Summary of recent metabolomic studies on anticancer therapies of pure compounds from Chinese medicines.
Cancer is one of the most prevalent diseases all over the world with poor prognosis and the development of novel therapeutic strategies is still urgently needed. The large amount of successful experiences in fighting against cancer-like diseases with Chinese medicine has suggested it as a great source of alternative treatments to human cancers. Cancer cells have been shown to own a predominantly unique metabolic phenotype to facilitate their rapid proliferation. Metabolic reprogramming is a remarkable hallmark of cancer and therapies targeting cancer metabolism can be highly specific and effective. Based on the sophisticated study of small molecule metabolites, metabolomics can provide us valuable information on dynamically metabolic responses of living systems to certain environmental condition. In this chapter, we systematically reviewed recent studies on metabolism-targeting anticancer therapies based on metabolomics in terms of glucose, lipid, amino acid, and nucleotide metabolisms and other altered metabolisms, with special emphasis on the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines. The trends of future development of metabolism-targeting anticancer therapies were also discussed. Overall, the elucidation of the underlying molecular mechanism of metabolism-targeting pharmacologic therapies will provide us a new insight to develop novel therapeutics for cancer treatment.
- cancer metabolism
- adjuvant therapies
- Chinese medicines
Despite all recent improvements in early detection and pleiotropic therapeutics, cancer is still the leading cause of death all over the world . It is one of the most prevalent diseases with complex risk factors, and the mortality rate is similar to its morbidity, which reflects its poor prognosis. It has been projected that approximately 3.12 million new cases of cancer and a cancer death toll of 2.5 million will occur per year in China, which brings a huge burden on society . To date, there are three conventional cancer therapies for cancer, including surgical resection, chemotherapy, and radiotherapy. However, diverse drawbacks and limitations have been observed in these cancer therapies either alone or in combination. For example, most cancer patients are not suitable to undergo the surgical resection due to the late diagnosis and other factors. As the major therapies for cancer patients in middle and advanced stages, chemotherapy and radiotherapy have been shown to present serious side effects and complications, such as myelosuppression, hematological toxicity, cardiac damage, and liver and kidney dysfunction [1, 3]. Moreover, tumor cells have the ability to develop resistance to evade cell death, and the therapeutic efficacy of the current chemotherapeutic drugs is significantly reduced by the increasingly acquired drug resistance . Therefore, it imminently deserves to develop more effective and less toxic adjuvant therapies for cancer prevention and treatment.
1.1 Cancer metabolism
It has been reported that cell metabolism has an essential role in the pathological progression of cancer and metabolic reprogramming is a remarkable hallmark of cancer . Cancer cells have been shown to own a predominantly unique metabolic phenotype to facilitate their rapid proliferation, which is dramatically different from normal cells. Cancer cells tend to acquire energy via glycolysis rather than the much more efficient oxidative phosphorylation pathway even in aerobic conditions, which is the famous phenomenon of cancer called the “Warburg effect” . Besides the consumption of glucose, cancer cells have also been reported to favor glutamine as a preferential fuel . Accumulating evidences indicate that mutations in metabolic enzymes can promote the development of cancer. For example, mutations in the tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase, succinate dehydrogenase, and fumarate hydratase can affect the corresponding metabolites a-ketoglutarate, succinate, and fumarate. These changes can further affect the 2-oxoglutarate-dependent dioxygenases and then result in some cancers, such as paraganglioma and renal cell cancer [8, 9, 10]. What is more, the drug resistance of cancer cells is also shown to be associated with their metabolic alterations . In this perspective, cancer metabolism has become a potentially fertile area, and therapies targeting cancer metabolism can be highly specific and effective. Nowadays metabolism-targeting anticancer therapies are drawing researchers’ great attention and becoming a new therapeutics for cancer treatment .
1.2 Metabolomics and cancer
As a valuable complement to emerging “omics” science including genomics, transcriptomics, and proteomics, metabolomics utilizes leading-edge analytical chemistry technologies and advanced computational approaches to characterize the small endogenous and exogenous molecule metabolites in various biochemical metabolisms from complex biochemical mixtures . Metabolomics can provide us a direct readout on dynamically metabolic responses of living systems to certain genetic modifications or pathophysiological stimuli , which has been extensively adopted in the field of disease diagnosis, pharmacodynamic evaluation, therapeutical monitoring, and drug discovery . There are three main analytical chemistry platforms in metabolomics research, namely, nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography mass spectrometry (LC-MS), and gas chromatography MS (GC/MS). Each platform has its own strengths and limitations. There are three main methodological approaches to analyze the small metabolites in metabolomics, namely, targeted, untargeted, and stable isotope-resolved metabolomics (SIRM). Numerous systemic reviews have shown in detail how each analytical platform and methodological approach works in metabolomics studies [16, 17, 18, 19, 20].
As mentioned above, cell metabolism has an essential role in the pathological progression of cancer, and metabolic reprogramming is a remarkable hallmark of cancer. In this context, it would be conducive to employ metabolomics in the field of cancer research for exploration of tumorigenesis mechanisms, diagnosis and monitoring of tumor, as well as discovery of novel anticancer therapies [21, 22, 23].
1.3 Chinese medicines and cancer treatment
Due to their various biological activities and low toxicity, natural products derived from Chinese medicines are reported to be an excellent source for anticancer drugs as a complementary and alternative approach . Chinese medicines have evolved with their own unique theoretical system in Asian countries, especially China over thousands of years. Chinese medicines are usually divided into pure compounds, herb extracts, and formulations. Formulations from Chinese medicines are extensively employed in Chinese hospitals for clinical cancer treatment . Numerous Chinese herb extracts have been reported to show inhibitory effects on cancers . An increasing number of pure compounds derived from Chinese medicine herbs have been shown to inhibit the development of cancers through various mechanisms [27, 28, 29, 30]. Besides, a large number of studies have revealed that Chinese medicines in combination with conventional chemotherapy and radiotherapy could increase the therapeutic efficacy and decrease the serious side effects and complications of these therapies [31, 32]. It is convinced that Chinese medicines are gaining increasing reputation and credibility as adjuvant therapies for cancer prevention and treatment.
Although Chinese medicines have been employed in cancer prevention and treatment for a long time, the underlying mechanisms on how they work remain to be fully elucidated because of their unique medical system with multicomponent nature. In accordance with the holistic perspective of Chinese medicines, metabolomics opens up a unique and novel insight into efficacy evaluation and action mechanism exploration of Chinese medicines as adjuvant therapies for cancer prevention and treatment.
Increasing excellent reviews have been focused on the application of metabolomics in the metabolic changes and the possible underlying mechanisms behind these alterations in the pathogenesis of different kinds of cancer [33, 34, 35]. Little reviews have been highlighted on the metabolism-based anticancer therapies. Since Chinese medicine has been suggested to be a great source of alternative treatments to human cancers, in this chapter we systematically reviewed recent studies from 2015 to March 2019 on metabolism-targeting anticancer therapies based on metabolomics in terms of glucose, lipid, amino acid, and nucleotide metabolisms and other altered metabolisms, with special emphasis on the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines. The typical flowchart of metabolomics studies on antineoplastic Chinese medicines is shown in Figure 1. Table 1 summarized the recent metabolomics studies on anticancer therapies of pure compounds from Chinese medicines. At the same time, the trends of future development of metabolism-targeting anticancer therapies were also discussed.
|References||Pure compound||Cancer||Study||Method||Significantly changed metabolites or pathways||Main findings|
|26,700,591||Geranylgeranoic acid||Hepatoma||HuH-7 cells in vitro||UPLC/TOF/MS||GGA induced a time-dependent increase in the cellular contents of fructose 6-phosphate and decrease of fructose 1,6-diphosphate||GGA may shift HuH-7 cells from aerobic glycolysis to mitochondrial respiration through the immediate upregulation of TIGAR and SCO2 protein levels|
|26,160,839||Halofuginone||Colorectal cancer||HCT116 cells in vitro||UPLC-MS/MS, GC/MS and UPLC/LTQ-Orbitrap MS||Metabolomics delineated the slower rates in both glycolytic flux and glucose-derived tricarboxylic acid cycle flux||HF regulates Akt/mTORC1 signaling pathway to dampen glucose uptake and glycolysis in CRC cells|
|29,589,762||(−)-5-Hydroxy-equol||Hepatocellular Carcinoma||SMMC-7721 cells in vitro||1H NMR||(−)-5-Hydroxy-equol treatment significantly altered energy and amino acid metabolism||Integrated metabolomics and further verifications may facilitate the exploration of the anti-HCC mechanisms of (−)-5-hydroxy-equol|
|29,802,724||Nummularic acid (NA)||Prostate cancer (PCa)||DU-145 and C4-2 cells in vitro||ALEX-CIS GC–TOF-MS||The metabolism pathways related to glycolysis, TCA, and glutamine metabolisms were changed after NA treatment||NA may induce energy crisis to inhibit PCa|
|30,391,728||Magnoline||Prostate cancer||22RV1 cells in vitro||UPLC-MS||Magnoline markedly restored the energy metabolism, amino acid metabolism, and fatty acid metabolism||Cancer cells may result in death because of insufficient material basis to favor their rapid proliferation|
|28,651,973||1,25-Dihydroxyvitamin D3||Prostate cancer||LNCaP cells in vitro||GC/ MS||1,25(OH)2D3 decreased glucose uptake and increased citrate/isocitrate due to TCA cycle truncation||Re-wiring glucose metabolizing pathways, and induction of a “differentiated” metabolic phenotype by 1,25(OH)2D3, may prove clinically beneficial|
|26,541,605||Vitamin C||Colorectal cancer||KRAS and BRAF mutant lines and isogenic wild-type counterparts in vitro||LC-MS/MS||High levels of vitamin C increased uptake of dehydroascorbic acid (DHA) and decreased glutathione||These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations|
|28,916,726||β-Lapachone||Pancreatic ductal adenocarcinoma||MiaPaCa2 cells in vitro||GC/MS and 1H NMR||β-lap treatment was found to decrease the NAD-sensitive pathways, such as glycolysis and TCA cycle||Targeting NQO1 may sensitize the treatment of β-lap|
|28,737,429||Diethylstilbestrol||Prostate cancer||PC3 cells in vitro||1H NMR||Lactate, phosphocreatine, and GSH were the biomarkers for DES treatment||DES upon conjugation had a more specific effect and less toxicity|
|28,918,937||Koningic acid||Colorectal cancer||HCT116 cells in vitro||Integrated pharmacogenomics and LC-HRMS metabolomics||Glycolysis was the highest scoring pathway only in KA-treated cells||KA efficacy is not determined by the status of individual genes but by the quantitative extent of the WE, leading to a therapeutic window in vivo|
|30,114,709||Omega-3 polyunsaturated fatty acids||Breast cancer||MCF7 cells in vitro||GC/MS||Glycolysis and glutamine metabolism pathways were markedly reduced when treated with the combination of Rp and ω-3 PUFAs||ω-3 PUFA could increase the anti-breast cancer potential of Rp|
|28,198,625||Curcumin||Hepatocarcinoma||Serum from DEN-induced hepatocarcinogenesis model||GC/MS||Curcumin attenuated metabolic disorders via increasing concentration of glucose and fructose, and decreasing levels of glycine and proline||Curcumin exhibited a potent liver protective agent inhibiting chemically induced liver injury through suppressing liver cellular metabolism in the prospective application|
|29,448,205||6,7-Dimethoxy-1,2,3,4-tetrahydro-iso- quinoline-3-carboxylic acid||Colorectal carcinoma||Serum from DMH-induced CRC albino Wistar rat model in vivo||1H NMR||M1 exhibited to reverse the perturbed metabolism pathways in CRC condition, including glycolysis, TCA cycle, choline, phosphatidylinositol and gluconeogenesismetabolisms||M1 has the anti-CRC potential via the blockade of IL-6/JAK2/STAT3 oncogenic signaling|
|27,416,811||Physapubenolide||Hepatocellular carcinoma||HepG2 cells in vitro and tumor tissues and plasma from a mouse-xenograft model bearing liver carcinoma H22 cells in vivo||GC/MS||PB disturbed the metabolic pattern and significantly decreased lactate production||PB exhibits anticancer activities through suppression of glycolysis via the Akt-p53 pathway|
|30,322,263||Naringenin||Lung cancer||Serum from the urethane-induced lung cancer rat model in vivo||1H NMR||The glycolysis was restored to normal levels with co-therapy of Gnb and Nar||Co-therapy has the superiority over alone treatment to improve the therapeutic efficacy|
|26,859,520||Flexibilide||Colon cancer||HCT-116 cells in vitro||UPLC/Q-TOF MS||Flexibilide exhibited the therapeutic effect on colon cancer mainly via downregulating PC biosynthesis pathway||Flexibilide exhibited the therapeutic effect on colon cancer mainly via down-regulating PC biosynthesis pathway|
|28,296,891||Englerin A||Clear cell renal carcinoma||A498 cells in vitro||LC-MS/MS||Englerin A significantly reversed lipid metabolism and increase ceramides levels||Ceramides may be a mediator of some of the actions of englerin A|
|28,948,276||Isoquercitrin||Bladder cancer||T24 cells in vitro||UPLC/Q-TOF MS||Isoquercitrin treatment was found to regulate lipid and anaerobic glycolysis||ISO influenced T24 bladder cancer cell metabolism, and this process was mainly involved in activating the AMPK pathway|
|28,496,003||Peiminine||Colorectal cancer||UPLC-MS and GC/MS||UPLC-MS and GC/MS||Peiminine treatment altered several metabolites, including lignocerate (24:0), oleate (18:1n9), glutamine, and glucose||Peiminine exerted the predominant therapeutic effect mainly via the metabolic regulation of lipids, amino acids, and carbohydrates|
|29,321,577||8u||Hepatocellular carcinoma||HepG2 cells in vitro||UPLC/Q-TOF MS||8u was found to significantly inhibit the invasion and metastasis of HepG2 cells and regulate intracellular lipid metabolism||8u could efficiently suppress the invasion and metastasis of HepG2 cells by decreasing the expression of HSP90α protein and inhibiting the PI3K/Akt signaling pathway|
|28,125,641||Genistein and calcitriol||Osteosarcoma||MG-63 Cells in vitro||GC/MS||Co-therapy of genistein and calcitriol was found to regulate lipids and amino acids rather than energy metabolism||The promotional effects of high level of genistein on osteosarcoma could be decreased by the co-treatment of calcitriol|
|27,533,043||Silibinin||Prostate cancer||Tumor tissues from 22Rv1 Xenograft model in vivo||1H-NMR||Silibinin treatment did not greatly affect glucose uptake of PCa tumor but decreased the lipid synthesis||These findings further support silibinin usefulness against PCa through inhibiting hypoxia-induced signaling|
|26,744,170||Acyclic retinoid||Hepatocellular carcinoma||Liver tissues from mouse DEN-induced HCC model in vivo||CE-TOFMS and LC-TOFMS||ACR predominantly reversed lipogenesis but not glucose metabolism by inhibiting linoleic acid metabolites||Lipid metabolic reprogramming plays a critical role in the protective effects of ACR on HCC|
|30,871,192||Delta-tocotrienol||Non-small cell lung cancer||A549 and H1299 cells in vitro||1H-NMR||Cellular metabolomics analysis showed significant inhibition in the uptake of glutamine, its derivatives glutamate and glutathione, and some EAAs in both cell lines with δT treatment||δT treatment could suppress the glutamine uptake via suppressing glutamine transporters and then resulted in the induction of apoptosis and suppression of cell proliferation|
|30,068,874||Celastrol||Colon cancer||HCT116 cells in vitro||UPLC/MS||Metabolomics analysis found celastrol changed the levels of lipid markers, carnitine and amino acids. Tryptophan was further identified as a special biomarker by targeted metabolite analysis||The suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells|
|27,754,384||Melittin||Ovarian cancer||A2780 and A2780CR cell lines in vitro||LC-MS||Melittin treatment of cisplatin-sensitive cells decreased glutamine, proline, and arginine pathways||Melittin might have some potential as an adjuvant therapy in cancer treatment|
|28,674,386||Chlorogenic acid and caffeic acid||Hepatocellular carcinoma||Serum from DEN-induced HCC model in vivo||16 S rRNA and LC-MS, GC/MS-MS, GC/MS||Both CaA and ChA treatment reverse 28 metabolites||The levels of ethanolamine, L-methionine, L-tyrosine, and bilirubin were associated with diminished Prevotella 9 and Lachnospiraceae incertae sedis and elevated Ruminococcaceae UCG-004|
|29,202,102||Resveratrol, curcumin and ursolic acid||Prostate cancer||Serum from a mouse allograft model of prostate cancer in vivo||LC-MS and GC/|
|Glutamine metabolism was regulated by the compound combinations||Compared with the individual treatment, the combined treatment has the greater antineoplastic property|
|29,651,531||Hepatoma||SMMC7721 cells in vitro||GC/MS and LC/MS||GLA treatment diminished amino acid metabolism and elevated the metabolisms of sphingolipid, purine, and pyrimidine||GC/MS- and LC/MS-based metabolomics applied to cell culture enhanced our current understanding of the metabolic response to GLA treatment and its mechanism|
|26,851,007||Taurine||Breast cancer||Plasma from dimethylbenz[a]anthracene-induced breast carcinogenesis in rats in vivo||GC–TOFMS||Taurine treatment regulated 23 differential metabolites, which were associated with glucose, energy and amino acid, as well as nucleic acid metabolism||The antitumor activity of taurine in rats is mediated through altered metabolism of breast cancer cells|
|27,374,097||Celastrol||Acute promyelocytic leukemia||HL-60 cells in vitro and tumor tissue from mice xenograft model in vivo||UPLC-MS||Celastrol treatment regulated uridine metabolite, which further enhances apoptosis||The study firstly reveals that uridine deficiency contributes to mitochondrial apoptosis induced by celastrol in APL cells|
|29,787,425||Gamma-tocotrienol||Cancer||Serum from nonhuman primate models in vivo||UPLC/Q-TOF MS||GT3 could regulate the changed fatty acid beta-oxidation, amino acid and purine catabolism metabolism caused by irradiation||This initial assessment also highlights the utility of metabolomics in determining underlying physiological mechanisms responsible for the radioprotective efficacy of gamma-tocotrienol|
|27,335,141||Fisetin||Prostate cancer||Tumor tissues from prostate cancer xenografts in vivo||HPLC/ESI–MS||Fisetin treatment was shown to downregulate secreted and intracellular hyaluronan (HA), which conferred resistance to prostate oncogenesis||Fisetin is an effective, nontoxic, potent HA synthesis inhibitor|
|29,978,476||Galactolipid 1,2-di-O-linolenoyl-3-O- β-galactopyranosyl-sn-glycerol||Melanoma||Serum from a syngeneic mouse model implanted with B16 melanoma in vivo||LC-MS/MS||dLGG treatment markedly elevated 12/15-LOX catalyzed oxylipin products in serum||This study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma|
|30,668,340||Deoxyelephantopin||Melanoma||Kidney tissues from murine B16 metastatic allograft model in vivo||UPLC/ESI-QTOF MS||Co-therapy of DET and cisplatin could reverse the changed urea cycle metabolites and hippuric acid in renal tissues caused by cisplatin||The co-therapy of DET and cisplatin could be an effective treatment with low toxicity for melanoma|
2. Review on metabolism-targeting Chinese medicine treatment on human cancers
2.1 Glucose metabolism
As mentioned above, cancer cells tend to acquire energy via glycolysis rather than the much more efficient oxidative phosphorylation pathway even in aerobic conditions. Glucose and energy metabolisms play an important role in the tumorigenesis of cancer and could be the therapeutic targets for cancer treatment. Pure compounds, herb extracts, and formulations from Chinese medicines, which target glucose and energy metabolisms, are attracting increasing attention for the development of anticancer therapies.
Geranylgeranoic acid (GGA), a kind of acyclic diterpenoids, is derived from some medicinal herbs such as turmeric. UPLC/TOF/MS-based metabolomics analysis was used to study the underlying anticancer mechanism of GGA in human hepatoma-derived HuH-7 cells . It was found that GGA may shift the energetic state of HuH-7 cells from aerobic glycolysis to mitochondrial respiration, which was revealed by a time-dependent augment of fructose 6-phosphate and decline of fructose 1,6-diphosphate in HuH-7 cells after GGA treatment. Halofuginone (HF) is an active compound derived from the febrifugine which can be extracted from the Chinese herb
Silymarin, extracted from the seeds of milk thistle (
2.2 Lipid metabolism
Besides the glucose and energy metabolisms having an essential role in the tumorigenesis process of cancer, it has been also reported that lipid metabolism such as de novo lipogenesis regulates the synthesis of cellular membranes and the important signaling molecules of rapidly proliferating tumor cells . Targeting the lipid metabolism could be a novel therapeutics for cancer treatment. Here the recent metabolomics studies of pure compounds, herb extracts, and formulations from Chinese medicines, which target lipid metabolism, have been reviewed.
Flexibilide is a natural compound derived from the soft coral
2.3 Amino acid metabolism
As mentioned above, besides the consumption of glucose, cancer cells have also been reported to favor glutamine as a preferential fuel. Glutamine metabolism has an essential role in the pathological progression of cancer and could be a potential therapeutic option for cancer. Besides the key metabolite glutamine, it has been reported many other amino acids also play an essential role in cancer.
Delta-tocotrienol (δT) is one of the isomers of vitamin E with antineoplastic property. To explore underlying action mechanism, a 1H-NMR-based metabolomics of A549 and H1299 cells in vitro was used . In detail, δT treatment could suppress the glutamine uptake via suppressing glutamine transporters and then resulted in the induction of apoptosis and suppression of cell proliferation. Celastrol is a bioactive compound derived from
Polyphenols are characterized as a hydroalcoholic chestnut shell extract. Sorice et al. used 1H-NMR-based metabolomics of HepG2 cells in vitro to study the anti-HCC activity of polyphenols extracted from chestnut shell (PECS) . PECS was found to regulate the levels of some amino acids. Annonaceous acetogenins (ACGs) are a group of C35 or C37 secondary metabolites isolated from plants in
2.4 Nucleotide metabolism
To support the rapid proliferation of cancer cells, nucleic acid synthesis is shown to be accelerated. Accordingly, the anticancer therapy targeting nucleotide metabolism has obtained numerous attentions. Here the recent metabolomics studies of Chinese medicines targeting nucleotide metabolism have been reviewed.
Glaucocalyxin A (GLA) is an ent-kaurene diterpenoid derived from
Red kidney bean, also named as
2.5 Other related metabolisms
Except for the anticancer therapies of Chinese medicine targeting the changed metabolisms mentioned above, there are also some other related metabolisms which are the targets by Chinese medicine. Fisetin is a kind of plant flavonoid with antineoplastic property. A HPLC/ESI-MS-based metabolomics of tumor tissues from PCa xenografts in vivo was conducted to explore its therapeutic benefit for PCa . Fisetin treatment was shown to downregulate secreted and intracellular hyaluronan (HA), which conferred resistance to prostate oncogenesis. Yang et al. developed a LC-MS/MS-based metabolomics to study the bioefficacy of a plant galactolipid 1,2-di-O-α-linolenoyl-3-O-β-D- galactopyranosyl-sn-glycerol (dLGG) against melanoma . dLGG treatment markedly elevated 12/15-LOX catalyzed oxylipin products in serum, revealing the novel therapeutic mechanism of phytoagent dLGG against melanoma. Derived from the medicinal plant
Liu et al. developed a UHPLC-MS/MS-based targeted metabolomics to evaluate the efficacy of anticancer drugs, including a traditional Chinese medicine injection Aidi injections and fluorouracil . It was found that with the progression of squamous cell carcinoma of the lung, the levels of 1,3-diaminopropane, cadaverine, and N-acetylputrescine altered. The two-drug treatment alone or co-therapy reversed the levels of 1,3-diaminopropane, cadaverine, and N-acetylputrescine. The team also used this metabolomics method to evaluate the efficacy of Aidi injections on CRC . It was found that Aidi injection treatment could reverse polyamine metabolism, especially agmatine and putrescine, revealing that plasma polyamine could be a biomarker for both early diagnosis and medical treatment of CRC.
3. Current perspectives and future challenges
In accordance with the holistic perspective of Chinese medicines, metabolomics can help to explain the underlying mechanisms of the anticancer effects of Chinese medicines or the reversion of the drug resistance of chemotherapy and radiotherapy. It can also help to rapidly compare the anticancer effects of multiple compounds from Chinese medicines and act as a quick preliminary platform to screen the most dominant compound related to anticancer bioactivity. Based on the metabolomics analyses of modern studies of Chinese medicines with antineoplastic properties, the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines is gaining numerous attentions. However, many challenges still exist in the metabolomics study of antineoplastic Chinese medicines, and there is still a long way for the wide application of metabolomics of Chinese medicines into the treatment of cancer. Firstly, it is critical to make good experimental design before starting the experiment, such as the choices of samples, analytical platforms, and methodological approaches. Secondly, it is quite essential for researchers to develop metabolomics, such as the development of data excavation and the identification and quantification of more metabolites. Thirdly, it is important for us to validate the results from metabolomics studies with more mechanical biological experiments. Fourthly, as no one single technology could achieve a comprehensive result, it is strongly suggested to combine metabolomics with some other advanced technologies for better investigation of the action mechanisms of antineoplastic Chinese medicines, such as other “omics” technologies, network pharmacology, and gut microbiome analyses. Last but not least, more attentions will be drawn to personalized treatment based on metabolomics. It has been reported that because of the interaction between genes and environment (polypharmacy, gut microbiota, xenobiotics), not all patients present the same response to drug treatment . Personalized treatment has been put forward and of great importance nowadays. Although pharmacogenomics is still the only means in terms of personalized treatment, its limitation of ignoring the environmental influences has been increasingly recognized. As an alternative and complementary manner, pharmacometabolomics is an emerging “omics” and has been proposed for personalized treatment . As the results of both genetic and environmental influences, pharmacometabolomics can help to understand individual phenotypic variations in drug responses by providing individual metabolic signatures of both gene-derived endogenous and environment-derived exogenous metabolites . Pharmacometabolomics will offer an intriguingly avenue for personalized treatment in the future.
In this chapter, we systematically reviewed recent studies on metabolism-targeting anticancer therapies based on metabolomics in terms of glucose, lipid, amino acid, and nucleotide metabolisms and other altered metabolisms, with special emphasis on the potential of metabolic treatment with pure compounds, herb extracts, and formulations from Chinese medicines. The trends of future development of metabolism-targeting anticancer therapies were also discussed. Hopefully, we expect that through the systematic review on the recent metabolomics studies targeting Chinese medicine treatment on human cancers, more attention will be drawn to the promising candidates from the resourceful Chinese medicine as effective neoadjuvant therapies for cancer treatment clinically.
The study was financially supported by grants from the research council of the University of Hong Kong (Project Codes: 104004092, 104004460, 104004746), the Research Grants Committee (RGC) of Hong Kong, HKSAR (Project Codes: 764708, 766211, 17152116), Wong’s Donation on Modern Oncology of Chinese Medicine (Project code: 200006276), Gala Family Trust (Project Code: 200007008), Innovation Technology Fund of Hong Kong (ITF. Project code: 260900263), and HMRF (Project code: 16172751).