Shikonin | Histonemethyltransf Signal

Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy

Shan Wang, Jia-Lei Fu, Hui-Feng Hao, Yan-Na Jiao, Ping-Ping Li *, Shu-Yan Han *
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital and Institute, Beijing 100142, PR China

A R T I C L E I N F O

Keywords:
Cancer cell metabolic reprogramming Traditional Chinese medicine Glycolysis
Lipid metabolism Amino acid metabolism
Chemical compounds studied in this article: Tetrandrine (PubChem CID: 73708) Chlorogenic acid (PubChem CID: 1794427) DT-13 (PubChem CID: 101514160)
Matrine (PubChem CID: 91466) Rhein (PubChem CID: 10168) Emodin (PubChem CID: 3200)
Oleanolic acid (PubChem CID: 10494) Atractylenolide I (PubChem CID: 5321018) Tanshinone IIA (PubChem CID: 164676) Dioscin (PubChem CID: 119245)
Polyphyllin Ⅵ (PubChem CID: 10417550)
Licochalcone A (PubChem CID: 5318998) Euxanthone (PubChem CID: 5281631) Chrysin (PubChem CID: 5281607) Shikonin (PubChem CID: 479503) Scutellarin (PubChem CID: 185617)
Astragaloside IV (PubChem CID: 13943297) Berberine (PubChem CID: 2353)
Brutieridin (PubChem CID: 101485561) Melitidin (PubChem CID: 101485562) L42 (PubChem CID: 5288052)
Resibufogenin (PubChem CID: 6917974) Bufalin (PubChem CID: 9547215) Quercetin (PubChem CID: 5280343) Osthole (PubChem CID: 10228)

A B S T R A C T

Metabolic reprogramming, characterized by alterations of cellular metabolic patterns, is fundamentally impor- tant in supporting the malignant behaviors of cancer cells. It is considered as a promising therapeutic target against cancer. Traditional Chinese medicine (TCM) and its bioactive components have been used in cancer therapy for an extended period, and they are well-known for their multi-target pharmacological functions and fewer side effects. However, the detailed and advanced mechanisms underlying the anticancer activities of TCM remain obscure. In this review, we summarized the critical processes of cancer cell metabolic reprogramming, including glycolysis, mitochondrial oxidative phosphorylation, glutaminolysis, and fatty acid biosynthesis. Moreover, we systemically reviewed the regulatory effects of TCM and its bioactive ingredients on metabolic enzymes and/or signal pathways that may impede cancer progress. A total of 46 kinds of TCMs was reported to exert antitumor effects and/or act as chemosensitizers via regulating metabolic processes of cancer cells, and multiple targets and signaling pathways were revealed to contribute to the metabolic-modulating functions of TCM. In conclusion, TCM has its advantages in ameliorating cancer cell metabolic reprogramming by its poly- pharmacological actions. This review may shed some new light on the explicit recognition of the mechanisms of anticancer actions of TCM, leading to the development of natural antitumor drugs based on reshaping cancer cell metabolism.

Abbreviations: TCM, traditional Chinese medicine; OXPHOS, oxidative phosphorylation; HK, hexokinase; PI3K, phosphatidylinositide 3-kinases; Akt, protein kinase B; GLUT1, glucose transporter type 1; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species; PHGDH, phosphoglycerate dehydrogenase; IDH1, isocitrate dehydrogenase 1; PET/CT, positron emission tomography/computed tomography; PFK, phosphofructokinase; LDHA, lactate dehydrogenase; PKM1/2,pyruvate kinase1/2; ATP, adenosine triphosphate; HIF-1α, hypoxia-inducible factor-1α; VEGF, vascular endothelial growth factor; ADP, adenosine diphosphate; mTOR, mammalian target of rapamycin; ERK, extracellular regulated protein kinases; MNNG, N-methyl-N′-nitro-N-nitrosoguanidine; MCT4, monocarboxylate transporters 4; TNBC, triple-negative breast cancer; FAK, focal adhesion kinase; FASN, fatty acid synthase; ACLY, ATP-citrate lyase; ACAT, acetyl-CoA acetyl- transferase; ACC, acetyl-CoA carboxylase; SREBP, sterol regulatory element binding protein; FABPs, fatty acid-binding proteins; SCD1, stearyl-CoA dehydrogenase1; LDLR, low-density lipoprotein receptor; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3; PCYT2, phosphocholine cytidylyltransferase.

* Correspondence to: Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing 100142, PR China.
E-mail addresses: [email protected] (P.-P. Li), [email protected] (S.-Y. Han).

https://doi.org/10.1016/j.phrs.2021.105728

Received 31 March 2021; Received in revised form 2 June 2021; Accepted 9 June 2021
Available online 11 June 2021
1043-6618/© 2021 Elsevier Ltd. All rights reserved.

Desmethoxycurcumin (PubChem CID:
5469424)
Oridonin (PubChem CID: 5321010) Astragalus polysaccharide (PubChem CID: 2782115)
Protopanaxadiol (PubChem CID: 9920281) Carnosic acid (PubChem CID: 65126) MAP30 (PubChem CID: 451600)
Melittin (PubChem CID: 16133648) Celastrol (PubChem CID: 122724)
Physapubescin I (PubChem CID: 132529929)

1. Introduction

Cell metabolic reprogramming refers to a shift of metabolic patterns of cellular glucose, amino acids, lipids, and nucleic acids. Altered metabolic activities exist in various cancer cells and are considered to be salient hallmarks of cancer [1]. Normal mammalian differentiated cells gain enough energy for cell division and growth from mitochondrial respiration and oxidative phosphorylation (OXPHOS) at normoxic con- ditions and glycolysis at lower oxygen conditions [2]. In contrast, cancer cells still prefer to utilize glycolysis at normoxic conditions rather than OXPHOS to generate energy, which is the most classical reprogrammed metabolic pathway termed as “aerobic glycolysis” or “Warburg effect”
[3,4]. In addition to glucose metabolism, the metabolic patterns of lipids and amino acids in cancer cells have changed as well. For instance, the uptake and de novo biosynthesis of fatty acids and cholesterol increase significantly in some tumor cells, and the excessive lipids are accumu- lated to form lipid droplets for bioenergetics storage [5]. Similarly, certain specific amino acids, such as glutamine, serine, and glycine, are overexpressed in various cancers and show tumor promotion effects [6]. In brief, the metabolic reprogramming is adapted to the bioenergetic, biosynthetic, and redox homeostatic demands for the vigorous prolif- eration of cancer cells.
Cancer cells undergo complex metabolic regulations and alterations. Oncogenic mutation and proto-oncogenes expression may enhance the activity of certain metabolic enzymes to achieve nutrients acquisition and maintenance, resulting in metabolic reprogramming in cancer cells [7]. For example, high expression of c-Myc facilitates glucose/glutamine transportation and uptake. It also increases metabolic enzyme levels to enhance glycolysis, glutaminolysis, fatty acids synthesis, nucleotide, and mitochondrial metabolism [8–11]. Mutated Ras and c-Src may assist
cancer cells in transporting extracellular proteins and cellular debris through phagocytosis for much more amino acids and lipids demands [12]. K-ras could directly regulate glycolytic enzyme, such as hexoki- nase1 (HK1) [13], and its transformation leads to mitochondrial dysfunction and a metabolic switch from OXPHOS to glycolysis [14], which promotes tumorigenesis, particularly in the lung, colorectal, and pancreatic tissues [15]. Besides, some signaling transduction pathways also play a significant role in metabolic reprogramming. The activated PI3K/Akt pathway stimulates glucose uptake and enhances glycolysis and lipids biosynthesis by regulating glucose transporter type1 (GLUT1) expression and translocation from cell endomembrane to the surface [16,17]. In contrast, tumor suppressors like p53 and PTEN could reverse the Warburg effect and function their antitumor effects by inhibiting metabolic-associated pathways [18]. The loss of p53 would break the balance of glycolysis and OXPHOS and induce the production of reactive
[21–23]. For example, 18 F-fluorodeoxyglucose, a radioactive fluorine-labeled glucose analog, has been successfully used in PET/CT imaging to help tumor diagnosis, staging, and therapy efficacy evalua- tion due to different glucose uptake rates between tumor and adjacent normal tissue [24]. Moreover, some chemodrugs derived from natural herbal products, such as vinca alkaloids, taxanes, and camptothecins, exert their antitumor effects by interfering with cell metabolic path- ways. Besides, the inhibitors of critical metabolic enzymes are consid- ered as potentially promising antitumor agents. However, their non-specific cell toxicity could impair the proliferation of normal cells like immune cells and stem cells and might bring serious side effects or drug resistance [25]. Therefore, finding more effective and safe com- pounds derived from herbal medicines would be constructive and meaningful for anticancer drug development [26].

TCM has been widely used alone or as a complementary approach for cancer treatment in East Asia over hundreds of years [27]. Extensive evidence indicated that TCM possesses definite advantages over conventional therapies in terms of fewer side effects, lower toxicity, and less economic burden [27–29]. Although previous studies have summarized the progress of TCM for their antitumor and chemo-sensitization effects by regulating reprogrammed metabolic pathways [30,31], a compre- hensive and systematic review on their molecular mechanisms still needs to be replenished and re-summarized. Therefore, we retrieved relevant literature through the database Web of Science over the past six years (from 2015 to 2020), mainly focusing on regulatory effects of TCM on glycolysis, mitochondrial metabolism, fatty acid biosynthesis, cholesterol biosynthesis, and glutaminolysis in cancer cells. This review provides more detailed information on the influence and mechanisms of TCM and their active ingredients on cancer metabolic reprogramming, which would contribute to a deeper understanding of TCM’s effects on
cancer cells. We hope, through this review, to illustrate certain bioactive compounds with desirable efficacy and lower side effects from TCM and offer promising therapeutic agents by targeting cancer metabolic reprogramming.

2. Regulatory effects of traditional Chinese medicine on cancer metabolic reprogramming
2.1. Regulation on glucose and mitochondrial metabolism
Glucose is an essential intracellular source of energy and material for cancer cells. Reprogrammed glucose metabolism provides enough en- ergy and abundant biosynthetic intermediates for the biosynthesis of necessary macromolecules (lipids, amino acids, and nucleic acids) to support the rapid proliferation of cancer cells [32,33]. Meanwhile,oxygen species (ROS), resulting in tumorigenesis [19]. Notably,
lactate, a by-product of glycolysis, interacts synergistically with thealthough it is rare, genetic mutation of metabolic enzymes could also lead to abnormal metabolisms, such as phosphoglycerate dehydroge- nase (PHGDH) mutation in breast cancer and melanoma or isocitrate dehydrogenase1 (IDH1) mutation in glioma and acute myelocytic leu- kemia [20].

Admittedly, illuminating molecular mechanisms of reprogrammed metabolic process in cancer cells and targeting the key pathways would
tumor microenvironment to facilitate tumor immunosuppression [34]. Mechanistically, multiple oncogenes and their targeted metabolic en- zymes, including phosphofructokinase (PFK), hexokinase (HK), lactate dehydrogenase (LDHA), and pyruvate kinase1/2 (PKM1/2) [35], could promote glycolysis, leading to tumorigenesis, progression, and metas- tasis [36,37]. Inversely, blockage of glycolysis could reverse this process in various cancer types [38,39]be helpful to discover novel therapeutic approaches for cancer treatment
Notably, although high glycolytic flux exists in tumor glucose metabolism, mitochondrial respiration and OXPHOS still generate the majority of ATP to support cancer cell proliferation [40].

Proper cellular ATP level and redox balance are essential for tumor cell growth, and the disruption of mitochondrial homeostasis would promote tumor prolif- eration and metastasis [21]. Interestingly, it has been reported that some cancer cells adapted to the changes of the metabolic environment through a transition between glycolysis and OXPHOS [41]. Besides, ROS, produced by mitochondrial respiration and OXPHOS, have dual effects on tumor cells. ROS could activate multiple redox signaling pathways to promote tumorigenesis, progression, and metastasis, but excessive ROS may lead to tumor cell death by inducing cell stress and damage [42].

Recent studies indicate that some antineoplastic components from TCM possess regulatory effects on glucose metabolism, and metabolic- associated factors and enzymes may become their potential targets [43]. The detailed regulatory mechanisms are summarized in Table 1. Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, was reported to possess antitumor effects [44] and enhance efficacies of protein kinase inhibitor H89 [45] and paclitaxel [46]. Tetrandrine reduced glucose uptake and induced apoptosis in human prostate cancer PC-3 cells [47], and it impaired mitochondrial metabolism and increased ROS production to inhibit the growth of HepG2 [48] and A459 cells [49]. Chlorogenic acid, a phenolic acid derived from Eucommia ulmoides Oliv. or Lonicera japonica Thunb, could
regulate glucose uptake and transportation in HepG2 cells [50] and inhibit hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial
growth factor (VEGF) expression in DU145 [51] and A549 cells [52] to suppress tumor angiogenesis and progression. Besides, chlorogenic acid can also inhibit the viability of HT-29 and HCT-116 cells via inducing ROS generation [53]. DT-13, a saponin monomer derived from Liriopes Radix, was reported to inhibit glucose uptake, ATP generation, and lactate production via remarkably hindering GLUT1 expression in human colorectal cancer cells.

Mechanistic investigation indicated that DT-13 activated AMPK and inhibited mTOR to block cell growth in vitro [54]. Matrine, a significant ingredient from dried roots of Sophora fla- vescens Ait. (Leguminosae), was demonstrated to possess antitumor ef- ficacy via reversing the Warburg effect, decreasing the expression ofHIF-1α and its target genes including GLUT1, HK2, and LDHA, thus
inhibiting glucose uptake and lactate production [55,56]. Likewise, matrine down-regulated HK2 expression in breast cancer MCF-7 cells
[57] and myeloid leukemia cells [58], and it also induced apoptosis through activating Mst1-JNK pathways mediated mitochondrial fission in liver cancer HepG2 cells [59].

Moreover, in pancreatic cancer cells, matrine suppressed K-ras-driven growth by inhibiting mitochondrial metabolic function and energy level [60]. Interestingly, compound Kushen injection, a herbal mixture containing matrine, oxymatrine, as well as other alkaloids and flavonoids, was demonstrated to decrease glucose uptake and lactate production in breast cancer MDA-MB-231 cells and HepG2 cells [61].
Rhein and emodin, the bioactive components isolated from Rheumpalmatum, could inhibit pancreatic cancer cell growth by inhibiting the expression of HIF-1α in vitro and attenuate cachexia in athymic mice [62]. Rhein was also reported to inhibit hepatocellular carcinoma cell
growth and reverse doxorubicin resistance via decreasing cellular ATP and ADP levels and altering the ratio of ATP to ADP [63]. Oleanolic acid, a triterpenoid component derived from the leaves and roots of Oleaceae family plants, suppressed gastric tumor cell growth through lessening glucose uptake and consumption by down-regulating the expression ofHIF-1α, HK2, and PFK1 [64].

Similarly, oleanolic acid reversed the
Warburg effect by down-regulating the expression of aerobic glycolytic enzymes and inducing cell apoptosis in breast cancer cells [65]. Carpe- sium abrotanoides L. was used widely as a medical herb in Asia, and its ethanol extract exerted anti-breast cancer activity by lowering the expression levels of GLUT-1, HK2, LDHA, and PKM2 [66]. Atractyle- nolide I is one of the main antineoplastic bioactive components of Baizu (Atractylodes macrocephala Koidz). A study revealed that atractylenolide I inhibited colorectal cancer cell proliferation and invasion by raising ROS generation and reducing the Warburg effect via Akt/mTOR signaling pathway [67]. Tanshinone IIA, a diterpenoid naphthoquinone derived from Salvia miltiorrhiza, inhibited cervical cancer SiHa cell viability and decreased glycolysis through suppressing GLUT1, PKM2,and HK2, as well as Akt/mTOR and HIF-1α [68].

Likewise, another studyproved that Tan IIA inhibited HK2-mediated aerobic glycolysis in oral squamous carcinoma cells via reducing Akt/c-myc signaling [69].Dioscin is a kind of steroid saponins isolated from Dioscoreae rhizome or Paridis rhizome, which was demonstrated to inhibit colorectal cancer cell proliferation and xenograft growth in nude mice. Mechanistically, dioscin promoted the ubiquitination of c-myc and subsequently inhibi- ted HK2 expression [70]. Polyphyllin Ⅵ, another bioactive component from Paridis rhizome, decreased glycolysis associated proteins like GLUT1, HK2 and, LDHA through inhibiting ERK/c-myc pathway in esophageal cancer cells [71]. Licochalcone A, a chalcone extracted from liquorice, significantly suppressed glucose consumption and lactate production in gastric cancer cells via blocking the Akt/HK2 pathway [72]. Furthermore, euxanthone and chrysin were reported to inhibit glycolysis through weakening HK2 expression and inducing apoptosis in epithelial ovarian cancer and hepatocellular carcinoma cells [73,74].

Shikonin, a naphthoquinone bioactive component isolated from Lithospermumn erythrorhizon, dose-dependently inhibited glucose uptake and lactate production via decreasing PKM2 activity in Lewis lung car- cinoma and B16 melanoma cells. Moreover, Shikonin also decreased tumor cell ATP generation and triggered mitochondrial dysfunction in human hepatocellular carcinoma cells [75,76]. Similarly, Scutellarin, a bioactive flavonoid isolated from Erigeron breviscapus, directly inhibited PKM2 cytosolic activity to suppress glycolysis [77]. Astragaloside IV, a main bioactive ingredient of Astragalus membranaceus, inhibited the growth of gastric cancer BGC823 cells [78] and reversed N-methyl–
N′-nitro-N-nitrosoguanidine (MNNG) induced precancerous lesions of gastric carcinoma in rats via up-regulating the expression of LDHA, p53, HIF-1α, and CD147 [79]. Weipixiao decoction, a traditional herbal formula, was found to have protective effects against MNNG-induced gastric precancerous lesions through reducing the expression levels of monocarboxylate transporters 4 (MCT4), LDHA, CD147, PI3K, Akt,
mTOR, and HIF-1α [80].

Berberine is a bioactive alkaloid isolated from various Chinese herbs such as Coptis chinensis Franch. Combined treatment with berberine and 2-deoxyglucose, an inhibitor of glucose metabolism, synergistically enhanced tumor suppression by inhibiting OXPHOS and subsequent ATP depletion [81]. Brutieridin and melitidin, natural bioactive components isolated from bergamot, had been demonstrated to possess inhibitory effects on OXPHOS and fatty acid oxidation in breast cancer cells [82]. L42, extract of Lippia origanoides, triggered rapid and irreversible apoptosis via suppressing mitochondrial metabolism in triple-negative breast cancer (TNBC) cells [83].

Some bioactive ingredients originated from animals in TCM also exert antitumor effects through reducing aerobic glycolysis. For example, Oviductus ranae is extracted from desiccated oviducts of fe- male R. chensinensis, and is composed of proteins, unsaturated fatty acids, polysaccharides, and nucleic acids. Research suggested that its protein hydrolysate significantly inhibited human hepatocellular carci- noma cell growth, proliferation, migration, and invasion through regu- lating miR-491–5p/PKM2 axis and subsequent glycolysis [84].

Cinobufacini is extracted from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor, and its marker ingredient resibufo- genin was reported to possess antitumor activities. Specifically, resibu- fogenin could downregulate the expression of proto-oncogene PIM1 and suppress the glycolysis and cell growth in ovarian cancer cells [85]. Bufalin, the major digoxin-like component of Bufonis venenum, was
reported to inhibit cell growth by suppressing the integrin β2/FAK
signaling pathway in ovarian cancer [86].

Table 1
Regulation of traditional Chinese medicine and its bioactive compounds on glucose and mitochondrial metabolism.
Bioactive compounds Chinese herbs Cancer cells Regulatory ways Potential mechanisms
Tetrandrine Stephania tetrandra S. Moore PC-3
HepG2 Glucose uptake Mitochondrial Induces glucose uptake and cell apoptosis [47] Impairment of mitochondrial function [48]

metabolism
A549 Mitochondrial
metabolism

Inhibition of ATP biosynthesis and induction of ROS [49]

Chlorogenic acid Eucommia ulmoides Oliv. Lonicera japonica Thunb.
HepG2 Glucose uptake Modulation in glucose uptake [50]
DU145 Glycolysis Decrease in expression of HIF-1α protein level [51]
A549 Glycolysis Decrease in expression of HIF-1αprotein level [52]
HCT-116 HT-29 Mitochondrial function Induction of ROS generation [53]

DT-13 Liriopes Radix HCT-15, HCT-116, COLO- 205, HT-29, SW-620 and SW480
Glucose uptake and glycolysis
Inhibition of GLUT1 and mTOR and activation of AMPK [54]

Matrine Sophora flavescens Ait. HCT-116 SW620 Glucose uptake and
Glycolysis
Inhibition on glucose uptake and lactate production and decrease in expression of HIF-1α, GLUT1, HK2 and LDHA [56]

MCF-7 Glycolysis Down-regulation of HK2 expression [57]
K562 HL-60 Glycolysis Down-regulation of HK2 expression and up-regulation
of Bad expression [58]

Human liver cancer cell lines: Huh-7, Huh-7.5, Bel-7402, HepG2, Hep3B, SMMC-7221, LM3 and HL-7702. Human prostate cancer cell lines: LNCaP, C4-2, PC-3 and DU145. Human breast cancer cell lines:MD-MBA-231, MDA-MB-157, MDA-MB-468, MCF-7, HBL-100, HCC1806, DLD1 and T47D. Ovarian cancer cell lines: HEY-T30, SKOV3, A2780 and OVCAR-3. Human colorectal cancer: SW480, SW620, HCT-116, HT-29, HCT-15, LOVO and COLO-205. Uveal melanoma cell lines: OCM-1, MUM2B. Human pancreatic cancer cell lines: SW1990, Capan1, AsPC-1, BxPC-3, 8988 T, MiaPaCa2 and Panc-1. Fibrosarcoma cell lines: HT1080. Nasopharyngeal carcinoma: C666-1. Human lung carcinoma cell lines: A549, H460, H1299. Human gastric adenocarcinoma cell lines: SGC-7901, MKN-45, GES-1. Human CML cell
line: K562. Human AML cell line: HL-60. Human cervical cancer cell lines: SiHa, HeLa and C33a. Human oral squamous carcinoma cell lines: SCC9, SCC15, SCC25 and CAL27. Human esophageal cancer cell lines: KYSE150, EC109. Human melanoma cell line: B16.

2.2. Regulation on lipids metabolism

Lipids are indispensable for the development and progression of malignant cells. Specifically, fatty acids, triglycerides, phospholipids, and cholesterol participate in multiple biological processes, including energy storage, membrane biosynthesis, and cellular signaling trans- duction [87]. Metabolic rate-limiting enzymes such as fatty acid syn- thase (FASN), ATP-citrate lyase (ACLY), acetyl-CoA acetyltransferase 2 (ACAT2), and acetyl-CoA carboxylase (ACC) overexpressed, particularly in some non-glycolytic tumors like lymphoma [88] and prostate cancer [89], which increase the de novo biosynthesis of fatty acids and cholesterol. Sterol regulatory element-binding protein (SREBP), a crit- ical activator for the lipid metabolic pathways [90], facilitates and regulates the biosynthesis and homeostasis of fatty acids and cholesterol [91]. In detail, SREBP1 and SREBP2 regulate the biosynthesis of fatty acids and cholesterol, respectively, which jointly promote tumorigen- esis, tumor development, and progression [92].
Previous reviews indicated that some natural products derived from TCM suppressed fatty acids biosynthetic pathway by targeting metabolic enzymes and were regarded as promising inhibitors for cancer treatment [93].

Fatty acid-binding proteins (FABPs) are intercellular fatty acid transporters and overexpress in tumor cells. GL22, a natural triterpene compound isolated from Ganoderma mushrooms, decreases the expres- sion of FABPs in human hepatocellular carcinoma cells, resulting in the loss of mitochondrial lipid cardiolipin, mitochondrial dysfunction, and cell death [94]. Ganoderma tsugae is another species of ganoderma. Its ethanol extract could decrease the levels of intracellular fatty acids and lipids via inhibiting SREBP-1 expression and thus exert an anti-proliferation effect in prostate cancer cells [95]. Processed Heshouwu is the product of Polygoni multifori Radix, and its ethanol extract was reported to reduce fatty acids production via inhibiting SREBP-1 and its downstream factor stearyl-CoA dehydrogenase1 (SCD1) in hepatocellular carcinoma cells [96]. Quercetin is a flavonoid com- pound widely presented in red onions, apples, tea, nuts, and berries. Studies had demonstrated that quercetin induces apoptosis in HepG2 and TNBC cell lines by potently inhibiting FASN expression [97,98].

Osthole, a coumarin derivative isolated from the fruit of Cnidium mon- nieri (L.) Cusson, was demonstrated to inhibit FASN expression and induce apoptosis in breast and hepatocellular cancer cell lines through restraining Akt/mTOR pathway and ERK phosphorylation [99,100]. Desmethoxycurcumin, a kind of curcuminoid from the rhizomes of turmeric, showed potent cytotoxic effects on TNBC cells by inhibiting FASN and ACC expression levels [101]. Oridonin is a natural diterpenoidisolated from Rabdosia rubescens and was shown to have broad anti-
cancer activities.

A study pointed out that oridonin effectively inhibited SREBP1 and FASN expression and reduced the transcriptional activity of FASN promoter region in human colorectal cancer cells [102]. Another study revealed that oridonin could suppress FASN expression and enhance proapoptotic protein Bim expression in uveal melanoma cells [103]. Astragalus polysaccharides, as one of the main effective compo- nents of Astragalus, significantly decreased cellular triglyceride and cholesterol levels and inhibited cell proliferation and invasion via lowering the expression and nuclear translocation of SREBP1 in prostate cancer [104].

On the other hand, cholesterol metabolism is equally vital for the survival and growth of cancer cells. Extensive investigations have shown that multiple intrinsic and extrinsic factors reprogramed cholesterol metabolism, and interfering cholesterol metabolic process may under- mine tumorigenesis and progression [105]. Emodin, aside from its inhibitory effect on glycolysis mentioned above, also abated SREBP2 transcriptional activity to attenuate cholesterol biosynthesis and sup- press Akt signaling in human hepatocellular carcinoma cells [106]. Protopanaxadiol is a ginseng metabolite and was shown to inhibit the expression of FASN, SCD, and ACAT2, and induced apoptosis in colo- rectal cancer cells [107]. Carnosic acid, a polyphenol extract from rosemary, decreased cholesterol synthesis via inhibiting ACAT2 expression in human colorectal cancer HT-29 cells [108]. Compound Fuling granule suppressed cell growth, migration, and metastasis of ovarian cancer, and its inhibitory effects were likely associated with disruption of mitochondrial function, galactose, and fatty acid meta- bolism [109]. Bitter melon extract was demonstrated to suppress TNBC cell growth via disrupting cholesterol esterification by inhibiting ACAT1 expression [110]. MAP30, a bioactive protein isolated from bitter melon, exhibited potent anticancer and anti-chemoresistance effect on ovarian cancer cells via suppressing GLUT-1/ 3-mediated glucose up- take, adipogenesis, and lipid droplet formation during tumor develop- ment and progression [111].

Actinidia chinensis Planch root extract was used to treat various types of cancer. A study indicated that it inhibited human hepatocellular carcinoma cell proliferation by lessening low-density lipoprotein uptake and intracellular cholesterol levels via reduction of low-density lipoprotein receptor (LDLR) expression [112]. Melittin, a water-soluble toxic peptide derived from bee venom, was reported to down-regulate the cholesterol biosynthesis, promoting cell apoptosis and cell-cycle arrest in pancreatic ductal adenocarcinoma cells [113]. Celastrol, a triterpene derived from the Tripterygium wilfordii Hook f, was demonstrated to trigger lipophagy and ultimately inhibit cell growth, proliferation, migration, and invasion in clear cell renal cell carcinoma [114]. The detailed information about the effect of natural products on lipids metabolism is summarized in Table 2.

2.3. —
Regulation on amino acids metabolism Amino acids are irreplaceable intermediates linked glucose meta- bolism to lipids metabolism. Reprogrammed amino acid metabolism plays a vital role in malignant cancers, including breast cancer, non- small cell lung cancer, ovarian cancer, and melanoma. Glutamine is a non-essential amino acid for humans and could replace glucose in the TCA cycle at hypoxic conditions. Consequently, high glutamine levels provide carbon and nitrogen sources to support tumor growth and progression [115]. Glutaminolysis-associated biomarkers such as glutamine transport proteins and glutamine biosynthetic enzyme glutaminase are highly expressed in various cancer types [116]. In contrast, inhibition of glutaminase could contribute to restraining tumorigenesis and progression [117]. Besides, serine/glycine biosyn- thesis is critical and vital for tumorigenesis [118], the absence of ser- ine/glycine was found to decrease glutathione synthesis and increase ROS levels [119]. Down-regulated metabolic rate-limiting enzymes like phosphoserine phosphatase and enolase1 could disrupt the ser- ine/glycine metabolism mediated tumor-promoting effect [20].
Targeting amino acid metabolism would be another promising way to discover potent and selective inhibitors and effective novel strategies in cancer treatment [120]. Recent studies reported that certain Chinese herbs and formulas targeted amino caid metabolic pathways to function their antitumor efficacy. Physapubescin I, a bioactive ingredient isolated from the fruits of edible herb Physalis pubescens L. increased intracellular glutamine and decreased glutamate and its metabolites, thus inhibiting cell proliferation and inducing cell apoptosis in pancreatic cancer [121]. Glycyrrhiza glabra is a typical Chinese herbal medicine used for treating inflammation and allergy, and its root extract was proved to have anticancer efficacy in nasopharyngeal carcinoma cells. Metabolomics analysis pointed out that down-regulated metabolites of fatty acid biosynthesis, abated metabolism of glutamate, serine, and threonine may contribute to the anticancer effect of G.glabra [122]. Another study showed that the depression of glutamine levels and related metabolic alteration might contribute to the antitumor properties of Hedyotis dif- fusa [123]. Llex tarajois (Kudingcha) is a traditional beverage in China

Table 2
Regulation of traditional Chinese medicine and its bioactive compounds on lipids and amino acids metabolism.

Bioactive compounds Chinese herbs Cancer cells Regulatory ways Potential mechanisms
GL22 Ganoderma leucocontextum Huh7.5 Lipids metabolism Inhibition of FABPs expression [94]
Ganoderma tsugae ethanol Ganoderma tsugae LNCaP and C4–2 Lipids metabolism Inhibition of the expression of SREBP-1

extract [95]
Zhiheshouwu ethanol extract Polygoni multifori Radix Bel-7402 Lipids metabolism Inhibition of the mRNA and protein levels
of SCD1 and SREBP1 [96]
Quercetin Red onions, apples, tea and berries, etc. HepG2 Lipids metabolism Inhibition of FASN expression [97]

MDA-MB-231 MDA-MB-157
Osthole Cnidium monnieri (L.) SKOV3, MDA- MB-231, MCF-7 and HBL-100 HepG2 and SMMC-7221
Lipids metabolism Inhibition of FASN expression [98] Lipids metabolism Inhibition of FASN expression [99]
Lipids metabolism Inhibition of FASN expression [100]

Desmethoxycurcumin rhizomes of turmeric MDA-MB-231 Lipids metabolism Inhibition of FASN and ACC [101]

Oridonin Rabdosia rubescens SW480 and SW620
OCM-1 and MUM2B
Lipids metabolism Inhibition of FASN and SREBP1 mRNA
and protein expression and reduction of transcriptional activity of FASN [102]
Lipids metabolism Inhibition of FASN expression and
increase in Bim expression [103]

Astragalus polysaccharides Astragalus PC3 and DU145 Lipids metabolism Inhibition of SREBP-1 expression and nuclear translocation [104]

Emodin Rheum palmatum HepG2, Hep3B, SK-HEP-1, Huh7 PLC/PRF5
Lipid metabolism Inhibition the transcriptional activity of SREBP-2 [106]

Protopanaxadiol Ginseng HCT116 Lipids metabolism Inhibition of gene expression involved in fatty acid and cholesterol synthesis [107]
Carnosic acid Rosmarinus officinalis L. HT-29 Lipids metabolism Inhibition of ACAT-2 expression [108]

Compound Fuling granule Poria cocos (Schw.) Wolf HEY-T30 and SKOV3
Mitochondrial function and lipid metabolism
Disruption of mitochondrial function, galactose and fatty acid metabolism [109]

Bitter melon extract Momordica charantia MDA-MB-231 MDA-MB-468
Lipids metabolism Suppression of cholesterol esterification
by inhibiting ACTA-1 expression [110]

MAP30 Momordica charantia A2780cp Glucose uptake and lipids metabolism
Suppression of GLUT-1/— 3,
adipogenesis, lipid droplet formation [111]

Actinidia chinensis Planch root extract
Actinidia chinensis LM3, HepG2 and
HL-7702
Lipids metabolism Inhibition of LDLR expression and low-
density lipoprotein uptake [112]

Melittin Bee venom SW1990, Capan1, AsPC-1 and BxPC- 3
Celastrol Tripterygium wilfordii Hook f 786-O, A498, SN12C, OS-RC-2
and HK-2
Lipids metabolism Downregulation of cholesterol pathways
[113]

Lipids metabolism Induction of lipophagy and cholesterol efflux [114]

Physapubescin I Physalis pubescens L. (Solanaceae) SW1990 and HT1080
Amino acids metabolism
Increase of glutamine and decrease of glutamate and its downstream metabolites[121]

Glycyrrhiza glabra root extract Glycyrrhiza glabra L. C666–1 Lipid metabolism and
amino acids metabolism
Hedyotis diffusa Hedyotis diffusa Walker-256 Amino acids metabolism
Down-regulation of the level of lipids and amino acids [122]
Decrease of glutamine expression levels [123]

Kudingcha Ligustrum robustum MDA-MB-231 and HCC1806
Glycolysis and amino acid metabolism
Inhibition of glycolysis and glutamine metabolism [124]

Betulinic acid Betulonic acid Botulin Semialactic acid
Rhus chinensis Mill SW620 and
HCT116
Glycolysis and amino acid metabolism
Inhibition in glucose, aspartate and glutamine metabolism [125]

Modified Si Jun Zi Tang Baizhu, Ginseng, Fuling, Gancao, Huanglian, and
Oldenlandia diffusa

Qi-Yu-San-Long Decoction Astragali radix Polygonati odorati rhizoma Scolopendra
Pheretima Solanum nigrum Hedyotis diffusa Coicis semen Euphorbia helioscopia Curcumae Rhizoma Fritillariae cirrhosae bulbus
SGC-7901 Glycolysis, amino acids and lipids metabolism
A549 Amino acids and lipids metabolism
Inhiation of mRNA and proteins expression of LDH, GS and PCYT2 [126]
Regulation of bookmarks of amino acid and lipids metabolism [127]

Human liver cancer cell lines: Huh 7.5, Bel-7402, HepG2, SMMC-7221, LM3, HL-7702. Rat liver cancer cell lines: Walker-256 cells. Human prostate cancer cell lines: LNCaP, C4-2, PC-3, DU145. Human breast cancer cell lines:MD-MBA-231, MDA-MB-157, MDA-MB-468, MCF-7, HBL-100, HCC1806. Ovarian cancer cell lines: HEY- T30, SKOV3, A2780cp, Human colorectal cancer: SW480, SW620, HCT116, HT-29. Uveal melanoma cell lines: OCM-1, MUM2B. Pancreatic ductal adenocarcinoma cell lines: SW1990, Capan1, AsPC-1 and BxPC-3. Fibrosarcoma cell lines: HT1080. Nasopharyngeal carcinoma: C666-1. Human lung carcinoma cell lines: A549. Human gastric adenocarcinoma cell lines: SGC-7901. Human ccRCC cell lines: 786-O, A498, SN12C, and OS-RC-2. Renal epithelial cell line: HK-2 with poly-pharmacological functions. The study indicated that Kuding- cha treatment caused metabolic alteration of glycolysis and glutamine and induced ROS production, ultimately suppressing TNBC cell growth [124]. Rhus chinensis Mill was used to treat some types of cancer, and its flavonoids ingredients could inhibit colorectal cancer cell proliferation.

A recent study revealed that its triterpenoid ingredients, such as semi- alactic acid, betulinic acid, betulonic acid, and botulin, could inhibit glycolysis and glutaminolysis-related enzymes such as enolase1, fructose-bisphosphate aldolase A (ALDOA), phosphofructo-2-kinase/ fructose-2,6-biphosphatase3 (PFKFB3), PKM2, and LDHA in colorectal medicines, was reported to exhibit potent antitumor effects on nude mice models of gastric cancer by decreasing the expression levels of LDHA, glutamine synthetase, and phosphocholine cytidylyltransferase (PCYT2) in glycolysis, glutaminolysis, and lipid metabolism [126]. Qi-Yu-San-Long Decoction, a prescription consisted of 10 traditional Chinese herbs, was used to treat lung carcinoma with a credible clinical curative effect for over twenty years. Metabolomics analysis revealed that intercellular amino acids and lipids metabolic pathways may contribute to its inhibitory efficacy [127]. The detailed information about the effect of natural products from TCM and its formulas on amino acid metabolism is summarized in Table 2.

3. Discussion

Cancer metabolic reprogramming is heterogeneous and has diverse metabolism pattern preferences in different cancer types. In contrast to predominantly manipulate single metabolic pathway target by con- ventional chemotherapeutics and molecular inhibitors, TCM and its bioactive ingredients usually affect multiple metabolic targets to exert antitumor effects. In this review, we summarized the molecular mech- anisms progress of 46 TCMs and their bioactive components (including 40 herbal medicines, 3 animal medicines, and 3 Chinese prescriptions)
organic acids, and triterpenoids, targeting the critical metabolic rate- limiting enzymes (e.g., HK2, LDHA, SREBP-1, FASN). For example, studies revealed that multiple components, including matrine [56], oleanolic acid [64], dioscin [70], and chrysin [74], could suppress tumor proliferation by inhibiting HK2 expression. I

n addition, the ma- jority of bioactive components were reported to regulate glucose and/or lipids metabolic pathways, and a few of them modulated amino acid metabolism. For example, matrine could inhibit two metabolic path- ways, including glucose uptake and glycolysis [56–58]. Similarly, emodin and rhein could suppress glycolysis and attenuate cholesterol biosynthesis simultaneously [62,106]. Only one prescription, Modified Si Jun Zi Tang, was found to decrease the expression of various metabolic-associated enzymes in glucose, lipid, and amino acid meta- bolism by metabolomic analysis. However, the interaction mechanisms need further study [126]. Overall, the detailed mechanisms of metabolic reprogramming by TCM illustrated in this paper were summarized in Tables 1–2 and visualized in Fig. 1. Additionally, we have found that apart from directly inhibiting cancer cell viabilities, some TCM could also enhance the antitumor ef- ficacies of conventional chemotherapeutics via interfering with the metabolic pathways. For instance, Shikonin, a bioactive component derived from Lithospermum erythrorhizon, was demonstrated to inhibit Regulatory mechanisms on reprogrammed metabolic pathways by traditional Chinese medicines TET: Tetrandrine, CGA: Chlorogenic acid, DT-13: a saponin monomer derived from Liriopes Radix MAT: Matrine, CKI: Compound Kushen Injection, OA: Oleanolic acid, PCA: ethanol extract of Carpesium abrotanoides L. ATL1: Atractylenolide I, Tan IIA: Tanshinone IIA, POL: Polyphyllin Ⅵ, LicA: Licochalcone A, EUX: Euxanthone, CHR: Chrysin, SHI: Shikonin, SCU: Scutellarin, ASIV: Astragaloside IV, WPXD: Weipixiao decoction, BBR: Berberine, BRU: Brutieridin, MEL: Melitidin, L42: extract of Lippia origanoides, ORPH: protein hydrolysate of Oviductus ranae, RB: resibufogenin, GTEE: ethanol extract of Ganoderma tsugae, HSWE: ethanol extract of Polygoni multifori Radix, QUE: Quercetin, OST: Osthole, DMC: Desmethoxycurcumin, ORI: Oridonin, PPD: Protopanaxadiol, CFG: Compound Fuling granule, BME: Bitter melon extract, MP30: a bioactive protein from bitter melon, acRoots: Actinidia chinensis Planch root extract, MEL: Melittin, CEL: Celastrol. PHY: Physapubescin I, GGE: Glycyrrhiza glabra extract, KDC: Llex tarajois (Kudingcha), RHU: Rhus chinensis Mill, MSJZT: Modified Si Jun Zi Tang, QYSLD: Qi-Yu-San-Long Decoction.glycolytic pathway via decreasing PKM2 activity [75,76] and induced intracellular oxidative stress by activating the mitochondrial pathway. Additionally, Shikonin could effectively enhance the antitumor effect of cisplatin and reverse its drug resistance in vivo and in vitro [128]. Corilagin is a low toxic bioactive component from Phyllanthus niruri L and could sensitize epithelial ovarian cancer cells to paclitaxel and carboplatin treatment by inhibiting glycolytic pathways [129].

Huang Qi injection alleviated cisplatin-induced nephrotoxicity and improved the disturbed metabolic balance caused by repeated cisplatin treatment [130]. In theory, we consider that these typical Chinese herbal medi- cines could be used as potential antitumor agents and chemosensitizers to overcome drug resistance and reduce side effects. Unlike conventional cancer therapies such as surgery, chemotherapy, and radiotherapy that mainly focus on the disease itself, the practice of TCM aims to enhance the body’s ability to fight against cancer by mobilizing and regulating the whole body’s function. Spe- cifically, the treatment strategies of TCM emphasize on promoting blood circulation, supporting health and energy while strengthening body resistance against diseases, clearing excessive heat, delivering systemic detoxification, resolving phlegm production, dispersing edema, and relieving pain [30]. For instance, berberine, an alkaloid isolated from Coptis chinensis Franch., apart from controlling cancer development [131], could simultaneously alleviate neuropathic pain induced by paclitaxel or tumor invasion, improving cancer patient’s life quality
[132].

TCM shows substantial advantages in inhibiting cancer cell growth and proliferation in vitro by regulating metabolic pathways. A few studies verified the inhibitory effects of natural constituents in vivo via the mice xenograft model. Nevertheless, it should be pointed out that the quality of some studies is not good enough and need further systemic research. Besides, we cannot confuse the concept that natural constitu- ents are must be more gentle or non-toxic than synthesized chemical drugs [29]. Some TCM possesses hepatotoxicity or nephrotoxicity that may cause irreversible impairment to patients. According to the tradi- tional theory of compatibility, toxic herbal medicines should be used in combination with other proper traditional Chinese medicines to reduce the possible toxicity [133]. Therefore, there are still challenges for TCM
in production standardization and quality control. Moreover, random- ized controlled clinical trials are necessary for the TCM’s efficacy eval- uation on cancer treatment through interfering reprogrammed cell
metabolism.

4. Conclusion

In conclusion, this review primarily focuses on the regulatory effects of Chinese herbal medicines and their ingredients on reprogrammed cancer cell metabolism in terms of glucose, lipid, and amino acid metabolism. Overall, TCM has efficient inhibitory effects on tumor cells and chemo-sensitizing effects on chemodrugs by regulating cancer cell metabolic reprogramming. More importantly, TCM could ameliorate cancer/chemotherapy-induced pain and improve the life quality of cancer patients because of its poly-pharmacological effects. We consider that TCM has potent potential as an alternative approach and chemo- sensitizer for clinical cancer therapy. More bioactive compounds iden- tified with specific antitumor effects from TCM are screened to discover and develop efficacious and safe drugs or chemosensitizers in cancer treatment.

Conflict of interest
The authors declare that they have no conflicts of interest.

Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grant No. 81873054 and No. 82074062).

References
[1] R.J. Deberardinis, N.S. Chandel, Fundamentals of cancer metabolism, Sci. Adv. 2 (2016), 1600200 e1600200-e1600200.
[2] R.A. Cairns, I.S. Harris, T.W. Mak, Regulation of cancer cell metabolism, Nat. Rev. Cancer 11 (2011) 85–95, https://doi.org/10.1038/nrc2981.
[3] O. Warburg, F. Wind, E. Negelein, The metabolism of tumors in the body, J. Gen.
Physiol. 8 (1927) 519–530, https://doi.org/10.1085/jgp.8.6.519.
[4] M.G. Vander Heiden, L.C. Cantley, C.B. Thompson, Understanding the Warburg effect: the metabolic requirements of cell proliferation, Science 324 (2009)
1029–1033.
[5] J.A. Menendez, R. Lupu, Fatty acid synthase and the lipogenic phenotype in
cancer pathogenesis, Nat. Rev. Cancer 7 (2007) 763–777.
[6] S.U. Lan-Hong, S. Lin-Chong, G. Ping, The alterations and significance of amino acid metabolism in cancers, Chin. J. Biochem. Pharm. (2016).
[7] N.N. Pavlova, C.B. Thompson, The emerging hallmarks of cancer metabolism, Cell Metab. 23 (2016) 27–47, https://doi.org/10.1016/j.cmet.2015.12.006.
[8] P. Gao, I. Tchernyshyov, T.C. Chang, Y.S. Lee, K. Kita, T. Ochi, K.I. Zeller, A.M. De Marzo, J.E. Van Eyk, J.T. Mendell, C.V. Dang, c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism,
Nature 458 (2009) 762–765.
[9] Y.C. Liu, F. Li, J. Handler, C.R. Huang, Y. Xiang, N. Neretti, J.M. Sedivy, K.
I. Zeller, C.V. Dang, Global regulation of nucleotide biosynthetic genes by c-myc, PLoS One 3 (2008) 2722, https://doi.org/10.1371/journal.pone.0002722.
1 H. Shim, C. Dolde, B.C. Lewis, C.S. Wu, G. Dang, R.A. Jungmann, R. Dalla-Favera,
C.V. Dang, c-Myc transactivation of LDH-A: implications for tumor metabolism and growth, Proc. Natl. Acad. Sci. U.S.A. 94 (1997) 6658–6663, https://doi.org/ 10.1073/pnas.94.13.6658.
[11] T. Wang, B. Cai, M. Ding, Z. Su, Y. Liu, L. Shen, c-Myc overexpression promotes
oral cancer cell proliferation and migration by enhancing glutaminase and glutamine synthetase activity, Am. J. Med. Sci. 358 (2019) 235–242, https://doi. org/10.1016/j.amjms.2019.05.014.
[12] C. Commisso, S.M. Davidson, R.G. Soydaner-Azeloglu, S.J. Parker, J.
J. Kamphorst, S. Hackett, E. Grabocka, M. Nofal, J.A. Drebin, C.B. Thompson, J.
D. Rabinowitz, C.M. Metallo, M.G. Vander Heiden, D. Bar-Sagi, Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells, Nature 497
(2013) 633–637, https://doi.org/10.1038/nature12138.
[13] C.R. Amendola, J.P. Mahaffey, S.J. Parker, I.M. Ahearn, M.R. Philips, KRAS4A
directly regulates hexokinase 1, Nature 576 (2019) 1–5.
[14] Y. Hu, K-rasG12V transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. 细胞研究:英文版(2012).
[15] R. Nussinov, G. Wang, C.J. Tsai, H. Jang, S. Lu, A. Banerjee, J. Zhang,
V. Gaponenko, Calmodulin and PI3K signaling in KRAS cancers, Trends Cancer 3 (2017) 214–224, https://doi.org/10.1016/j.trecan.2017.01.007.
[16] H.L. Wiernan, J.A. Wofford, J.C. Rathmell, Cytokine stimulation promotes
glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking, Mol. Biol. Cell 18 (2007) 1437–1446, https://doi.org/10.1091/ mbc.E06-07-0593.
[17] A.P. Yang, J.R. Yu, Q.K. Ma, Glut-1 inhibits proliferation and invasion of laryngeal cancer cells through regulating AKT/mTOR, Int. J. Clin. Exp. Med. 12 (2019) 9969–9976.
[18] M.S. Song, L. Salmena, P.P. Pandolfi, The functions and regulation of the PTEN tumour suppressor, Nat. Rev. Mol. Cell Biol. 13 (2012) 283–296, https://doi.org/ 10.1038/nrm3330.
[19] F. Kruiswijk, C.F. Labuschagne, K.H. Vousden, p53 in survival, death and metabolic health: a lifeguard with a licence to kill, Nat. Rev. Mol. Cell Biol. 16
(2015) 393–405.
[20] Functional genomics reveal that the serine synthesis pathway is essential in breast cancer, Nature 476, 2011, 346–350.
[21] S. Wen, D. Zhu, P. Huang, Targeting cancer cell mitochondria as a therapeutic
approach, Future Med. Chem. 5 (2013) 53–67.
[22] B.J. Altman, Z.E. Stine, C.V. Dang, From Krebs to clinic: glutamine metabolism to cancer therapy, Nat. Rev. Cancer 16 (2016) 619–634.
[23] Yoshida, J. Go, Metabolic reprogramming: the emerging concept and associated
therapeutic strategies, J. Exp. Clin. Cancer Res. 34 (2015) 1–10.
[24] A. Almuhaideb, N. Papathanasiou, J. Bomanji, F-18-FDG PET/CT imaging in
oncology, Ann. Saudi Med. 31 (2011) 3–13, https://doi.org/10.4103/0256-
4947.75771.
[25] A. Erez, R.J. DeBerardinis, Metabolic dysregulation in monogenic disorders and cancer — finding method in madness, Nat. Rev. Cancer 15 (2015) 440–448.
[26] A.L. Harvey, Natural products in drug discovery, Drug Discov. Today 13 (2008)
894–901.
[27] F. Qi, A. Li, Y. Inagaki, J. Gao, W. Tang, Chinese herbal medicines as adjuvant treatment during chemoor radio-therapy for cancer, Biosci. Trends 4 (2010)
297–307.
[28] W.L.W. Hsiao, L.A. Liu, The role of traditional Chinese herbal medicines in cancer
therapy – from TCM theory to mechanistic insights, Planta Med. 76 (2010) 1118–1131, https://doi.org/10.1055/s-0030-1250186.
[29] T. Efferth, P.C. H. Li, V.S. B. Konkimalla, B. Kaina, From traditional Chinese medicine to rational cancer therapy.
[30] Z. Zhong, W.W. Qiang, W. Tan, H. Zhang, S. Wang, C. Wang, W. Qiang, Y. Wang,
Chinese herbs interfering with cancer reprogramming, Metab. Evid. Based Complement. Altern. Med. 2016 (2016) 1–10.
[31] W. Guo, H.Y. Tan, F.Y. Chen, N. Wang, Y.B. Feng, Targeting cancer metabolism to resensitize chemotherapy: potential development of cancer chemosensitizers
from traditional Chinese medicines, Cancers 12 (2020), https://doi.org/10.3390/ cancers12020404.
[32] R. Lin, S. Elf, C. Shan, H.B. Kang, Q. Ji, L. Zhou, T. Hitosugi, L. Zhang, S. Zhang, J.
H. Seo, J. Xie, M. Tucker, T.L. Gu, J. Sudderth, L. Jiang, M. Mitsche, R.
J. DeBerardinis, S. Wu, Y. Li, H. Mao, P.R. Chen, D. Wang, G.Z. Chen, S.
J. Hurwitz, S. Lonial, M.L. Arellano, H.J. Khoury, F.R. Khuri, B.H. Lee, Q. Lei, D.
J. Brat, K. Ye, T.J. Boggon, C. He, S. Kang, J. Fan, J. Chen, 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting
LKB1–AMPK signalling, Nat. Cell Biol. 17 (2015) 1484–1496.
[33] M.A. Kowalik, A. Columbano, A. Perra, Emerging role of the pentose phosphate pathway in hepatocellular carcinoma, Front. Oncol. 7 (2017) 87, https://doi.org/ 10.3389/fonc.2017.00087.
[34] T. Zhang, C. Suo, C. Zheng, H. Zhang, Hypoxia and metabolism in metastasis, Adv. Exp. Med. Biol. 1136 (2019) 87–95.
[35] B. Jorge, M. Gina, Metabolic pathways of the warburg effect in health and disease: perspectives of choice, chain or chance, Int. J. Mol. Sci. 18 (2017), 2755-.
[36] J. Zhang, S. Wang, B. Jiang, L. Huang, Z. Ji, X. Li, H. Zhou, A. Han, A. Chen,
Y. Wu, H. Ma, W. Zhao, Q. Zhao, C. Xie, X. Sun, Y. Zhou, H. Huang, M. Suleman,
F. Lin, L. Zhou, F. Tian, M. Jin, Y. Cai, N. Zhang, Q. Li, c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis, Nat. Commun. 8 (2017) 13732.
[37] F. Morani, S. Phadngam, C. Follo, R. Titone, G. Aimaretti, A. Galetto, O. Alabiso,
C. Isidoro, PTEN regulates plasma membrane expression of glucose transporter 1
and glucose uptake in thyroid cancer cells, J. Mol. Endocrinol. 53 (2014) 247–258.
[38] M.K. Sun, R.Y. Mi, K.H. Yun, F. Solca, B.C. Cho, Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation, Mol. Cancer Ther. 12 (2013).
[39] H.M. Li, J.G. Yang, Z.J. Liu, W.M. Wang, Z.L. Yu, J.G. Ren, G. Chen, W. Zhang,
J. Jia, Blockage of glycolysis by targeting PFKFB3 suppresses tumor growth and metastasis in head and neck squamous cell carcinoma, J. Exp. Clin. Cancer Res. 36 (2017) 7.
[40] E. Giampazolias, S.W.G. Tait, Mitochondria and the hallmarks of cancer, FEBS J. 283 (2016) 803–814.
[41] M. Elgendy, M. Ciro`, A. Hosseini, J. Weiszmann, L. Mazzarella, E. Ferrari,
R. Cazzoli, G. Curigliano, A. DeCensi, B. Bonanni, A. Budillon, P.G. Pelicci,
V. Janssens, M. Ogris, M. Baccarini, L. Lanfrancone, W. Weckwerth, M. Foiani,
S. Minucci, Combination of hypoglycemia and metformin impairs tumor metabolic plasticity and growth by modulating the PP2A-GSK3β-MCL-1 axis, Cancer Cell 35 (2019) 798–815, https://doi.org/10.1016/j.ccell.2019.03.007.
[42] M.L. Verschoor, R. Ungard, A. Harbottle, J.P. Jakupciak, G. Singh, Mitochondria and cancer: past, present, and future, Biomed. Res. Int. 2013 (2013), 612369.
[43] U. Elia, E. Flescher, Combined chemotherapy or biotherapy with jasmonates:
targeting energy metabolism for cancer treatment, Curr. Pharm. Biotechnol. 14 (2013) 331–341, https://doi.org/10.2174/1389201011314030008.
[44] N. Bhagya, K.R. Chandrashekar, Tetrandrine and cancer – an overview on the
molecular approach, Biomed. Pharmacother. 97 (2018) 624–632, https://doi. org/10.1016/j.biopha.2017.10.116.
[45] M. Yu, T. Liu, Y.C. Chen, Y.F. Li, W.H. Li, Combination therapy with protein kinase inhibitor H89 and Tetrandrine elicits enhanced synergistic antitumor efficacy, J. Exp. Clin. Cancer Res. 37 (2018) 114, https://doi.org/10.1186/ s13046-018-0779-2.
[46] M. Jiang, R. Zhang, Y. Wang, W. Jing, Y. Liu, Y. Ma, B. Sun, M. Wang, P. Chen,
H. Liu, Z. He, Reduction-sensitive paclitaxel prodrug self-assembled nanoparticles with tetrandrine effectively promote synergistic therapy against drug-sensitive
and multidrug-resistant breast cancer, Mol. Pharm. 14 (2017) 3628–3635,

https://doi.org/10.1021/acs.molpharmaceut.7b00381.

[47] W. Qiu, M. Su, F. Xie, J. Ai, Y. Guo, Tetrandrine blocks autophagic flux and induces apoptosis via energetic impairment in cancer cells, Cell Death Dis. 5 (2014) 1123.
[48] M. Wang, et al., Effects of Tetrandrine on energy metabolism in human heptocarcinoma HepG-2 cell lines, China J. Tradit. Chin. Med. Pharm. 32 (2017)
1925–1929.
[49] L. Chow, K.S. Cheng, F. Leong, C.W. Cheung, L.R. Shiao, Y.M. Leung, K.L. Wong, Enhancing tetrandrine cytotoxicity in human lung carcinoma A549 cells by suppressing mitochondrial ATP production, Naunyn Schmiede Arch. Pharmacol.
392 (2019) 427–436, https://doi.org/10.1007/s00210-018-01601-2.
[50] L. Chen, H. Teng, H. Cao, Chlorogenic acid and caffeic acid from Sonchus oleraceus Linn synergistically attenuate insulin resistance and modulate glucose
uptake in HepG2 cells, Food Chem. Toxicol. 127 (2019) 182–187, https://doi.
org/10.1016/j.fct.2019.03.038.
[51] M.S. Lee, S.O. Lee, K.R. Kim, H.J. Lee, Sphingosine kinase-1 involves the inhibitory action of HIF-1α by chlorogenic acid in hypoxic DU145 cells, Int. J. Mol. Sci. 18 (2017), https://doi.org/10.3390/ijms18020325.
[52] J.J. Park, S.J. Hwang, J.H. Park, H.J. Lee, Chlorogenic acid inhibits hypoxia-
induced angiogenesis via down-regulation of the HIF-1 alpha/AKT pathway, Cell. Oncol. 38 (2015) 111–118, https://doi.org/10.1007/s13402-014-0216-2.
[53] N. Hou, N. Liu, J. Han, Y. Yan, J. Li, Chlorogenic acid induces reactive oxygen species generation and inhibits the viability of human colon cancer cells, Anti
Cancer Drugs 28 (2017) 59–65, https://doi.org/10.1097/
cad.0000000000000430.
[54] X. Wei, T. Mao, S. Li, J. He, X. Hou, H. Li, M. Zhan, X. Yang, R. Li, J. Xiao, S. Yuan,
L. Sun, DT-13 inhibited the proliferation of colorectal cancer via glycolytic metabolism and AMPK/mTOR signaling pathway, Phytomedicine 54 (2019) 120–131, https://doi.org/10.1016/j.phymed.2018.09.003.

[55] H.W. Cao, H. Zhang, Z.B. Chen, Z.J. Wu, Y.D. Cui, Chinese traditional medicine
matrine: a review of its antitumor activities, J. Med. Plants Res. 5 (2011) 1806–1811.
[56] X. Hong, L. Zhong, Y. Xie, K. Zheng, J. Pang, Y. Li, Y. Yang, X. Xu, P. Mi, H. Cao,
W. Zhang, T. Hu, G. Song, D. Wang, Y. Zhan, Matrine reverses the warburg effect and suppresses colon cancer cell growth via negatively regulating HIF-1α, Front. Pharmacol. 10 (2019) 1437.
[57] L. Wu, Matrine suppresses the ER-positive MCF cells by regulating energy
metabolism and endoplasmic reticulum stress signaling pathway, Phytother. Res. 31 (2017) 671–679.
[58] G. Lin, Y. Wu, F. Cai, Z. Li, S. Su, J. Wang, J. Cao, L. Ma, Matrine promotes human myeloid leukemia cells apoptosis through warburg effect mediated by hexokinase 2, Front. Pharmacol. 10 (2019) 1069, https://doi.org/10.3389/ fphar.2019.01069.
[59] J. Cao, R.J. Wei, S.K. Yao, Matrine has pro-apoptotic effects on liver cancer by
triggering mitochondrial fission and activating Mst1-JNK signalling pathways, J. Physiol. Sci. 69 (2019) 185–198, https://doi.org/10.1007/s12576-018-0634-4.
[60] Y.R. Cho, J.H. Lee, J.H. Kim, S.Y. Lee, S. Yoo, M.K. Jung, S.J. Kim, H.J. Yoo, C.
G. Pack, J.K. Rho, J. Son, Matrine suppresses KRAS-driven pancreatic cancer growth by inhibiting autophagy-mediated energy metabolism, Mol. Oncol. 12
(2018) 1203–1215, https://doi.org/10.1002/1878-0261.12324.
[61] C. Jian, Z. Qu, Y. Harata-Lee, T.N. Aung, D.L. Adelson, Anti-cancer activities of diterpenoids derived from euphorbia fischeriana steud, Molecules 23 (2018).
[62] L. Hu, R. Cui, H. Liu, F. Wang, Emodin and rhein decrease levels of hypoxia- inducible factor-1&aplha; in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying these cells, Oncotarget 8 (2017).
[63] L. Wu, K. Cao, Z. Ni, S. Wang, W. Li, X. Liu, Z. Chen, Rhein reverses doxorubicin resistance in SMMC-7721 liver cancer cells by inhibiting energy metabolism and
inducing mitochondrial permeability transition pore opening, Biofactors 45 (2019) 85–96, https://doi.org/10.1002/biof.1462.
[64] Y.Y. Li, Q.F. Xu, W. Yang, T.L. Wu, X.R. Lu, Oleanolic acid reduces aerobic glycolysis-associated proliferation by inhibiting yes-associated protein in gastric cancer cells, Gene 712 (2019), 143956, https://doi.org/10.1016/j. gene.2019.143956.
[65] S. Amara, M. Zheng, V. Tiriveedhi, Oleanolic acid inhibits high salt-induced
exaggeration of warburg-like metabolism in breast cancer cells, Cell Biochem. Biophys. 74 (2016) 427–434, https://doi.org/10.1007/s12013-016-0736-7.
[66] X.X. Chai, Y.F. Le, J.C. Wang, C.X. Mei, J.F. Feng, H. Zhao, C. Wang, D.Z. Lu, Carpesium abrotanoides (L.) root as a potential source of natural anticancer
compounds: targeting glucose metabolism and PKM2/HIF-1α axis of breast cancer cells, J. Food Sci. 84 (2019) 3825–3832, https://doi.org/10.1111/1750-
3841.14953.
[67] K. Wang, W. Huang, X. Sang, X. Wu, Q. Shan, D. Tang, X. Xu, G. Cao, Atractylenolide I inhibits colorectal cancer cell proliferation by affecting metabolism and stemness via AKT/mTOR signaling, Phytomedicine 68 (2020), 153191, https://doi.org/10.1016/j.phymed.2020.153191.
[68] Z. Liu, W. Zhu, X. Kong, X. Chen, X. Sun, W. Zhang, R. Zhang, Tanshinone IIA
inhibits glucose metabolism leading to apoptosis in cervical cancer, Oncol. Rep. 42 (2019) 1893–1903, https://doi.org/10.3892/or.2019.7294.
[69] M. Li, F. Gao, Q. Zhao, H. Zuo, W. Liu, W. Li, Tanshinone IIA inhibits oral squamous cell carcinoma via reducing Akt-c-Myc signaling-mediated aerobic glycolysis, Cell Death Dis. 11 (2020) 381, https://doi.org/10.1038/s41419-020- 2579-9.
[70] Z. Wu, X. Han, G. Tan, Q. Zhu, H. Chen, Y. Xia, J. Gong, Z. Wang, Y. Wang, J. Yan, Dioscin inhibited glycolysis and induced cell apoptosis in colorectal cancer via
promoting c-myc ubiquitination and subsequent hexokinase-2 suppression, Oncotargets Ther. 13 (2020) 31–44, https://doi.org/10.2147/ott.S224062.
[71] F. Zhong, W. Lyu, L. Fang, B. Ye, J. Hu, Polyphyllin Ⅵ induces apoptosis of
esophageal cancer cells through activating JNK pathway and regulates aerobic
glycolysis through inhibition of ERK/c-myc pathway, Bull. Chin. Cancer 29 (2020) 63–69.
[72] J. Wu, X. Zhang, Y. Wang, Q. Sun, M. Chen, S. Liu, X. Zou, Licochalcone A suppresses hexokinase 2-mediated tumor glycolysis in gastric cancer via
downregulation of the Akt signaling pathway, Oncol. Rep. 39 (2018) 1181–1190,

https://doi.org/10.3892/or.2017.6155.

[73] J. Zou, Y. Wang, M. Liu, X. Huang, W. Zheng, Q. Gao, H. Wang, Euxanthone inhibits glycolysis and triggers mitochondria-mediated apoptosis by targeting
hexokinase 2 in epithelial ovarian cancer, Cell Biochem. Funct. 36 (2018) 303–311, https://doi.org/10.1002/cbf.3349.
[74] D. Xu, J. Jin, H. Yu, Z. Zhao, D. Ma, C. Zhang, H. Jiang, Chrysin inhibited tumor glycolysis and induced apoptosis in hepatocellular carcinoma by targeting hexokinase-2, J. Exp. Clin. Cancer Res. 36 (2017) 44, https://doi.org/10.1186/ s13046-017-0514-4.
[75] X. Zhao, Y. Zhu, J. Hu, L. Jiang, L. Li, S. Jia, K. Zen, Shikonin inhibits tumor growth in mice by suppressing pyruvate kinase M2-mediated aerobic glycolysis, Sci. Rep. 8 (2018) 14517, https://doi.org/10.1038/s41598-018-31615-y.
[76] H. Wang, Z. Liu, X. Li, R. Zhao, W. Guan, Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human
hepatoma cells, Exp. Ther. Med. 15 (2017) 1484–1492.
[77] L. You, H. Zhu, C. Wang, F. Wang, Y. Li, Y. Li, Y. Wang, B. He, Scutellarin inhibits
Hela cell growth and glycolysis by inhibiting the activity of pyruvate kinase M2, Bioorg. Med. Chem. Lett. 27 (2017) 5404–5408, https://doi.org/10.1016/j. bmcl.2017.11.011.
[78] T. Wang, X. Xuan, M. Li, P. Gao, G. Zhao, Astragalus saponins affect proliferation, invasion and apoptosis of gastric cancer BGC-823 cells, Diagn. Pathol. 8 (2013) 179.
[79] C. Zhang, T. Cai, X. Zeng, D. Cai, Y. Chen, X. Huang, H. Gan, J. Zhuo, Z. Zhao,
H. Pan, S. Li, Astragaloside IV reverses MNNG-induced precancerous lesions of gastric carcinoma in rats: Regulation on glycolysis through miRNA-34a/LDHA
pathway, Phytother. Res. 32 (2018) 1364–1372, https://doi.org/10.1002/
ptr.6070.
[80] T. Cai, C. Zhang, X. Zeng, Z. Zhao, Y. Yan, X. Yu, L. Wu, L. Lin, H. Pan, Protective effects of Weipixiao decoction against MNNG-induced gastric precancerous lesions in rats, Biomed. Pharmacother. 120 (2019), 109427, https://doi.org/ 10.1016/j.biopha.2019.109427.
[81] L.X. Fan, C.M. Liu, A.H. Gao, Y.B. Zhou, J. Li, Berberine combined with 2-deoxy- d-glucose synergistically enhances cancer cell proliferation inhibition via energy
depletion and unfolded protein response disruption, Biochim. Biophys. Acta 1830 (2013) 5175–5183.
[82] M. Fiorillo, M. Peiris-Pag`es, R. Sanchez-Alvarez, L. Bartella, L. Di Donna,
V. Dolce, G. Sindona, F. Sotgia, A.R. Cappello, M.P. Lisanti, Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-
signalling and mitochondrial metabolism, Biochim. Biophys. Acta Bioenerg. 1859 (2018) 984–996, https://doi.org/10.1016/j.bbabio.2018.03.018.
[83] V. Raman, U.K. Aryal, V. Hedrick, R.M. Ferreira, J.L. Fuentes Lorenzo, E.
E. Stashenko, M. Levy, M.M. Levy, I.G. Camarillo, Proteomic analysis reveals that
an extract of the plant lippia origanoides suppresses mitochondrial metabolism in triple-negative breast cancer cells, J. Proteome Res. 17 (2018) 3370–3383, https://doi.org/10.1021/acs.jproteome.8b00255.
[84] Q. Xu, C. Dou, X. Liu, L. Yang, C. Ni, J. Wang, Y. Guo, W. Yang, X. Tong,
D. Huang, Oviductus ranae protein hydrolysate (ORPH) inhibits the growth,
metastasis and glycolysis of HCC by targeting miR-491-5p/PKM2 axis, Biomed. Pharmacother. 107 (2018) 1692–1704, https://doi.org/10.1016/j. biopha.2018.07.071.
[85] Q. Li, C. Jiang, Y. Wang, M. Wei, H. Zheng, Y. Xu, X. Xu, F. Jia, K. Liu, G. Sun,
J. Zang, P. Mo, Resibufogenin suppresses tumor growth and inhibits glycolysis in
ovarian cancer by modulating PIM1, Naunyn Schmiede Arch. Pharmacol. 392 (2019) 1477–1489, https://doi.org/10.1007/s00210-019-01687-2.
[86] H. Li, S. Hu, Y. Pang, M. Li, L. Chen, F. Liu, M. Liu, Z. Wang, X. Cheng, Bufalin inhibits glycolysis-induced cell growth and proliferation through the suppression of Integrin beta 2/FAK signaling pathway in ovarian cancer, Am. J. Cancer Res. 8
(2018) 1288–1296.
[87] Erin, et al., Cellular Fatty Acid Metabolism and Cancer, Cell Metab. (2013).
[88] P. Caro, A.U. Kishan, E. Norberg, I.A. Stanley, B. Chapuy, S.B. Ficarro, K. Polak,
D. Tondera, J. Gounarides, H. Yin, F. Zhou, M.R. Green, L. Chen, S. Monti, J.
A. Marto, M.A. Shipp, N.N. Danial, Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma, Cancer Cell 22 (2012)
547–560, https://doi.org/10.1016/j.ccr.2012.08.014.
[89] Y. Liu, L.S. Zuckier, N.V. Ghesani, Dominant uptake of fatty acid over glucose by prostate cells: a potential new diagnostic and therapeutic approach, Anticancer
Res. 30 (2010) 369–374.
[90] J.D. Horton, J.L. Goldstein, M.S. Brown, SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver, J. Clin. Invest. 109
(2002) 1125–1131, https://doi.org/10.1172/jci200215593.
[91] M.S. Brown, J.L. Goldstein, The SREBP pathway: regulation of cholesterol
metabolism by proteolysis of a membrane-bound transcription factor, Cell 89 (1997) 331–340, https://doi.org/10.1016/s0092-8674(00)80213-5.
[92] T. Jiang, G. Zhang, Z. Lou, Role of the sterol regulatory element binding protein pathway in tumorigenesis, Front. Oncol. 10 (2020) 1788, https://doi.org/ 10.3389/fonc.2020.01788.
[93] C. Cheng, Z. Wang, J. Chen, Targeting FASN in breast cancer and the discovery of promising inhibitors from natural products derived from traditional chinese medicine, Evid. Based Complement. Altern. Med. 2014 (2014), 232946.
[94] G. Liu, K. Wang, S. Kuang, R. Cao, L. Bao, R. Liu, H. Liu, C. Sun, The natural compound GL22, isolated from Ganoderma mushrooms, suppresses tumor growth by altering lipid metabolism and triggering cell death, Cell Death Dis. 9 (2018) 689, https://doi.org/10.1038/s41419-018-0731-6.
[95] S.Y. Huang, G.J. Huang, H.C. Wu, M.C. Kao, W.C. Huang, Ganoderma tsugae inhibits the SREBP-1/AR axis leading to suppression of cell growth and activation of apoptosis in prostate cancer cells, Molecules 23 (2018), https://doi.org/ 10.3390/molecules23102539.
[96] H. Li, L. Xiang, N. Yang, F. Cao, C. Li, P. Chen, X. Ruan, Y. Feng, N. Zhou,
X. Wang, Zhiheshouwu ethanol extract induces intrinsic apoptosis and reduces unsaturated fatty acids via SREBP1 pathway in hepatocellular carcinoma cells,
Food Chem. Toxicol. 119 (2018) 169–175, https://doi.org/10.1016/j.
fct.2018.04.054.
[97] P. Zhao, J.M. Mao, S.Y. Zhang, Z.Q. Zhou, Y. Tan, Y. Zhang, Quercetin induces
HepG2 cell apoptosis by inhibiting fatty acid biosynthesis, Oncol. Lett. 8 (2014) 765–769.
[98] A.S. Sultan, M.I.M. Khalil, B.M. Sami, A.F. Alkhuriji, O. Sadek, Quercetin induces apoptosis in triple-negative breast cancer cells via inhibiting fatty acid synthase
and beta-catenin, Int. J. Clin. Exp. Pathol. 10 (2017) 156–172.
[99] V.C. Lin, C.H. Chou, Y.C. Lin, J.N. Lin, C.C. Yu, C.H. Tang, H.Y. Lin, T.D. Way, Osthol suppresses fatty acid synthase expression in HER2-overexpressing breast cancer cells through modulating Akt/mTOR pathway, J. Agric. Food Chem. 58
(2010) 4786–4793.
[100] Y. Mo, Y. Wu, X. Li, H. Rao, X. Tian, D. Wu, Z. Qiu, G. Zheng, J. Hu, Osthole delays hepatocarcinogenesis in mice by suppressing AKT/FASN axis and ERK phosphorylation, Eur. J. Pharmacol. 867 (2020), 172788, https://doi.org/ 10.1016/j.ejphar.2019.172788.
[101] J.M. Shieh, Y.C. Chen, Y.C. Lin, J.N. Lin, W.C. Chen, Y.Y. Chen, C.T. Ho, T.
D. Way, Demethoxycurcumin inhibits energy metabolic and oncogenic signaling

pathways through AMPK activation in triple-negative breast cancer cells, J. Agric. Food Chem. 61 (2013) 6366–6375, https://doi.org/10.1021/jf4012455.
[102] H.Y. Kwan, Z. Yang, W.F. Fong, Y.M. Hu, The anticancer effect of oridonin is
mediated by fatty acid synthase suppression in human colorectal cancer cells, J. Gastroenterol. 48 (2013) 182–192.
[103] Z. Gu, X. Wang, R. Qi, L. Wei, Y. Huo, Y. Ma, L. Shi, Y. Chang, G. Li, L. Zhou, Oridonin induces apoptosis in uveal melanoma cells by upregulation of Bim and downregulation of fatty acid synthase, Biochem. Biophys. Res. Commun. 457
(2015) 187–193, https://doi.org/10.1016/j.bbrc.2014.12.086.
[104] S.Q. Guo, B.J. Ma, X.K. Jiang, X.J. Li, Y.J. Jia, Astragalus polysaccharides inhibits tumorigenesis and lipid metabolism through miR-138-5p/SIRT1/SREBP1 pathway in prostate cancer, Front. Pharmacol. 11 (2020) 598, https://doi.org/ 10.3389/fphar.2020.00598.
[105] B. Huang, B.L. Song, C. Xu, Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities, Nat. Metab. 2 (2020) 132–141.
[106] Y.S. Kim, Y.M. Lee, T.I. Oh, D.H. Shin, G.H. Kim, S.Y. Kan, H. Kang, J.H. Kim, B.
M. Kim, W.J. Yim, J.H. Lim, Emodin sensitizes hepatocellular carcinoma cells to the anti-cancer effect of sorafenib through suppression of cholesterol metabolism, Int. J. Mol. Sci. 19 (2018), https://doi.org/10.3390/ijms19103127.
[107] H.R. Jin, C.H. Du, C.Z. Wang, C.S. Yuan, W. Du, Ginseng metabolite protopanaxadiol interferes with lipid metabolism and induces endoplasmic reticulum stress and p53 activation to promote cancer cell death, Phytother. Res.
33 (2019) 610–617, https://doi.org/10.1002/ptr.6249.
[108] A. Valdes, G. Sullini, E. Ibanez, A. Cifuentes, V. Garcia-Canas, Rosemary polyphenols induce unfolded protein response and changes in cholesterol
metabolism in colon cancer cells, J. Funct. Foods 15 (2015) 429–439, https://doi.
org/10.1016/j.jff.2015.03.043.
[109] S. Ruan, Z. Zhang, X. Tian, D. Huang, W. Liu, B. Yang, M. Shen, F. Tao, Compound fuling granule suppresses ovarian cancer development and progression by disrupting mitochondrial function, galactose and fatty acid metabolism, J. Cancer
9 (2018) 3382–3393, https://doi.org/10.7150/jca.25136.
[110] S.H. Shim, S. Sur, R. Steele, C.J. Albert, C. Huang, D.A. Ford, R.B. Ray, Disrupting
cholesterol esterification by bitter melon suppresses triple-negative breast cancer cell growth, Mol. Carcinog. 57 (2018) 1599–1607, https://doi.org/10.1002/ mc.22882.
[111] D.W. Chan, M.M. Yung, Y.S. Chan, Y. Xuan, H. Yang, D. Xu, J.B. Zhan, K.K. Chan,
T.B. Ng, H.Y. Ngan, MAP30 protein from Momordica charantia is therapeutic and has synergic activity with cisplatin against ovarian cancer in vivo by altering metabolism and inducing ferroptosis, Pharmacol. Res. 161 (2020), 105157, https://doi.org/10.1016/j.phrs.2020.105157.
[112] M. He, J. Hou, L. Wang, M. Zheng, T. Fang, X. Wang, J. Xia, Actinidia chinensis
Planch root extract inhibits cholesterol metabolism in hepatocellular carcinoma through upregulation of PCSK9, Oncotarget 8 (2017) 42136–42148, https://doi. org/10.18632/oncotarget.15010.
[113] X. Wang, J. Xie, X. Lu, H. Li, C. Wen, Z. Huo, J. Xie, M. Shi, X. Tang, H. Chen,
C. Peng, Y. Fang, X. Deng, B. Shen, Melittin inhibits tumor growth and decreases resistance togemcitabine by downregulating cholesterol pathway geneCLUinpancreatic ductal adenocarcinoma, Cancer Lett. 399 (2017) 1–9.
[114] C.J. Zhang, N. Zhu, J. Long, H.T. Wu, L. Qin, Celastrol induces lipophagy via the LXRα/ABCA1 pathway in clear cell renal cell carcinoma, Acta Pharmacol. Sin. (2020).
[115] B.J. Altman, Z.E. Stine, C.V. Dang, From Krebs to clinic: glutamine metabolism to cancer therapy, Nat. Rev. Cancer 16 (2016) 619–634, https://doi.org/10.1038/ nrc.2016.71.
[116] L. Xiang, J. Mou, B. Shao, Y. Wei, H. Liang, N. Takano, G.L. Semenza, G. Xie, Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization, Cell Death Dis. 10 (2019) 40, https://doi.org/10.1038/s41419-018-1291-5.
[117] C. Lobo, M.A. Ruiz-Bellido, J.C. Aledo, J. M´arquez, I. Nún˜ez De Castro, F.
J. Alonso, Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells, Biochem. J. 348 (2000) 257–261, https://doi.org/10.1042/0264-6021:3480257.
[118] R.J. DeBerardinis, Serine metabolism: some tumors take the road less traveled, Cell Metab. 14 (2011) 285–286, https://doi.org/10.1016/j.cmet.2011.08.004.
[119] J.W. Locasale, Serine, glycine and one-carbon units: cancer metabolism in full circle, Nat. Rev. Cancer 13 (2013) 572–583, https://doi.org/10.1038/nrc3557.
[120] M.J. Lukey, W.P. Katt, R.A. Cerione, Targeting amino acid metabolism for cancer
therapy, Drug Discov. Today 22 (2017) 796–804, https://doi.org/10.1016/j. drudis.2016.12.003.
[121] K.Y. Yang, C.R. Wu, M.Z. Zheng, R.T. Tang, X.Z. Li, L.X. Chen, H. Li, Physapubescin I from husk tomato suppresses SW1990 cancer cell growth by targeting kidney-type glutaminase, Bioorg. Chem. 92 (2019), 103186, https:// doi.org/10.1016/j.bioorg.2019.103186.
[122] C.P. Zheng, L. Han, S.H. Wu, A metabolic investigation of anticancer effect of G. glabra root extract on nasopharyngeal carcinoma cell line, C666-1, Mol. Biol. Rep.
46 (2019) 3857–3864, https://doi.org/10.1007/s11033-019-04828-1.
[123] Z. Wang, K. Gao, C. Xu, J. Gao, Y. Yan, Y. Wang, Z. Li, J. Chen, Metabolic effects of Hedyotis diffusa on rats bearing Walker 256 tumor revealed by NMR-based
metabolomics, Magn. Reson. Chem. 56 (2018) 5–17, https://doi.org/10.1002/
mrc.4658.
[124] S. Zhu, L. Wei, G. Lin, Y. Tong, J. Zhang, X. Jiang, Q. He, X. Lu, D.D. Zhu, Y.
Q. Chen, Metabolic alterations induced by kudingcha lead to cancer cell apoptosis and metastasis inhibition, Nutr. Cancer Int. J. 72 (2020) 696–707, https://doi. org/10.1080/01635581.2019.1645865.
[125] G. Wang, Y.Z. Wang, Y. Yu, J.J. Wang, P.H. Yin, K. Xu, Triterpenoids extracted from rhus chinensis mill act against colorectal cancer by inhibiting enzymes in

glycolysis and glutaminolysis: network analysis and experimental validation, Nutr. Cancer Int. J. 72 (2020) 293–319, https://doi.org/10.1080/
01635581.2019.1631858.
[126] S. Nie, Y. Zhao, X. Qiu, W. Wang, Y. Yao, M. Yi, D. Wang, Metabolomic study on nude mice models of gastric cancer treated with modified Si Jun Zi Tang via HILIC UHPLC-Q-TOF/MS analysis, Evid. Based Complement. Altern. Med. 2019 (2019), 3817879, https://doi.org/10.1155/2019/3817879.
[127] H. Wu, Y. Chen, Q. Li, Y. Gao, X. Zhang, J. Tong, Z. Zhang, J. Hu, D. Wang,
S. Zeng, Z. Li, Intervention effect of Qi-Yu-San-Long Decoction on Lewis lung carcinoma in C57BL/6 mice: Insights from UPLC-QTOF/MS-based metabolic
profiling, J. Chromatogr. B Anal. Technol. Biomed. Life Sci. 1102 (2018) 23–33,

https://doi.org/10.1016/j.jchromb.2018.10.013.

[128] G. He, G. He, R. Zhou, Z. Pi, T. Zhu, L. Jiang, Y. Xie, Enhancement of cisplatin-
induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in Shikonin vivo, Biochem. Biophys. Res. Commun. 469 (2016) 1075–1082, https://doi.org/10.1016/j.bbrc.2015.12.100.
[129] L. Jia, J. Zhou, H. Zhao, H. Jin, M. Lv, N. Zhao, Z. Zheng, Y. Lu, Y. Ming, Y. Yu,
Corilagin sensitizes epithelial ovarian cancer to chemotherapy by inhibiting Snail- glycolysis pathways, Oncol. Rep. 38 (2017) 2464–2470, https://doi.org/ 10.3892/or.2017.5886.
[130] C.Y. Li, H.T. Song, X.X. Wang, Y.Y. Wan, X.S. Ding, S.J. Liu, G.L. Dai, Y.H. Liu, W.
Z. Ju, Urinary metabolomics reveals the therapeutic effect of HuangQi Injections in cisplatin-induced nephrotoxic rats, Sci. Rep. 7 (2017) 3619, https://doi.org/ 10.1038/s41598-017-03249-z.
[131] D. Liu, X. Meng, D. Wu, Z. Qiu, H. Luo, A natural isoquinoline alkaloid with antitumor activity: studies of the biological activities of berberine, Front. Pharmacol. 10 (2019) 9.
[132] R. Rezaee, A. Monemi, M.A. Sadeghibonjar, M. Hashemzaei, Berberine alleviates paclitaxel-induced neuropathy, J. Pharmacopunct. 22 (2019) 90–94.
[133] P.P. Cai, H. Qiu, F.H. Qi, X.Y. Zhang, The toxicity and safety of traditional Chinese
medicines: please treat with rationality, Biosci. Trends 13 (2019) 367–373, https://doi.org/10.5582/bst.2019.01244.