 3-bromopyruvate (3BP) has been amply shown to efficiently block glycolysis in tumor cells and to potentiate the anti-cancer effects of other drugs. However, toxicity issues have limited the use of these compounds in the clinic.29,30 Another important glycolytic checkpoint is the conversion of fructose 6-phosphate to fructose 1,6-bisphosphate by phosphofructokinases (PFKs). PFK1 can be activated by oncogenes or the hypoxia-inducible factor (HIF)-1α, and its activity has been reported to be increased in malignant cells.31 Moreover, triggering Akt phosphorylation could potentially release PFK from ATP inhibition, leading to enzyme activation.32 On the other hand, fructose-2,6-bisphosphate is the most effective allosteric activator of PFK, suggesting upregulation of enzyme activity to be dependent on high levels of fructose-2,6bisphosphate in cancer cells.33 The production and degradation of fructose-2,6-bisphosphate are, in turn, supported by a family of bifunctional enzymes, the 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatases (PFKFB), more specifically PFKFB3. PFKFB3 is often overexpressed in human cancers and has an important role in cell proliferation through regulation of cell cycle.33 In the last committed step of glycolysis, pyruvate kinases (PK) catalyze the conversion of phosphoenolpyruvate (PEP) to pyruvate, with concomitant production of ATP. There are four mammalian PK isoenzymes with distinctive tissue expression: L (major isoform in the liver), R (found in red blood cells), M1 (present mainly in the heart, brain, and muscle), and M2 (expressed in some differentiated tissues, such as the lungs and fat tissue, as well as in cells of the intestinal epithelium). PKM1 and PKM2 are encoded by the same gene through alternative splicing, and their relative expression in cells relates to the preference for either glycolysis or oxidative phosphorylation.34 While normal adult cells preferentially express PKM1, rapid proliferating tumor cells and non-malignant proliferating cells abundantly express PKM2.35 Both metabolic and non-metabolic functions of PKM2 promote cancer cells growth, thus specific PKM2 inhibitors have been studied, and a peptidic inhibitor of PKM2 has entered Phase II clinical trials.36 However, in several tumor types (cell lines), PKM2 expression is accompanied by decreased pyruvate kinase activity, thus contributing to attenuation of this last glycolytic step, in opposition to the upstream increase in glucose flux.34 Hence, it is still unclear how PKM2 can be used as a metabolic target in cancer therapy. Tumor cells typically display increased generation of lactate from pyruvate, a reaction catalyzed by lactate dehydrogenases (LDH), whereby NAD+ is regenerated allowing for the glycolytic flux to be maintained. The five active LDH isoenzymes in human tissues are combinations of two different subunits, H and M, encoded by LDHA and LDHB genes, respectively.37 The LDHA isoform is known to be overexpressed in many tumors, while inhibiting its activity was demonstrated to decrease metastatic and invasive potential of cancer cells.37 Hence, LDHA has receive much attention, not only as a potential metabolic target, but also as a predictive biomarker for cancer. Indeed, high serum LDH has been positively correlated with an increased risk of death from prostate, pulmonary, colorectal, gastro-esophageal, gynecological, and hematological cancers.38 Monocarboxylate transporters (MCTs), which export intracellular lactate, are often upregulated in tumors, with MCT4 expression having been

brief overview of the main metabolic proteins/enzymes known to be differentially expressed or deregulated in tumor cells will be presented. This is expected to provide basic background information on cancer metabolism, which may be complemented by other available reviews.4,15,16 Second, the effects on major tumor cell energetic and biosynthetic pathways reported for compounds belonging to three main chemical families phenolics, isoprenoids, and alkaloidswill be reviewed. The information is systematized in Tables 1−3, and in Figure 1, while some examples are further explored in the text. Although other recent reviews have addressed either a specific family of natural compounds17,18 or particular metabolic pathways,19−21 to our knowledge, a comprehensive and state-of-the-art account on the metabolic impact of plant-derived natural compounds (organized by chemical class), as hereby presented, has not been published, entailing a new and substantial contribution to current literature. Such systematic review is expected to offer an integrated view on the ability of these compounds to hit different metabolic targets, and should enable the therapeutic potential of natural product-mediated metabolic reprogramming to be critically ascertained.

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OVERVIEW OF MAIN METABOLIC TARGETS IN TUMOR CELL ENERGETIC AND BIOSYNTHETIC PATHWAYS Cancer cells undergo profound metabolic reprogramming to sustain survival and proliferation, with compelling evidence showing strong interconnections between cancer-related signaling pathways and several metabolic alterations.7 Indeed, such alterations are currently considered to actively participate in the process of tumor development, by conferring malignant cells survival advantages, rather than being mere end points of oncogenic activation. This has led to the identification of novel therapeutic targets within tumor cell energetic and biosynthetic pathways. Glucose is the most abundant nutrient in blood and the primary substrate for mammalian cells’ metabolism. The transport of glucose across the cell membrane is mediated by two classes of hexose transporters: the sodium-dependent glucose co-transporters (SGLTs) and the family of glucose transporters (GLUTs). GLUTs are part of the major facilitator superfamily (MFS), and their many isoforms differ mainly in substrate recognition and tissue distribution, while possessing a similar transmembrane anatomy.22,23 Class I facilitative glucose transporters encompass the classical transporters GLUT1−4.24 GLUT1 is the most widely distributed isoform, and is frequently overexpressed in cancer, being correlated with poor survival in most solid tumors.25 Hence, GLUTs, in particular GLUT 1, represent potential anti-cancer targets, for which several compounds are being currently investigated.26 While differentiated non-proliferating cells obtain most of their energy through oxidative phosphorylation in the mitochondria, tumor cells typically display intensified glycolytic flux and lactate production, which constitute an advantage for rapid energy generation, biomass accumulation, redox maintenance, and facilitation of tumor invasion.27 Several isoforms of rate-limiting glycolytic enzymes have been found differentially expressed in tumor cells. Among hexokinases (HKs), which phosphorylate glucose to glucose-6-phosphate within the first committed (irreversible) step of glycolysis, HK2 has been reported to be highly expressed in malignant cells, in contrast with HK1, abundantly expressed in normal tissues.28 Indeed, inhibition of HK2 by the glucose analogue 2C


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Journal of Agricultural and Food Chemistry correlated with worse prognosis in diverse types of cancers.39 Their activity is required to sustain the metabolic phenotype of cancer cells, thus supporting the idea to explore MCTs in anticancer therapy, either as specific molecular targets or as drug transporters.40 Elevated glucose uptake and glycolytic flux, together with attenuation of the last committed glycolytic reaction, contribute to fueling anabolic pathways required for tumor cell growth and proliferation, such as the pentose phosphate pathway (PPP) and the serine biosynthesis pathway. The PPP makes use of glycolytic intermediates to generate NADPH, essential for fatty acid synthesis and antioxidant defense,41 as well as ribose-5-phosphate, needed for nucleotide biosynthesis. Human cancer cells express relatively high levels of glucose-6-phosphate dehydrogenase (G6PD), involved in the oxidative branch of the PPP, and some tumor suppressors are thought to modulate PPP through G6PD activity.42 6-phosphogluconate dehydrogenase (6PGD) is also upregulated in several human cancers and, recently, it was shown that suppression of this enzyme in tumor cells resulted in decreased levels of lipogenesis and RNA biosynthesis, together with increased reactive oxygen species (ROS) generation.43 This process was proposed to be mediated by ribulose-5-phosphate, a product of 6PGD, through inhibition of LKB1-AMP-activated protein kinase (AMPK) signaling. Transketolase (TKT) and trans-aldolase (TALDO1) are key enzymes of the non-oxidative branch of the PPP, which is usually engaged by cancer cells to generate ribonucleotides de novo for the synthesis of RNA and DNA.41 TALDO1 has been reported to be increased in head and neck squamous cell carcinoma, brain, bladder, breast, and esophageal cancers, while TKT was shown to be upregulated and associated with aggressive clinicopathology in hepatocellular carcinoma (HCC).44 Other branches diverting from glycolysis and implicated in cancer are the serine biosynthesis pathway, through which non-essential amino acids are generated, and the subsequent one-carbon metabolism cycle, required for methylation reactions, as well as for purine and glutathione (GSH) biosynthesis. Some tumor types (cell lines) show amplification or overexpression of phosphoglycerate dehydrogenase (PHGDH), which catalyzes the first step in the serine biosynthesis pathway. Hence, its inhibition could selectively target tumor cells with upregulated de novo serine biosynthesis.45 In addition to glucose, glutamine is another crucially important substrate for tumor cell growth and metabolism. This non-essential amino acid not only supplies nitrogen for the biosynthesis of other amino acids, nucleic acids, and hexosamines, as it is metabolized via the tricarboxylic acid (TCA) cycle, replenishing depleted intermediates and contributing to energy generation.46 Furthermore, glutamine is an alternative carbon donor to lipid synthesis, via reductive carboxylation to citrate, and is involved in the synthesis of GSH, an important anti-oxidant in cells.46 Hence, glutamine metabolism is another appealing therapeutic target, and drug strategies are being specially directed to the inhibition of glutaminase, the enzyme responsible for the conversion of glutamine to glutamate.8 Promotion of pyruvate mitochondrial oxidation, modulation of TCA cycle enzymes, and interference with respiratory chains complexes have also been exploited as possible therapeutic targets.8 The pyruvate dehydrogenase complex (PDC), which is responsible for converting pyruvate into acetyl-CoA

(required to feed the TCA cycle, de novo lipogenesis, and protein acetylation), is negatively regulated by pyruvate dehydrogenase kinases (PDKs). These enzymes are typically overexpressed in cancer cells, often as a result of HIF activation, partially explaining their diminished mitochondrial function.47,48 Pharmacological inhibition of PDKs with dichloroacetate stimulates the pyruvate-to-acetyl-CoA flux, thus promoting the TCA cycle.49 Notably, this compound has already entered clinical trials with promising results. TCA cycle reactions are catalyzed by multiple enzymes which can be either mutated or deregulated in malignant tissues. Indeed, some drugs targeting TCA cycle enzymes, such as aconitase (AH), isocitrate dehydrogenase (IDH), fumarate hydratase (FH), or succinate dehydrogenase (SDH), are currently under investigation.7 Furthermore, the anti-cancer effect obtained from inhibiting mitochondrial respiratory complexes has also been highlighted. For instance, metformin, a glucose-lowering drug derived from guanidines of Galega of f icinalis, is a complex-I inhibitor under evaluation within several cancer clinical trials.50 As rapidly proliferating cells have increased demand for lipids and steroids, in order to sustain the production of phospholipid bilayers and signaling molecules, several enzymes involved in lipid synthesis have been associated with tumor progression and pinpointed as potential therapeutic targets.51 ATP citrate lyase (ACL) is the primary enzyme responsible for converting citrate into the lipogenic precursor acetyl-CoA, linking glucose and glutamine metabolisms to fatty acids synthesis. ACL is overexpressed in a large number of human cancers, being under direct regulation of the PI3K/Akt pathway.52 Acetyl-CoA carboxylase (ACC) catalyzes the conversion of acetyl-CoA into malonyl-CoA, a rate-limiting step in the fatty acid synthesis pathway. The overexpression of ACC1, found in several cancers, has been correlated with tumor progression and poor prognosis.53 On the other hand, AMPK was shown to directly phosphorylate and inactivate ACC1, through decreased expression of sterol regulatory element binding protein 1 (SREBP1).16 Fatty acid synthase (FAS) is another key enzyme in lipogenesis. FAS is a complex multifunctional enzyme that catalyzes the terminal steps of de novo fatty acid synthesis, the successive condensation reactions from malonyl-CoA and acetyl-CoA substrates to form palmitate.54 Many cancer cells have shown overexpression of this enzyme; hence, several inhibitors have been developed, and their efficacy assessed in preclinical models.51 Other enzymes involved in fatty acid synthesis and modification, which were found to be upregulated in some human cancers, include acyl-CoA synthetases (ACS)53 and stearoyl-CoA desaturases (SCDs).55 Furthermore, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and choline kinase, involved in cholesterol and choline synthesis, respectively, have recognized roles in tumor development, and some inhibitors were also evaluated in preclinical trials.8

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PLANT-DERIVED NATURAL PRODUCTS AS ANTI-CANCER METABOLIC MODULATORS Phenolic Compounds. Phenolic compounds are a major class of plant secondary metabolites bearing hydroxylated aromatic ring(s), which comprises phenolic acids, cinnamic acids, coumarins, flavonoids, xanthones, and stilbenes.56 A wide range of studies have shown the multiple effects of phenolic compounds on human health. These compounds are especially known for their potent anti-oxidant, anti-cancer, D


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Table 1. Effects of Phenolic Compounds on Energetic and Biosynthetic Metabolic Pathways of Human Tumor Cells compound

tumor cells

metabolic effects

reference

1-(+)-acetoxypinoresinol

breast (SK-BR-3, MCF-7)

↓ FAS protein level

Menendez et al., 200864

amentoflavone

breast (SKBR-3) breast (SKBR-3)

↓ FAS synthesis ↓ FAS protein level

Lee et al., 2009157 Lee et al., 2013158

apigenin

adenoid cystic carcinoma (ACC-2) breast (SKBR-3, MCF-7) colon (HCT116, HT29, DLD-1)

↓ ↓ ↓ ↓

GLUT1 mRNA and protein levels FAS protein level PKM2 protein level and activity glucose uptake, lactate production, and ATP generation ↓ GLUT1 mRNA and protein levels ↓ GLUT1 mRNA and protein levels ↓ glucose uptake, lactate production, and ATP and NADPH generation ↓ glucose uptake ↓ GLUT1 mRNA and protein levels ↑ glucose uptake ↑ GLUT1 and GLUT4 protein levels ↓ glucose uptake ↓ GLUT1 protein levels ↑ GLUT4 protein levels

Fang et al., 201461 Menendez et al., 200864 Shan et al., 201763

laryngeal (Hep-2) lung (H1299, H460)

pancreatic (S2−013 and CD18) prostate (LNCap) prostate (PC-3)

Xu et al., 201460 Lee et al., 201659

Melstrom et al., 200858 Gonzalez-Menendez et al., 201462

baicalen

gastric (AGS)

↓ HK2, LDHA, and PDK1 mRNA and protein levels ↓ glucose uptake, lactate production

Chen et al., 2015159

bavachinin

HeLa derivative (KB)

↓ GLUT1, HK2 mRNA, and protein levels (under hypoxia)

Nepal et al., 2012160

curcumina

breast (MCF-7)

↓ GLUT1 mRNA and protein levels in TNFα-stimulated cell restored glycolysis to basal levels (after TNFα-induced upregulation) ↑ HK2 activity ↑ glucose uptake, lactate production ↓ HK2 mRNA and protein level ↓ FAS activity and mRNA level ↓ HK2 protein level and activity little influence on other glycolytic enzymes (PFK, PGM, LDH) ↓ glucose uptake, lactate production, ATP generation ↓ GLUT4, HK2, PFKFB3, and PKM2 mRNA and protein levels ↓ FAS activity, mRNA, and protein levels ↓ GLUT1 mRNA and protein levels

Vaughan et al., 201365

breast (MCF-7) breast (MDA-MB-231) breast (SK-BR-3) colon (HCT116, HT-29)

esophageal (Ec109) hepatocellular carcinoma (HepG2) lung (A549)

Jung et al., 201670 Geng et al., 201669 Younesian et al., 201772 Wang et al., 201567

Zhang et al., 201568 Fan et al., 201471 Liao et al., 201566

demethoxycurcumin

prostate (LNCaP, DU145, PC-3)

↓ FAS protein level ↑ p-ACC protein level

Hung et al., 2012161

daidzein

breast (MCF-7, MDA-MB-231) prostate (LNCap)

PPP, glucose, and glutamine uptake ↑ glucose uptake ↑ GLUT1 and GLUT4 protein levels ↓ glucose uptake ↓ GLUT1 protein levels ↑ GLUT4 protein levels

Uifalean et al., 2016162 Gonzalez-Menendez et al., 201462

prostate (PC-3)

deguelin

lung (H460, H1650, H1299, H520, HCC827, H1975, H358)

↓ HK2 protein level ↓ glucose uptake, lactate production

Li et al., 2017163

EGCGb

breast (MCF-7)

↓ glucose uptake, lactate production ↑ GLUT1 mRNA levels ↓ FAS mRNA and protein levels

Moreira et al., 201377

breast (MCF-7) E

Yeh et al., 200382 DOI: 10.1021/acs.jafc.8b04104 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Journal of Agricultural and Food Chemistry Table 1. continued compound

tumor cells

metabolic effects

breast (SKBR-3) breast (MDA-MB-231) colon (HT29) colon (HT-29)

hepatocellular carcinoma (HCCLM3, HepG2) lung (A549) lung (NCI-H1299) pancreatic (MIA PaCa-2)

prostate (LNCap)

tongue squamous cell carcinoma (Tca8113, TSCCa)

reference

↓ synthesis of free fatty acids and cholesterol ↓ FAS activity ↓ PGAM1 activity ↓ 2-PG, lactate production ↓ GLUT1 mRNA levels ↑ p-ACC protein level ↓ glucose uptake ↑ glutamine consumption ↓ glutamate enrichment ↓ TKT and G6PD activity ↓ PFK activity, mRNA and protein levels ↓ glucose uptake, lactate production ↓ FAS activity and protein levels ↓ PGAM1 activity ↓ 2-PG, lactate production ↓ glucose uptake, lactate production ↓ TCA cycle anaplerosis ↓acetyl-CoA palmitate synthesis ↓ FAS activity ↑ FAS protein level ↓ synthesis of phospholipids, triglycerides, and cholesterol ↓ HK2 protein level ↓ glucose uptake, lactate production

Puig et al., 200880 Li et al., 201778 Hwang et al., 200773 Sanchez-Tena et al., 201374

Li et al., 201676 Relat et al., 201281 Li et al., 201778 Lu et al., 201583

Brusselmans et al., 200379

Gao et al., 201575

gallic acid

melanoma (B16F10)

↑ glucokinase, α-enolase, aldolase, and PK protein levels

Liu et al., 2014164

genisteinc

breast (MCF-7, MDA-MB-231) breast (MCF-7) colon (HT29)

PPP, glucose, and glutamine uptake sphingolipid metabolism ↓ GLUT1 mRNA levels ↑ p-ACC protein level glucose oxidation and PPP ↑ glucose uptake ↑ GLUT1 and GLUT4 protein levels ↓ glucose uptake ↓ GLUT1 protein levels ↑ GLUT4 protein levels

Uifalean et al., 2016162 Engel et al., 2012165 Hwang et al., 2005166

pancreatic (MIA PaCa-2) prostate (LNCap) prostate (PC-3)

Boros et al., 2001 167 Gonzalez-Menendez et al., 201462

genistein derivatives Gen-27

breast (MDA-MB-231, MCF-7, MDA-MB-468)

↓ HK2, PKM2, and LDHA protein levels ↓ glucose uptake, lactate production, and ATP generation

Tao et al., 2016151

hesperetin

breast (MDA-MB-231)

↓ glucose uptake ↓ GLUT1 mRNA and protein levels

Yang et al., 2013168

hydroxytyrosol

colon (SW620)

↓ FAS activity and mRNA level

Notarnicola et al., 2011169

kaempferol

breast (MCF-7)

↓ ↓ ↓ ↓ ↓

glucose uptake GLUT1 mRNA level lipid synthesis FAS activity synthesis of phospholipids, triglycerides, and cholesterol ↓ lipid synthesis ↓ FAS activity ↓ synthesis of phospholipids, triglycerides, and cholesterol

Azevedo et al., 2015170


Menendez et al., 200864

breast (MDA-MB-231)

prostate (LNCap)

luteolin

breast (MCF-7, SKBR-3)

F




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tumor cells

metabolic effects

breast (MDA-MB-231)

pancreatic (MIA PaCa-2) prostate (LNCap)

oroxylin A

breast (MDA-MB-231, MCF-7) breast (MDA-MB-231)

breast (MCF-7) colon (HCT116) colon (HCT116)

hepatocellular carcinoma (HepG2) hepatocellular carcinoma (HepG2)

lung (A549)

reference

↓ lipid synthesis ↓ FAS activity ↓ synthesis of phospholipids, triglycerides, and cholesterol ↓ de novo fatty acid synthesis ↓ lipid synthesis ↓ FAS activity ↓ synthesis of phospholipids, triglycerides, and cholesterol


dissociation of HK2 from the mitochondria ↓ HK2 mRNA and protein level ↓ glucose uptake, lactate production (under hypoxia) ↓ glucose uptake, lactate production ↓ glucose uptake, lactate production ↓ ADRP, Srebp1, and FAS mRNA and protein levels ↑ carnitine palmitoyltransferase 1 mRNA and protein levels ↓ glucose uptake, lactate production ↓ HK2, LDHA, PDK, PKM2 mRNA, and protein level ↓ glucose uptake, lactate production, ATP generation (under hypoxia) ↓ HK2 protein level and activity ↓ glucose uptake, lactate production, ATP generation

Wei et al., 201388 Wei et al., 201587

Harris et al., 201297 Brusselmans et al., 200594

Zhao et al., 201589 Zhao et al., 201589 Ni et al., 201790

Dai et al., 201385 Dai et al., 201686

Wei et al., 201384

osthole

ovarian (SK-OV-3)


Lin et al., 2010171

phloretin

prostate (LNCap)

↑ ↑ ↓ ↓ ↑

Gonzalez-Menendez et al., 201462

prostate (PC-3)

quercetin

↓ glucose uptake, lactate production ↑ GLUT1 mRNA levels ↓ glucose uptake, lactate production

breast (MCF-7) breast (MDA-MB-468, Hs578T, BT20) breast (MDA-MB-231)

breast (MDA-MB-157, MDA-MB-231) colon (RKO, HCT15) hepatocellular carcinoma (HepG2, Huh7, Hep3B2.1-7) cholangiocarcinoma (TFK-1) hepatocellular carcinoma (HepG2) pancreatic (MIA PaCa-2) prostate (LNCap)

resveratrold

glucose uptake GLUT1 and GLUT4 protein levels glucose uptake GLUT1 protein levels GLUT4 protein levels

↓ lipid synthesis ↓ FAS activity ↓ synthesis of phospholipids, triglycerides and cholesterol ↓ FAS protein level ↓ glucose uptake, lactate production ↑ GLUT1 membrane expression ↓ GLUT1 cytoplasmic fraction ↓ FAS activity and protein levels ↓ intracellular fatty acids ↓ glycogen synthesis ↓ lipid synthesis ↓ FAS activity ↓ synthesis of phospholipids, triglycerides, and cholesterol ↓ ↓ ↑ ↓ ↑ ↑ ↓

breast (MCF-7) breast (MCF-7) breast (MCF-7) breast (MDA-MB-231) breast (MCF-7, MDA-MB-231) G

Moreira et al., 201377

PKM2 mRNA and protein levels PFK activity glucose oxidation lactate production de novo ceramide synthesis SPT, nSMase activity lipogenesis

Morais-Santos et al., 201491 Brusselmans et al., 200594

Sultan et al., 201795 Amorim et al., 201592 Brito et al., 201693 Zhao et al., 201496 Harris et al., 201297 Brusselmans et al., 200594

Iqbal et al., 201298 Faber et al., 2006105 Saunier et al., 2017108 Scarlatti et al., 2003114 Pandey et al., 2011111 DOI: 10.1021/acs.jafc.8b04104 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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tumor cells

metabolic effects

reference

↓ FAS mRNA and protein levels nioagenic amine metabolism, lipid metabolism ↓ FAS protein level ↓ PKM2 mRNA and protein levels ↓ glucose uptake, lactate production ↓ G6PD, TKT activity ↑ glucose and pyruvate oxidation ↓ lactate production ↑ ATP generation ↓ PPP activity ↑ PDC activity ↑ ceramides ↓ sphingomyelins ↑ unsaturated fatty acids/saturated fatty acids ↑ fatty acid oxidation

breast (MCF-7, MDA-MB-231) breast (SKBR-3) cervical (HeLa) colon (HT-29) colon (Caco-2)

colon (SW620)

↑ ↓ ↓ ↓

colon (Caco-2)

G6PD protein level PGD protein level PGD and TKT protein levels G6PD, PGD, TKT, and PKM2 protein levels ↓ G6PD protein level ↑ PGD protein level ↓ lactate production ↓ glycolysis ↓ HK2, PFK1, and PGAM1 mRNA levels ↓ PKM2 mRNA and protein levels ↓ glucose uptake, lactate production ↓ glucose and amino acid metabolism ↓ lactate production ↑ succinate utilization ↓ HK2 mRNA and protein levels ↓ PKM2 mRNA and protein levels little influence on PFK1/2 or LDHA ↓ glucose uptake, lactate production ↑ p-ACC protein level

colon (COLO201, LoVo) colon (DLD-1) colon (WiDr) diffuse large B-cell lymphoma (OCI-Ly18)

hepatocellular carcinoma (HepG2) hepatocellular carcinoma (HepG2)

hepatocellular carcinoma (HCC-LM3, Bel-7402)

hepatocellular carcinoma (HepG2) leukemia (K-562)

lung (H460, H1650, HCC827) ovarian (SK-OV-3, CaOV-3, A2780, MDAH2774, HOC-1, HOC-8, OVCA 429, OVCA 432) ovarian (PA-1, OVCAR-3, MDAH2774, SK-OV-3)

ovarian (A2780) prostate (LNCaP)

↑ ↓ ↑ ↓ ↓ ↓

cellular ceramide sphingomyelin, S1P ASMase mRNA level and activity HK2 protein level glucose consumption, lactate production glucose uptake, lactate production

Jager et al., 2011113 Khan et al., 2014112 Iqbal et al., 201298 Vanamala et al., 2011107 Saunier et al., 2017108

Blanquer-Rossello et al., 2017172 Shibuya et al., 2015173

Faber et al., 2006104

Iqbal et al., 201298 Massimi et al., 201299

Dai et al., 2015100

Hou et al., 2008;109 Shin et al., 2009110 Mizutani et al., 2016115

Li et al., 2016101 Kueck et al., 2007174

↓ glucose uptake suppressed plasma membrane GLUT1 localization ↓ extracellular acidification rate (ECAR) ↑ 3-PGDH, PGK1, and aldolase C gene expression ↓ PDHA1, PGAM1, MSE, ENOG, PDHA, and ENOA gene expression ↓ PGAM1 mRNA and protein levels

Gwak et al., 2015102

Tan et al., 2016103 Narayanan et al., 2004106

rosmarinic acid

gastric (MKN45) colon (HCT8, HCT116)

↓ glucose consumption, lactate production ↓ glucose consumption, lactate production ↓ LDH level

Han et al., 2015175 Xu et al., 2015176

scutellarein

breast (MDA-MB-231)

↓ ECAR and oxygen consumption rate (OCR)


silibinine

colon (SW480)

glucose metabolism

Raina et al., 2013178

H


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tumor cells

metabolic effects

reference

↓ PC, total choline ↑ p-ACC protein level

prostate (LNCaP, 22Rv1)

Deep et al., 2016179

wogonin

colon (HCT116)

↓ HK2, PDK1m, and LDHA protein levels ↓ glucose uptake, lactate production (under hypoxia)

Wang et al., 2013180

xantohumol

cervical (HeLa)

↓ ↓ ↓ ↓

Zhang et al., 2015181

lung (A549)

mitochondrial complex-I activity ECAR mitochondrial complex-I activity ECAR


Compounds in cancer clinical trials: aClinicalTrials.gov identifiers: NCT00973869; NCT02439385; NCT02724202; NCT03211104; NCT01160302; NCT03072992; NCT00745134; NCT01859858; NCT0149099; NCT00192842; NCT01740323; NCT02321293; NCT01294072; NCT00094445; NCT02554344; NCT00027495; NCT00295035; NCT02724618; NCT02064673; NCT02138955; NCT02095717; NCT00852332; NCT00486460; NCT01608139; NCT02017353; NCT00113841; NCT00689195; NCT01712542; NCT02100423; NCT00969085. bClinicalTrials.gov identifiers: NCT02891538. cClinicalTrials.gov identifiers: NCT00244933; NCT00058266; NCT01628471; NCT01985763; NCT00584532; NCT00005827; NCT00882765; NCT00269555; NCT00546039; NCT00376948; NCT01325311; NCT00118040; NCT02499861; NCT01126879; NCT00276835; NCT02624388; NCT00004858. dClinicalTrials.gov identifiers: NCT00256334; NCT01476592; NCT01476592. eClinicalTrials.gov identifier: NCT00487721.

Figure 2. Structures of selected phenolic compounds: (A) apigenin, (B) curcumin, (C) epigallocatechin gallate, (D) oroxylin A, (E) quercetin, and (F) resveratrol.

flux and ATP production, while the expression of several glycolytic enzymes remained unaffected.59 In the same work, GLUT1 overexpression was shown to confer resistance to apigenin-induced apoptosis, in line with other reports where apigenin-induced downregulation of GLUT1 was suggested to contribute to cell growth inhibition, apoptosis, and enhanced sensitivity to chemotherapeutic drugs.60,61 On the other hand, in prostate cancer cells, researchers have found significant differences in GLUT1 and GLUT4 protein levels between androgen-sensitive and insensitive cells.62 In PC-3 cells, after 48 h incubation, apigenin (15.7 μM) reduced GLUT1 protein levels, but increased GLUT4, whereas in LNCaP cells, both GLUTs were increased upon exposure (7.1 μM). Also, apigenin was more potent in reducing growth of LNCaP cells than of PC-3 cells, suggesting phenotypic characteristics of prostate tumor cells to play an important role on GLUTs expression levels.62 Recently, apigenin (10−40 μM) was found to restrain colon cancer cells’ (HCT116, HT29, DLD-1) proliferation through modulation of PKM2 expression and activity, with concomitant decreases in glucose consumption, lactate production, and ATP generation.63 PKM2 was inhibited

anti-atherosclerotic, anti-inflammatory, anti-bacterial, and antiviral activities.57 The promising results of plant derived phenolic compounds in cancer inhibition have driven researchers to investigate how these compounds modulate tumor cell metabolism. Table 1 provides a compilation of studies reporting metabolic changes induced by phenolic compounds in different human tumor types (cell lines). Within these studies, a few selected examples, for which more extensive mechanistic information is available, are described below. Apigenin (Figure 2A) is a flavone commonly found in fruits and vegetables, recognized for its potent anti-oxidant, antiinflammatory, and anti-cancer properties. Downregulation of glucose uptake appears to be one of the processes through which this compound inhibits tumor cell growth and activity (Figure 1). In particular, apigenin (6.25−50 μM) was found to downregulate GLUT1 mRNA and protein levels in human pancreatic cancer cells, an effect suggested to be partially mediated by the PI3K/Akt pathway.58 In lung carcinoma cells, apigenin (10 μM) also caused GLUT1 mRNA and protein levels to decrease, with a concomitant drop of the glycolytic I


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decreasing its translocation to the mitochondrial outer membrane, hence, its anti-apoptotic effect. EGCG-treated (20−100 μM) HCC cells (HCC-LM3 and HepG2) also displayed reduced HK2 expression, although PFK was highlighted as the most down-regulated glycolytic enzyme, at the mRNA expression level.76 Protein expression levels and enzyme activity further corroborated the importance of PFK mediating EGCG-induced glycolytic inhibition in HCC cells. In MCF-7 breast cancer cells, EGCG (10−100 μM) inhibited glucose uptake and lactate production, and upregulated GLUT1 mRNA levels, which was postulated to reflect a compensatory effect.77 In another study involving the screening of a large library of natural products, EGCG (80 μM) was identified as a potent inhibitor of phosphoglycerate mutase 1 (PGAM1), a glycolytic enzyme catalyzing the conversion of 3phosphoglycerate into 2-phosphoglycerate (2-PG), hence playing an important role in regulating the PPP flux and biosynthesis in lung (NCI-H1299) and breast (MDA-MB-231) cancer cells.78 EGCG has also been extensively studied for its ability to inhibit FAS activity,79−81 having been reported to decrease its protein levels in diverse cell models.81,82 In MCF-7 breast cancer cells, Yeh and co-workers showed the expression of epidermal growth factor (EGF)-induced FAS to be inhibited by EGCG (10−40 μM) through modulation of the EGF receptor (EGFR)/PI3K/Akt/Sp-1 signal transduction pathway.82 In prostate cancer cells (LNCaP), although FAS activity was reduced, FAS protein levels were augmented upon EGCG treatment (40−150 μM), suggesting some kind of intracellular feedback.79 Furthermore, in pancreatic adenocarcinoma cells (MIA PaCa-2), ECGC treatment (50 μM) reduced acetylCoA, which in turn decreased the synthesis of palmitate, a key constituent of cellular membranes.83 The ability of oroxylin A (Figure 2D), a major bioactive flavonoid isolated from the root of Scutellaria, to affect glucose metabolism has been reported in several studies, where some underlying regulatory mechanisms were highlighted. In lung adenocarcinoma cells (A549), oroxylin A (100−200 μM) was seen to decrease HK2 protein expression, downregulating glycolysis, and to subsequently trigger pathways involving detachment-induced apoptosis (anoikis), by suppressing HK2 binding to voltage-dependent anion channel (VDAC), with a concomitant decrease in HK2 activity.84 The effect of oroxylin A on glycolysis and glycolytic enzymes has also been reported for HCC (HepG2) cells.85,86 When cultured under hypoxia (1% O2), HepG2 cells treated with oroxylin A (12.5−50 μM) displayed decreased expression of HK2, LDHA, PDK, and PKM2, at both mRNA and protein levels.86 This response was stronger within hypoxia conditions than under normoxia, and depended on oroxylin A-induced HIF-1α degradation, via increased expression of prolyl-hydroxylase domain (PHD2) and von-Hippel Lindau (VHL) tumor suppressor. Hypoxic MDA-MB-231 breast cancer cells also responded to oroxylin A (50−200 μM) by decreasing HK2 expression, glucose uptake, and lactate generation, an effect which was attributed to the suppression of HIF-1α stabilization via Sirtuin 3 (SIRT3) activation.87 Similar results were also obtained under normoxia.88 Upstream of glycolytic enzymes, the tumor suppressor p53 has been identified as a crucial modulator of oroxylin A-induced glycolytic inhibition in HCC, breast (MCF-7), and colon (HCT116) cancer cells.85,89 In HepG2 cells, oroxylin A (12.5−50 μM) increased protein and mRNA expression of key metabolic effectors partially regulated by p53,

by direct binding of apigenin, thus suggested to act as an allosteric inhibitor.63 Finally, in breast cancer cells, apigenin (50 μM) was reported to drastically suppress the expression of FAS, especially in the epidermal growth factor receptor 2 (HER2)-overexpressing SKBR3 cell line.64 Accordingly, the authors proposed several compounds extracted from extra virgin olive oils (such as apigenin) to be protective against HER2-positive breast carcinoma through inhibition of lipid synthesis. Curcumin (Figure 2B), a major component of the dietary spice turmeric (Curcuma longa), is one of the polyphenols for which the impact on glucose transport, uptake, and metabolism has been more extensively studied. GLUT1 mRNA and protein levels decreased upon curcumin treatment of MCF-7 breast cancer cells (5−10 μM)65 and lung carcinoma cells (A549) (15−30 μmol/L), where GLUT1 was associated with curcumin anti-invasive effect.66 In colorectal tumor cells (HCT116 and HCT29), curcumin (10−40 μmol/L) was shown to induce a significant decrease in glucose uptake, lactate production, and ATP generation, which was associated with decreased protein level and activity of HK2, while other glycolytic enzymes (phosphoglucomutase (PGM), PFK, and LDH) remained practically unaffected.67 Additionally, the authors suggested curcumin-induced HK2 dissociation from the mitochondria, via Akt phosphorylation, to explain mitochondrial-mediated apoptosis. In another study using esophageal cancer cells (Ec109), curcumin (1−10 μM) was reported to have a wider impact on glycolytic enzymes, decreasing GLUT4, HK2, PFKFB3, and PKM2 at the mRNA and protein levels (Figure 1), via AMPK-mediated regulation.68 Interestingly, for breast cancer cells, both suppression and stimulation of glycolysis by curcumin have been reported. In MDA-MB-231 cells, curcumin (5 μM) decreased HK2 expression and protein level, promoting sensitivity of these cells to 4-hydroxytamoxifen by inhibiting the transcription factor SLUG and its binding to HK2 promoter.69 On the other hand, curcumin-treated (5 μM) MCF-7 cells displayed increased glucose uptake, lactate production, and HK2 activity, together with suppressed mitochondrial respiration, a response viewed as a compensatory effect to deal with curcumin-induced mitochondrial dysfunction.70 Furthermore, curcumin has been shown to downregulate the expression and activity of the FAS lipogenic enzyme, both in HCC HepG2 cells (5−15 μg/mL)71 and in breast SKBR-3 tumor cells (5−20 μM).72 Epigallocatechin gallate (EGCG) (Figure 2C) is an abundant, bioactive polyphenol in green tea, which has been reported to affect tumor cell metabolism in multiple ways. In colon cancer cells (HT-29), EGCG (50−400 μM) was found to decrease GLUT1 mRNA levels, while promoting AMPK activation and reduction of vascular endothelial growth factor (VEGF).73 EGCG was also reported to increase phosphorylation of ACC, thereby linking AMPK activation to decreased fatty acid synthesis.73 In another study using the same cell line, Sánchez-Tena and colleagues reported that EGCG (70−140 μM) decreased glucose uptake and increased glutamine consumption, while reducing glutamate enrichment.74 The activities of key PPP enzymes, TKT and G6PD, were also reduced (Figure 1). EGCG treatment (20−80 μM) of human tongue carcinoma cells (Tca8113 and TSCCa) was found to inhibit glycolysis through HK2 downregulation, a process suggested to be partially mediated by the Akt signaling pathway and independent of ERK activity.75 Moreover, EGCG altered the subcellular localization of HK2 in those cells, J


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expression and activity, as well as the content of intracellular fatty acids, while its cytotoxicity could be suppressed by addition of exogenous palmitate (the end product of FAS).96 Moreover, quercetin (50 μM) has been reported to inhibit glycogen synthesis in pancreatic adenocarcinoma cells (MIA PaCa-2).97 Resveratrol (Figure 2F) is a polyphenol abundant in grapes, berries and other dietary sources, with multiple effects on tumor cell metabolism (Figure 1). Decreased glucose uptake and lactate production have been associated with resveratrol action in hepatocellular carcinoma cells,98−100 lung cells,101 and ovarian cells.102,103 Specifically, impaired GLUT1 trafficking due to suppressed GLUT1 membrane localization (linked to Akt inhibition), has been implicated in diminished glucose uptake by resveratrol-treated (50 μM) ovarian cancer cells (PA-1, OVCAR3, MDAH2774, SKOV3).102 Resveratrol has also been shown to modulate several glycolytic enzymes. Downregulation of HK2 expression was induced by resveratrol in non-small-cell lung cancer (NSCLC) cells (H460, HCC827, and H1650),101 LY18 human diffuse large B-cell lymphoma cells,104 and HCC cells (HCC-LM3 and Bel-7402).100 The glycolytic enzyme PFK has also been pointed as an important target of resveratrol (10−50 μM) in breast cancer MCF-7 cells.105 Particularly, resveratrol was reported to inhibit PFK activity when in contact with the purified enzyme, as well as in cell culture, where it also decreased glucose consumption and ATP generation, while increasing lactate production at higher concentrations, likely in relation with glutamine oxidation. Additionally, PFK and PGAM1 were downregulated upon resveratrol treatment of LY18 lymphoma cells104 and LNCaP cells.106 The effect of resveratrol (50 μM) on PKM2 expression was also highlighted as a major driver of metabolic reprogramming in HeLa, HepG2, and MCF-7 cancer cells.98 In particular, resveratrol downregulated PKM2 via inhibition of the mammalian target of rapamycin (mTOR) pathway, and caused both reduced glycolysis and macromolecular synthesis, the latter likely resulting from decreased levels of PPP intermediates. The impact of resveratrol on PPP enzymes has also been documented. In colorectal cancer cells, resveratrol (50−150 μM) decreased the activity and/or protein level of G6PD, TKT, and phosphogluconate dehydrogenase (PGD).107 Lactate production also decreased and ATP production increased, suggesting that resveratrol (10 μM) impacted on glycolysis, in association with PPP activity.108 Furthermore, in both Caco-2 and HCT116 colon cancer cell lines, pyruvate dehydrogenase (PDH) activity decreased upon resveratrol (10 μM) exposure, implying the resveratrol-induced glycolytic remodeling to possibly take place by regulation of the PDP1 gene expression.108 Resveratrol has also been strongly implicated in the modulation of tumor cell lipid metabolism. In HCC cells, this polyphenol increased ACC phosphorylation, in relation with AMPK activation.109,110 Moreover, AMPK-mediated inhibitory phosphorylation of GSK3Β downstream of poly(ADP-ribose) polymerase-LKB1 pathway was proposed to mediate the protective effects of resveratrol (30 μM) from arachidonic acid and iron-induced ROS production and mitochondrial dysfunction.110 In several breast cancer cell models, resveratrol suppressed both FAS mRNA and protein expression, suggesting the anti-proliferative effect of this compound to be mediated via FAS inhibition.111,112 In another study using MCF-7 and MDA-MB-231 breast cancer cell lines, resveratrol (25−100 μM) produced a noticeable increase in

namely TP53-induced glycolysis and apoptosis regulator (TIGAR) and SCO2 cytochrome c oxidase assembly.85 In another study, oroxylin A (100−200 μM) was shown to inhibit glycolysis in wt-p53 cancer cells (breast MCF-7 and colon HCT116) through the suppression of mouse double minute 2 (MDM2)-mediated p53 degradation.89 The effect of oroxylin A on lipid metabolism has also been reported. In colon HCT116 cells under hypoxia, this phenolic compound (50− 150 μM) could inactivate HIF-1α and reprogram fatty acid metabolism to downregulate lipid uptake and synthesis, while enhancing fatty acid oxidation and decreasing intracellular fatty acid levels.90 In turn, such reduction resulted in inactivation of the canonical Wnt signaling pathway, cell cycle arrest, and growth inhibition. Quercetin (Figure 2E), a flavonol widely distributed in the plant kingdom, has been investigated in several studies for its role in inhibiting glucose uptake and lactate efflux.77,91−93 In liver tumor cells, including HCC (HepG2, HuH7, and Hep3B2.1-7) and cholangiocarcinoma (TFK-1) cells, quercetin (5−100 μM) was reported to recruit GLUT1 from the cytoplasm to the plasma membrane, increasing its expression, while decreasing its function through competitive inhibition.93 Quercetin (100 μM) was also described to competitively inhibit GLUT1 in breast tumor cells (MCF-7 and MDA-MB231), independently of estrogen signaling.77 The inhibitory effect upon glucose uptake was accompanied by a compensatory upregulation of GLUT1 gene expression, in MCF-7 cells. Importantly, flavonoid-mediated glucose deprivation was related to downstream anti-proliferative and cytotoxic effects. In another study comprising a panel of breast tumor cells with varying phenotypes, metabolic disturbances associated with quercetin and other lactate transport inhibitors (α-cyano-4hydroxycinnamate (CHC) and lonidamine) were found to be highly dependent on the cell type.91 Whereas quercetin IC50 concentrations produced no metabolic alterations in MCF-7/ AZ, SKBR3, nor MDA-MB-231 cell lines, MDA-MB-468, Hs578T, and BT-20 cells displayed significant decreases in glucose consumption and/or lactate production. These results showed the potential of lactate transport inhibition for reducing breast cancer cell proliferation and invasion, especially in cells with pronounced glycolytic phenotype and MCT1 membrane expression. Concordantly, MCT1 inhibition with quercetin also disrupted the glycolytic phenotype and decreased viability and proliferation of colorectal cancer cells (HCT15, RKO).92 Moreover, in these cells, quercetin-induced lactate transport inhibition was reported to potentiate the cytotoxicity of the chemotherapeutic drug 5-fluorouracil (5FU), underlying the synergistic potential in using natural compounds combined with more standard anti-cancer drugs. The effects of quercetin on tumor biosynthetic processes have also been addressed in different studies. In prostate (LNCaP) and breast (MDA-MB-231) cancer cells, quercetin (25 μM) was one of the most efficient flavonoids inhibiting lipogenesis, decreasing it to 38% of the control level.94 Interestingly, only decreased enzymatic FAS activity, but not protein expression, was accountable for this effect, as well as for the overall decrease of phospholipids, triglycerides, and cholesterol. On the other hand, quercetin (150−415 μM) did decrease FAS protein levels, both in vitro and in vivo, in triple negative breast tumor models, an effect which, together with inhibition of β-catenin (involved mainly in cell adhesion), was linked to quercetin-induced apoptosis.95 In HepG2 cells, quercetin (25−100 μM) was reported to decrease FAS protein K


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Journal of Agricultural and Food Chemistry Table 2. Effects of Isoprenoids on Energetic and Biosynthetic Metabolic Pathways of Human Tumor Cells compound

tumor cells

metabolic effects

reference

andrographolidea

leukemia (MV-4-11, NB4)

↓ FAS, ACC1 protein levels ↑ stromal interaction molecule 1 (STIM1) protein level ↓ several fatty acid contents (oleic acid, stearic acid, palmitoleic acid, palmitic acid)


betulinic acid

breast (SK-BR-3)

↓ lactate production ↓PKM2 protein level ↓ HK2, PKM2 protein levels ↓ SCD-1 activity ↑ incorporation of saturated fatty acids in cardiolipin ↓ PKM2 activity ↓ PKM2 protein level ↑ PKM2 activity

Lewinska et al., 2017131

breast (MCF-7) cervical (HeLa) pancreatic (MIA PaCa-2) pancreatic (PANC-1)

Potze et al., 2015132 Pandita et al., 2014130

cacalol

breast (MCF-7, MDAMB-231)

↓ FAS mRNA level ↓ FAS protein level

Liu et al., 2011183

celastrol

cervical (HeLa)

glycolysis citrate cycle amino acid metabolism protein biosynthesis

Hu et al., 2013184

artimisinin derivatives:

lung (A549, PC-9)

↓ GLUT1 protein level ↓ glucose uptake; ATP generation, lactate production inhibits GLUT1 translocation to cytoplasmatic membrane ↓ glucose uptake, ATP generation, lactate production ↓ ACSL5, HADH, and FAS protein levels

Mi et al., 2015154

↓ ↓ ↓ ↓

Eskandani et al., 2015185

dihydroartemisinin

lung (H1975)

artesunate

colon (HCT116)

galbanic acid

lung (A549) ovarian (NIH:OVCAR-3)

geraniol

breast (MCF-7) hepatocellular carcinoma (HepG2) hepatocellular carcinoma (HepG2)

prostate (PC-3)

GLUT1 mRNA level ENO1 mRNA level GLUT1 mRNA level ENO1 mRNA level

Jiang et al., 2016155 Chen et al., 2017153

↓ HMGR activity ↓ HMGR activity

Duncan et al., 2004123 Polo et al., 2006121

↓ HMGR mRNA and protein levels fatty acid metabolism ↓ mevalonate pathway ↓ PC synthesis ↑ p-ACC protein level

Crespo et al., 2013122

Kim et al., 2012124

geranylgeranoic acid

hepatocellular carcinoma (Huh-7)

↑ ↓ ↑ ↓

ginsenoside 20(S)-Rg3

ovarian (SK-OV-3, 3AO)

↓ GLUT1 mRNA level ↓ glucose uptake; lactate production ↓HK2, PKM2 mRNA, and protein levels ↓ LDH, PDK, and PFK mRNA levels

Li et al., 2015187

oleanolic acid

breast (MCF-7)

↓ glucose uptake; lactate production

breast (MCF-7)

↑ ↓ ↓ ↓ ↓ ↓ ↓

Liu et al., 2014;133 Liu et al., 2015134 Liu et al., 2015134

breast (MDA-MB-231)

prostate (PC-3)

fructose 6-phosphate fructose 1,6-diphosphate spermine spermidine

p-ACC1, p-HMGR protein levels FAS protein level de novo fatty acid synthesis glucose uptake; lactate production HK, PKM2, and LDHA protein levels PK activity PKM2 protein level

L

Iwao et al., 2015186

Amara et al., 2016135

Liu et al., 2014133


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tumor cells

prostate (PC-3)

oleanolic acid derivative CDDO-Im

liposarcoma (LiSa-2)

colon (SW480)

oridonin

colon (SW480, SW620)

tveal melanoma (OCM-1, MUM2B)

metabolic effects ↑ ↑ ↑ ↓ ↓

PKM1 protein level PK activity p-ACC1, p-HMGR protein levels FAS protein level de novo fatty acid synthesis

↓ ↓ ↓ ↓ ↓ ↑

FAS mRNA level FAS protein level de novo fatty acid synthesis GLUT1, MCT1 mRNA, and protein levels glucose uptake; lactate export ATP generation

↓ ↓ ↓ ↓

FAS mRNA level FAS protein level palmitic acid, stearic acid FAS protein level

reference

Liu et al., 2015134

Hughes et al.,2008188

Yao et al., 2017125

Kwan et al., 2013126

Gu et al., 2015127

pomolic acid

breast (MCF-7)

↓ FAS protein level ↑ p-ACC1 protein level ↓ de novo fatty acid synthesis

Youn et al., 2012189

pristimerin

breast (SK-BR-3)

↓ FAS protein level ↓ FAS activity

Lee et al., 2013190

pseudolaric acid B

lung (A549)

↑ GLUT1 protein level ↑ glucose uptake, ATP generation, lactate production ↑ HK-2 protein level

Yao et al., 2017191

tanshinone IIA

gastric (AGS)

Lin et al., 2015128

esophageal (Ec109)

↓ GPI, LDHB, MDH1 ↑ phosphoenolpyruvate carboxykinase 2 ↓ PKM2 mRNA and protein levels

tanshinone IIA derivative acetyltanshinone IIA

breast (MDA-MB-453, SK-BR-3)

↓ FAS, p-ACL protein levels ↑ p-ACC protein level

Guerram et al., 2015152

thymoquinone

pancreatic (MIA PaCa-2) pancreatic (PANC-1)

↑ PKM2 activity ↓ PKM2 protein level ↓ PKM2 activity

Pandita et al., 2014130

ursolic acid

breast (MCF-7, MDA-MB-231, SK-BR-3)

↓ ↓ ↓ ↓

Lewinska et al., 2017131

breast (MCF-7, SK-BR-3) breast (MDA-MB-231, SK-BR-3) ursolic acid derivative US597

hepatocellular carcinoma (HepG2)

ATP generation PKM2 lactate production HK2 protein level

↓ HK activity ↓ ATP generation


Wang et al., 2014156

a

ClinicalTrials.gov identifier: NCT01993472.

(nSMase), key enzymes of sphingomyelin/ceramide pathway and ceramide biosynthetic pathway.114 In another cell model (K-562, a human erythroleukemia line), sphingomyelin and sphingosine-1-phosphate (S1P) levels decreased upon resveratrol (50−100 μM) treatment, suggesting ceramide accumulation due to upregulation of the sphingomyelin degradation pathway.115 Acid sphingomyelinase mRNA (ASMase) transcription level and activity also increased, indicating a possible role for resveratrol in ceramide accumulation. Furthermore, the lipidomic analysis of colon cancer cells (Caco-2) revealed

arachidonic acid and its metabolite 12S-HETE, which could have been released from cell membrane phospholipids after activation of phospholipase A2 and subsequent metabolism by 12-lipoxygenase.113 Resveratrol effect on lipid metabolism also appeared to implicate an increase of ceramide, an essential component of complex sphingolipids involved as second messengers in cell proliferation and apoptosis.108,114,115 In breast cancer cells (MDA-MB-231), the accumulation of ceramide seemed to be caused by the activation of serine palmitoyl transferase (SPT) and neutral sphingomyelinase M


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Figure 3. Structures of selected isoprenoids: (A) geraniol, (B) oridonin, (C) tanshinone IIA, (D) betulinic acid, and (E) oleanolic acid.

resveratrol-induced (10 μM) upregulation of ceramides and phosphatidylethanolamines, accompanied by decreased contents of sphingomyelins.108 Isoprenoids. Isoprenoids are a structurally diverse and abundant class of plant secondary metabolites, derived from the five-carbon precursors isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP).116 The number of five-carbon building blocks classifies these compounds into monoterpenoids (C10), sesquiterpenoids (C15), diterpenoids (C20), triterpenoids (C30), and tetraterpenoids (C40).117 Over the past decades, isoprenoids have been extensively studied due to their remarkable biological activities, with some of them having already reached the clinics. For instance, artemisinin, a sesquiterpene lactone isolated from Artemisia annua, along with its semisynthetic derivatives, are well-established anti-malarial drugs.118 Furthermore, paclitaxel (Taxol), a diterpenoid originally isolated from Taxus brevifolia bark, is currently used as part of the breast, ovarian, and lung cancer chemotherapeutical regimens.119 The role of metabolism in the anti-cancer activity of plant-derived isoprenoids has received growing attention. Table 2 offers a concise list of recent works on this subject, while a few selected examples are described below. Geraniol (Figure 3A) is a monoterpenoid found in the essential oils of several aromatic plants. Its preventive and therapeutic activity toward several cancers has been reported,120 although its effects on cellular metabolism are still scarcely known. In HepG2 HCC cells, geraniol (50−200 μmol/L) decreased fatty acid metabolism, as demonstrated by radioactive probe incorporation.121,122 Furthermore, results suggested that phosphatidylcholine (PC) synthesis was impaired, probably due to CTP-PC cytidylyl transferase inhibition. Additionally, HMGCR inhibition was likely responsible for mevalonate pathway inhibition, leading to reduced cell proliferation and apoptosis intensification.122 In breast cancer cells (MCF-7), geraniol also inhibited HMGCR activity and cell proliferation, but the depletion of mevalonate was not responsible for the inhibition of MCF-7 cell proliferation.123 In another study, geraniol (0.25−1 μM) was shown to increase p-ACC protein levels in PC-3 prostate cancer cells, through activation of the AMPK pathway.124 The diterpenoid oridonin (Figure 3B), originally isolated from Rabdosia rubescens, has been reported to induce autophagy in human colorectal cancer cells through inhibition of glucose metabolism.125 Indeed, oridonin (1.25−20 μM) was

shown to downregulate mRNA expression and protein levels of both GLUT1 and MCT1 in a colorectal cancer cell line (SW480), indicating impairment of energy supply and lactate export in these cells (Figure 1). Also in colorectal cancer cells (SW480 and SW620), oridonin (5−10 μM) was shown to reduce FAS mRNA and protein levels.126 This effect was suggested to arise from the reduced transcriptional activity of FAS promoter which contains the SREBP1 binding site. Moreover, LC/MS analysis showed oridonin to impact on cellular fatty acid levels, namely by decreasing palmitic and stearic acids.126 In another study, oridonin (5 μM) inhibited FAS protein level leading to apoptosis in uveal melanoma cells lines (OCM-1, MUM28).127 Tanshonine IIA (Figure 3C), a major lipophilic component extracted from Salvia miltiorrhiza Bunge roots, has been shown to affect glucose metabolism in relation to tumor cell growth suppression.128 In a human stomach adenocarcinoma AGS cell line, tanshinone IIA (5.3 μM) downregulated glucose-6phosphate isomerase (GPI), consequently decreasing glucose consumption and pyruvate production. The intracellular ATP levels and Akt expression reduction, coupled with enhanced p53 expression, contributed to the inhibitory effect of tanshinone IIA in glycolysis. Additionally, gluconeogenesis was also deregulated, with suppression of LDHB and malate dehydrogenase 1 (MDH1) and increased PCK2 gene expression. Tanshonine IIA (0.40−1.70 μM) was additionally reported to downregulate PKM2 mRNA and protein expression in an esophageal cancer cell line (Ec109).129 Betulinic acid (Figure 3D) is a pentacyclic lupanetriterpenoid that is abundantly present in birch trees’ outer barks (Betula spp.) and across a wide range of taxonomically diverse plant families.117 This triterpenoid has been widely studied for its anti-tumoral potential in multiple cancer models, and a few works have addressed its ability to modulate cellular metabolism. Pandita and colleagues have studied the combination of dietary molecules, such as betulinic acid, with gemcitabine, a common chemotherapeutic drug, in pancreatic cancer cells and their impact on a key glycolytic enzyme, PKM2.130 The results showed that betulinic acid (20 μM) was able to decrease PKM2 protein level in the PANC-1 cell line, although PKM2 activity increased with treatment. On the contrary, PKM2 activity decreased in treated (25 μM) MIA PaCa-2 cells. The combination of betulinic acid with gemcitabine produced a similar, enhanced effect, demonstrating that this triterpenoid could effectively potentiate N


Review

Journal of Agricultural and Food Chemistry Table 3. Effects of Alkaloids on Energetic and Biosynthetic Metabolic Pathways of Human Tumor Cells compound berberinea

tumor cells

metabolic effects ↓ ↑ ↓ ↑ ↑ ↑ ↓ ↑ ↓

breast (MCF-7) breast (MCF-7)

colon (HCT116) cervical (HeLa) lung (A549)

reference Chou et al., 2012142 Tan et al., 2015145

TPI, aldolase A, and ENOA protein level lactate production, ATP generation LDH, PFK protein levels p-PKM2 protein level citrate content p-ACC protein level p-ACL protein level Co-A content PKM2 activity

Li et al., 2017144

Slight decrease on ATP generation ↑ p-ACC protein level

Fan et al., 2013143

Impheng et al., 2014149

pancreatic (AsPC-1, BxPC-3)

↓ FAS protein level ↓ de novo fatty acid synthesis ↓ mitochondrial complex-I, -III activity

hernandezine

cervical (HeLa)

↑ p-ACC protein level

Law et al., 2016192

N-methylhemeanthidine chloride

pancreatic (AsPC-1, BxPC-3, Mia PaCa-2)

↓ glucose uptake; lactate production ↓ GLUT1, PGK1, LDHA, and PKM2 protein levels

Guo et al., 2014193

piperine

breast (SK-BR-3)

↓ FAS mRNA level ↓ FAS protein level

Do et al., 2013194

tetrandrine


↓ PGAM1, TALDO1 protein level

Cheng et al., 2010195

capsaicin


Pramanik et al., 2011148

a

ClinicalTrials.gov identifier: NCT03486496.

reversed in the presence of oleanolic acid. The protein levels of rate-limiting glycolysis-related enzymes, such as HK, PKM2, and LDH, also decreased in the presence of oleanolic acid, and so did PK activity (Figure 1). Alkaloids. Alkaloids are generally described as naturally occurring molecules with basic character, known for the presence of a basic nitrogen atom in any location of the molecule (excluding in amide or peptide bonds).136 Alkaloids were first identified in plants, but can also be produced by bacteria, fungi, or animals. The use of plant-containing alkaloids in traditional medicine remounts to the beginning of human civilization, and the discovery of morphine, in 1804, fueled research into new compounds with remarkable biological roles.137 The anti-cancer potential of alkaloids was first recognized in the 1950s, with the discovery of vinca alkaloids.138 These were the first anti-cancer agents derived from plants used in the clinic, currently remaining as important therapeutic agents within a wide variety of cancers.139 However, at the metabolic level, the information on alkaloids mode of action is still scarce, and, to the best of our knowledge, only a few studies have investigated their effects on bioenergetic and/or biosynthetic pathways (Table 3). Berberine (Figure 4A) is an isoquinoline quaternary alkaloid present in various plants, which has been shown to inhibit cell proliferation and to induce apoptosis in diverse tumor cell lines.140 The implication of berberine in metabolic-related diseases, such as diabetes, stimulated research on cancer metabolism modulation.141 In a proteomics study of berberine’s anti-tumor effect on breast cancer cells, a number of glycolytic enzymes, such as triosephosphate isomerase (TPI), fructose-bisphosphate aldolase A, and enolase α, were found to be downregulated upon treatment (36.91 μg/mL) (Figure

gemcitabine cytotoxicity in human pancreatic cancer cell lines.130 In a breast cancer cell line (SK-BR-3), betulinic acid (20 μM) treatment resulted in decreased PKM2 protein abundance and lactate level.131 Furthermore, betulinic acid decreased the protein levels of HK and PKM2 in the MCF-7 cell line, modulating the glycolytic pathway.131 Finally, in cervical cancer cells (HeLa cells), betulinic acid (10 μg/mL) was shown to inhibit the activity of SCD-1, an enzyme involved in de novo fatty acid synthesis.132 This resulted in an increased incorporation of saturated fatty acids in cardiolipin, inducing mitochondria to undergo ultrastructural changes and ultimately leading to cell death. Oleanolic acid (Figure 3E), an oleanane-type pentacyclic triterpenoid, is abundant in olive trees (Olea europaea), and in all the Oleaceae family. This compound has been associated with a broad spectrum of pharmacological activities, including anti-tumoral activity. In prostate (PC-3) and breast (MCF-7) cancer cell lines, glucose uptake and lactate generation were found to decrease upon oleanolic acid exposure (50−100 μg/ mL).133,134 This was accompanied by a decrease in PKM2 protein level, together with an increase in PKM1, in a doseand time-dependent manner.133 Furthermore, in the same cell lines, oleanolic acid (10−100 μg/mL) was shown to restrain fatty acid synthesis through activation of AMPK. Such effect was suggested to be accountable for ACC1 and HMGCR phosphorylation, as well as for reduced FAS protein level.134 Recently, Amara and co-workers demonstrated that oleanolic acid (5 μM) could effectively reverse the Warburg-like metabolism induced by high salt-mediated osmotic stress in breast cancer cells.135 The hypertonic culture conditions enhanced aerobic glycolysis, with an increase in glucose consumption and lactate generation, an effect which was O


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whereas, to our knowledge, only one alkaloid, N-methylhemeanthidine chloride, has been demonstrated to reduce GLUT1 protein levels in cancer cells. Inhibition of glycolytic enzymes activity and/or expression is also promising, especially when different isoforms are differentially expressed in normal and malignant cells. Otherwise, targeting glycolysis might also adversely affect normal tissues, particularly those which are highly dependent on glycolytic flux.150 Moreover, cells can quickly adapt and compensate for decreased glycolysis by activating other metabolic pathways, such as glutaminolysis.8 Still, a number of in vitro studies have established a causal relationship between glycolysis inhibition by phenolic compounds, isoprenoids, and alkaloids and their anti-proliferative and pro-apoptotic effects in different tumor cells. It is worth noting, for instance, that while a PFKFB3 synthetic inhibitor is being tested at a phase 1 clinical trial for patients with advanced solid malignancies (ClinicalTrials.gov identifier: NCT02044861), curcumin was shown to be highly effective in decreasing PFKB3 mRNA and protein levels in esophageal cancer cells. Targeting mitochondrial metabolism using natural compounds has also been explored with some success. For instance, the flavonoid xantohumol and the alkaloid capsaicin revealed the capacity to restrain mitochondrial complexes activity in vitro, in several cancer models. Inhibition of biosynthetic processes, such as nucleotide synthesis through the PPP, or de novo lipogenesis, also represents an attractive strategy in the context of anti-cancer metabolic therapies. Regarding PPP enzymes, resveratrol and ECGC showed effects toward G6PD, a key regulator of PPP flux, whereas TALDO1 was sensitive to treatment with tetrandine. In what concerns de novo lipogenesis, numerous plant-derived compounds have shown promising results in modulating FAS activity, as shown in Tables 1−3 for several in vitro cancer models. This is particularly relevant because, unlike solid tumors, most adult normal tissues (except for the liver, adipose, and lactating breast tissues) do not perform de novo fatty acid synthesis. Indeed, some FAS inhibitors like TVB-2640 (ClinicalTrials.gov identifiers: NCT02223247; NCT02980029) and omeprazole (ClinicalTrials.gov identifier: NCT02595372) have already entered cancer clinical trials. In addition to the plant-derived compounds hereby reviewed, natural product-inspired synthetics are also expected to continue gaining space in anti-cancer drug discovery. Indeed, there are already some examples in the literature sustaining this view. Gen-27, a synthetic isoflavone derivative of genistein inhibited glycolysis in human breast cancer cells, causing key glycolytic enzymes such as HK2, PKM2, and LDH to decrease protein expression.151 Acetyltanshinone IIA, a novel synthetic tanshinone, elicited decrease in FAS and pACL and a significant increase in p-ACC protein levels in human breast cancer cell lines positive for HER2.152 Artesunate, a synthetic derivative of artemisinin, was found to alter mitochondrial function and to suppress fatty acid biosynthesis in colorectal cancer cells.153 In particular, AcylCoA synthetase 5 (ACSL5), hydroxyacyl-coenzyme A dehydrogenase (HADH), and FAS were all confirmed to have decreased expression upon artesunate treatment. Dihydroartemisinin (DHA) is another semisynthetic derivative of artemisinin capable of suppressing glycolytic metabolism in lung tumor cell lines.154,155 Furthermore, in lung cancer cells, combination of DHA with the glycolytic inhibitor 2-DG further decreased cell viability and potentiated apoptosis, whereas such synergism was not observed in normal lung

Figure 4. Structures of selected alkaloids: (A) berberine and (B) capsaicin.

1).142 Such deregulation was related to berberine’s effect on pro-poptotic proteins (such as BAD) and suggested to configure a response whereby carbohydrate flux was redirected from glycolysis to pathways generating NADPH reducing power, in order to deal with ROS-induced oxidative stress.142 The suppressive effect of berberine (2−50 μM) toward glycolysis has been further corroborated in another study of MCF-7 breast cells, where the protein levels of several glycolytic enzymes were found to be altered upon treatment (e.g., decreased LDH and PFK and increased p-PKM2). In these cells, berberine was able to increase ATP generation, in agreement with OXPHOS upregulation, and contrarily to what had been observed in non-small-cell lung cancer cells.143 In colorectal (HCT116) and cervical (HeLa cells) cancer cell lines, berberine decreased PKM2 activity.144 At the level of lipid metabolism, berberine (7−20 μM) was found to enhance p-ACC protein levels, through activation of the AMPK pathway, in lung tumor cells.143 In breast MCF-7 cancer cells, berberine (2−100 μM) increased the p-ACC levels and decreased p-ACL, suggesting inhibition of fatty acid synthesis (Figure 1).145 Capsaicin (Figure 4B) is an alkaloid produced by pepper plants, which has gained attention for its significant anti-cancer activity.146 In pancreatic tumor cells, capsaicin (100−300 μM) was shown to induce apoptosis, likely in relation to ROS generation and mitochondrial disruption.147 In a later work, decreased activities of mitochondrial complex-I and complexIII in capsaicin (150 μM)-treated cells (BxPC-3 and AsPC-1 cell lines) corroborated this connection, implicating mitochondrial complexes in capsaicin-mediated ROS generation, and inhibition of anti-oxidant defenses that ultimately led to apoptosis.148 In HCC (HepG2) cells, capsaicin (0.05−0.5 mM) significantly downregulated FAS protein levels, compared with the control group, while having no effect on other lipid-related enzymes such as ACC and ACL.149 Furthermore, de novo fatty acid synthesis was suppressed upon capsaicin treatment, as shown by the reduced intracellular levels of longchain fatty acids and triglycerides.149

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SUMMARY AND OUTLOOK Interference with metabolic processes and metabolic enzymes has been increasingly recognized as an important mechanism underlying the anti-neoplastic activity of plant-derived natural products. Specifically, metabolic modulation of tumor cells involves regulating or blocking important pathways engaged in supplying nutrients for energy production, as well as the inhibition of molecular biosynthesis required for sustaining cell growth, proliferation, and invasion. Several phytochemicals have been shown to regulate the entry of glucose into cells by controlling GLUTs expression or modifying glucose binding. These include various phenolic compounds and isoprenoids (Tables 1 and 2, respectively), P


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Journal of Agricultural and Food Chemistry fibroblasts.154 US597, an ursolic acid derivative, used in conjunction with 2-DG, was also found to target both apoptosis and glycolysis, inducing death of HCC cells.156 US597 could reduce HK activity, and the combination of the two compounds resulted in a synergetic inhibition. These results underline the promising potential of drug combinations (involving natural, semi-synthetic, and/or synthetic compounds) to hit multiple targets in tumor cells and achieve enhanced therapeutic effect. Clearly, this is a strategy to be further explored in the future. The in-depth understanding of metabolic effects, and their regulation and functional consequences, is another important research line to be pursued. In this respect, omics technologies, namely transcriptomics, proteomics, and metabolomics, are particularly relevant, being expected to reveal unanticipated effects and to help shed light on the complex mechanisms through which natural compounds interact with tumor cells.

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growth factor receptor; ENO1, enolase 1; ENOG, human neuron-specific gamma-2 enolase; FAS, fatty acid synthase; FH, fumarate hydratase; G6PD, glucose-6-phosphate dehydrogenase; GLUTs, glucose transporters; GPI, glucose-6-phosphate isomerase; GSH, glutathione; HADH, hydroxyacyl-CoA dehydrogenase; HCC, hepatocellular carcinoma; HER2, epidermal growth factor receptor 2; HIF-1α, hypoxia-inducible factor-1 alpha; HK, hexokinase; HMGCR, 3-hydroxy-3methylglutaryl-CoA reductase; IDH, isocitrate dehydrogenase; IPP, isopentenyl pyrophosphate; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter; MDH1, malate dehydrogenase 1; MDM2, mouse double minute 2; MFS, major facilitator superfamily; MMP, matrix metalloproteinase; mRNA, messenger ribonucleic acid; MSE, muscle-specific enolase; MT1, membrane type 1; mTOR, mammalian target of rapamycin; NADPH, nicotinamide adenine dinucleotide phosphate; NSCLC, non-small-cell lung cancer; nSMase, neutral sphingomyelinase; OCR, oxygen consumption rate; PC, phosphatidylcholine; PDC, pyruvate dehydrogenase complex; PDH, pyruvate dehydrogenase; PDHA, pyruvate dehydrogenase alpha subunit; PDHA1, pyruvate dehydrogenase E1-alpha; PDK, pyruvate dehydrogenase kinase; PEP, phosphoenolpyruvate; PFK, phosphofructokinase; PFKFB, 6phosphofructo-2-kinase/fructose-2,6-bisphosphatase; PGAM1, phosphoglycerate mutase 1; PGD, phosphogluconate dehydrogenase; PGK1, phosphoglycerate kinase; PGM, phosphoglucomutase; PHD2, prolyl-hydroxylase domain; PHGDH, phosphoglycerate dehydrogenase; PK, pyruvate kinase; PPP, pentose phosphate pathway; RNA, ribonucleic acid; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; SCD, stearoyl-CoA desaturase; SDH, succinate dehydrogenase; SGLT, sodium-dependent glucose co-transporter; SIRT3, sirtuin 3; SPT, serine palmitoyl transferase; SREBP1, sterol regulatory element binding protein 1; STIM1, stromal interaction molecule 1; TALDO1, trans-aldolase; TCA, tricarboxylic acid; TIGAR, TP53-induced glycolysis and apoptosis regulator; TKT, transketolase; TNF-α, tumor necrosis factor alpha; TPI, triosephosphate isomerase; VDAC, voltage-dependent anion channel; VHL, von-Hippel Lindau

AUTHOR INFORMATION

Corresponding Authors

*M.F.D.: phone +351 284314399; E-mail fatima.duarte@ cebal.pt. *I.F.D.: phone +351 234401418; E-mail [email protected]. ORCID

Maria F. Duarte: 0000-0002-2223-7784 Iola F. Duarte: 0000-0003-4289-9256 Funding

This work was developed in the scope of the projects CICECO - Aveiro Institute of Materials (ref. FCT UID/CTM/50011/ 2013) and UID/AGR/00115/2013 to ICAAM - Institute of Mediterranean Agricultural and Environmental Sciences, financed by national funds through the FCT/MEC and when applicable co-financed by the European Regional Development Fund (FEDER) under the PT2020 Partnership Agreement. Funding to the project NEucBark−New valorization strategies for Eucalyptus spp. Bark Extracts (PTDC/ AGR-FOR/3187/2012) by FEDER through COMPETE and by national funds through FCT, financial support from the European Union Framework Programme for Research and Innovation HORIZON 2020, under the TEAMING Grant agreement No. 739572 - The Discoveries CTR, and the FCTawarded grants SFRH/BD/98635/2013 are also acknowledged. I.F.D. further acknowledges the FCT/MCTES for research contracts under the Program “Investigador FCT”.

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REFERENCES

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Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED 2-DG, 2-deoxy-D-glucose; 2-PG, 2-phosphoglycerate; 3BP, 3bromopyruvate; 3-PGDH, 3-phosphoglycerate dehydrogenase; 5-FU, 5-fluorouracil; 6PGD, 6-phosphogluconate dehydrogenase; ACC, acetyl-CoA carboxylase; ACL, ATP citrate lyase; ACS, acyl-CoA synthetase; ACSL5, acyl-CoA synthetase 5; ADP, adenosine diphosphate; AH, aconitase; Akt, protein kinase B; AMP, adenosine monophosphate; AMPK, AMPactivated protein kinase; ASMase, acid sphingomyelinase mRNA; ATP, adenosine triphosphate; cDNA, complementary deoxyribonucleic acid; CHC, α-cyano-4-hydroxycinnamate; CoA, coenzyme A; DHA, dihydroartemisinin; DMAPP, dimethylallyl diphosphate; DNA, deoxyribonucleic acid; ECAR, extracellular acidification rate; EGCG, epigallocatechin gallate; EGF, epidermal growth factor; EGFR, epidermal Q


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