Plant Metabolomics: The Future of Anticancer Drug Discovery
<p>Structure of plant secondary metabolites identified by metabolomics studies reviewed in this paper. Anticancer activity exerted by these compounds is due to individual or synergistic effects. Compounds highlighted in blue are involved in anticancer synergistic effects. Compounds highlighted in pink are suggested to be related to anticancer activity of extract.</p> "> Figure 2
<p>Plant metabolomics in drug discovery: concept, process, and outcomes.</p> ">
Abstract
:1. Introduction
2. Plant Metabolomics as a Key Tool for Anticancer Studies
Plant | Method Used | Number of Identified Metabolites | Metabolites Classes | Cancer Cell Lines Used | Metabolites Related to the Anticancer Activity of the Extract | Ref. |
---|---|---|---|---|---|---|
Ammi visnaga L. (roots) | High-performance liquid chromatography–heated electrospray ionization source–high-resolution mass spectrometry metabolic profiling (HPLC-HESI-HRMS) | Several | Phenylpropanoids, flavonoids, isobenzofuranones, coumarins, chromones | Colon cancer (Caco-2), breast cancer (Mcf-7), hepatocellular carcinoma (HepG-2) cell lines | Junipediol A 4-O-glucoside (1), Junipediol A 8-O-glucoside (2), Acacetin (3), Apiumetin-O-glucoside (4). (These compounds have a possible contribution to the antiproliferative activity of the plant extract as EGFR inhibitors) | [70] |
Annona muricata L. | Metabolomic analysis using liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis | NS | Flavonoids, steroids, sugars, alkaloids, tannins, phenols, indoles | Human lung carcinoma cell line (A549) | NS | [94] |
Antidesma bunius L. (leaves) | Flavonoids, steroids, sugars, alkaloids, tannins, phenols, indoles, coumarins, anthrones, anthraquinones | |||||
Cannabis sativa (leaves) | Untargeted metabolomic study using liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) | 38 (positive ionization mode) 41 (negative ionization mode) | N-containing products, polyphenols, phenylpropanoids, flavonoids, fatty acids derivates, terpenes | Gastric adenocarcinoma (AGS), melanoma (A375), human lung carcinoma (A549) cell lines | NS | [95] |
Chamomile (European) flower | Metabolomic study using high-performance liquid chromatography–mass spectrometry (HPLC-MS) and NMR | Several | Phenylpropanoids, flavonoids, phenolics | Breast cancer cell line (ZR-75) | Chrysosplenetin (4), Apigenin. (5) | [71] |
Chamomile (Jordanian) flower | - | |||||
Cissus incisa (leaves) | Metabolomic study using ultra-high-performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS/MS) | 171, 260, and 114 metabolites identified in different extracts | Phenolics, diterpenoids, flavonoids, fatty acid derivatives, sterols, fatty acyl, stilbene, acyl glycerol | Prostate ATCC® CRL-1435 (PC3), hepatocellular ATCC® HB-8064 (Hep3B), hepatocellular ATCC® HB-8065 (HepG2), breast (ATCC® HTB-22) MCF7, lung (ATCC® CCL-185) A549, cervical ATCC® CCL-2 (HeLa) cell lines | α-tocopherolquinone, phytol, grandifloric acid, cucurbitacin E, α-amyrin acetate, ursolic acid, δ-linolenic acid, oxyacanthine, stearic acid, matricin. (The cytotoxicity of the extracts might be explained by the presence of these metabolites.) | [96] |
Crocus cancellatus subsp. damascenus (stigmas) | Untargeted metabolomic study using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) | 14 (positive ionization mode) 24 (negative ionization mode) | Monoterpene glycoside, fatty acids, flavonoids | Human breast cancer cell lines (MDA-MB-231 and MCF-7) | Crocin (6), Crocetin (7), Picrocrocin (8), Safranal (9). (The antiproliferative activity of the plant extract is suggested to be due to these compounds.) | [72] |
Curcuma longa L. | Metabolomic study using liquid chromatography–high-resolution mass spectrometry (LC-HRMS) | 16 | Mostly fatty acids | Activity determined in silico | Curcumin (10). | [83] |
Cosmos caudatus | 13 | Lutein (11). | ||||
Dianthus caryophyllus (different colors of carnation flower) | Targeted metabolomic study using liquid chromatography with tandem mass spectrometry (LC-MS/MS) | 932 | Organic acids, phenolic acids, nucleotides, flavonoids, lipids saccharides, alcohols, nucleotides and derivatives, amino acids and derivatives | Osteosarcoma (U2OS), human lung carcinoma (A549) cell lines | 2’-Deoxyguanosine (12), 6-Hydroxykaempferol-3,6-O-diglucoside (13), Quercetin-3-O-sophoroside (14). (The combination of 2’-deoxyguanosine, 6-hydroxykaempferol-3,6-O-diglucoside, or quercetin-3-O-sophoroside increased antitumor activity of 2’-deoxyguanosine.) | [73] |
Dillenia suffruticosa (different organs) | Genomics, transcriptomics, and ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) analysis-based metabolomic study | Leaf (151), flower (134), root (134), stem (137) | Phenolics, alkaloids, flavonoids, terpenoids, lipids, nucleosides, amino acids, organic compounds | Cholangiocarcinoma (CCA), hepatocellular carcinoma (HCC), clear cell renal cell carcinoma (ccRCC), gastric cancer, colon cancer, prostate cancer, breast cancer, lung cancer, natural killer T cell Page 8/26 lymphoma (NKTL), diffused large B-cell lymphoma (DLBCL) | The root extract contains high levels of triterpenoids (including ursolic acid), which is known to have antiproliferative effects. | [97] |
Eleusine indica (roots) | Ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) analysis-based metabolomic study | NS | NS | Non-small-cell lung carcinoma (H1299), breast adenocarcinoma (MCF-7), liver adenocarcinoma (SK-HEP-1) cell lines | NS | [98] |
Astragalus boeticus (leaves) | 1H NMR (proton nuclear magnetic resonance) and 2D (two-dimensional) nuclear magnetic resonance spectroscopy-based metabolomic study | 31 | Amino acids, organic acids, sugars, flavonoids, phenols, cinnamic acid derivatives, caffeic acid | Colon cancer cell lines (Caco-2, HT-29, HCT-116) | Cycloartane glycoside (6-O-acetyl-3-O-β-D xylopiranosylcycloastragenol) (15). | [74] |
Trigonella esculenta (leaves) | Protodioscin derivative (25 R)-furost-5-ene-3β,22α,26-triol 3-O-α-L-rhamnopyranosyl-(1 → 4)-α-L-rhamnopyranosyl-(1 → 4)-[α-L-rhamnopyranosyl-(1 → 2)]-β-D-glucopyranosyl 26-O-β-D-glucopyranoside (16). | |||||
Glochidion velutinum (leaves) | Liquid chromatography– tandem mass spectrometry (LC-MS/MS) analysis- based metabolomic study | 48 | Benzoic acid derivatives, flavans, flavones, O-methylated flavonoids, flavonoid O- and C-glycosides, pyranocoumarins, hydrolysable tannins, carbohydrate conjugates, fatty acids, coumarin glycosides, monoterpenoids, diterpenoids, terpene glycosides | Prostate cancer (PC-3), breast cancer (MCF-7) cell lines | Epigallocatechin gallate (17), isovitexin (18), ellagic acid (19), rutin (20). | [75] |
Grapefruit (C. paradisi) | Nontargeted gas chromatography–mass chromatography (GC-MS) analysis-based metabolomic study | Several | Organic compounds (amino acids and derivatives, carbohydrates and derivatives), organic acids | Human melanoma cell line (A375) | NS. | [89] |
Kigelia africana (fruit) | Nontargeted HPLC coupled to high-resolution time-of-flight (TOF) mass spectroscopy-based metabolomic study | 356 | Alkaloids, flavanoids, tannins, phenolics | Jeg-3 choriocarcinoma cell line | NS. | [91] |
Manilkara zapota (leaves) | Liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis-based metabolomic study | NS | Flavonoids, steroids, sugars, anthraquinones, anthrones, coumarins phenols, tannins | Human adenocarcinoma cell line (A549) | NS. | [99] |
Lansium domesticum (leaves) | Flavonoids, steroids, sugars, anthraquinones, indoles, triterpenes, sterols | |||||
Lime peel (Citrus aurantifolia) | Metabolomic study using liquid chromatography– quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and gas chromatography–high-resolution mass spectrometry (GC-HRMS) | 62 (detected by LC-MS) 22 (detected by GC-MS) | Glycosides, saccharides, amino acids, organic acids, alkaloids, flavonoids, flavonoids glycosides, furanocoumarins, terpenoids | Liver cancer cell lines (PLC/PRF/5) | Hesperidin (21), limonin (22), and other phytochemical components (synergistic effect). | [76] |
Mahonia aquifolium | Proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomic study | Several | Sugars, unsaturated fatty acids, protoberberine-type, aporphine-type and bisbenzylisoquinoline-type alkaloids. | Human cervical adenocarcinoma cell line (HeLa) | Palmatine (23), berberine (24), berbamine (25). | [77] |
Myracrodruon urundeuva (bark, branch, and leaf) | Ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) analysis-based metabolomic study | 50 | Flavonoids, phenols, tannins, quercetin derivatives, anacardic acids | Colorectal (HCT-116), glioblastoma (SF-295), leukemia (HL-60), leukemia (RAJI) cell lines | Compounds derived from quercetin, galloy derivatives, and phenolic acids (Might contribute to the high cytotoxic activity of the extracts). Quercetin derivatives, corilagin, chlorogenic acid (are known to have antitumor activity), | [100] |
Oenothera rosea | Liquid chromatography–mass spectrometry (LC-MS) analysis-based metabolomic study | 307 | Organic compounds, terpenes, lipids, flavonoids | Human prostate cancer cell line (DU145) | 40 metabolites were identified for having anticancer and/or antiproliferative activity. | [101] |
Oldenlandia corymbose (roots, flowers, stems, and leaves) | Genomic, transcriptomic, and metabolomic study using liquid chromatography with tandem mass spectrometry (LC-MS/MS) | NS | NS | Breast cancer (SK-BR3) cell line | Ursolic acid (26). | [78] |
Picrorhiza kurroa (roots) | Gas chromatography–mass spectrometry (GC-MS) analysis-based metabolomic study and high-resolution atmospheric pressure chemical ionization mass spectroscopy (HR-APCI-MS) characterization | Several | Sesquiterpenoid, alkaloids, fatty ester, others | Breast cancer (MCF7, MDA-MB-231, SKBR3), ovarian cancer (SKOV3) cell lines | Dihydromikanolide (27). | [79] |
Plicosepalus curviflorus | Metabolomic profiling using liquid chromatography–electrospray ionization–quadrupole time-of-flight tandem mass spectrometry (LC-ESI-TOF-MS/MS) | NS | Phenolic compounds (flavonoid derivatives), triterpenes, sterols | Lung (A549), prostate (PC-3), ovarian (A2780), breast (MDA-MB-231) cancer cell lines | NS. | [102] |
Xanthium Strumarium (root) | Proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics | Several | NS | Human ovarian cancer cell line (A2780cp) | NS. | [103] |
3. Plant Secondary Metabolites Used for Cancer Therapy
4. Metabolomics as a Powerful Tool for Cancer Diagnosis and Therapy
5. Metabolomics Approaches to Cancer Research: Untargeted, Targeted, and Beyond
6. Plant Metabolomics Facing Challenges of Anticancer Drugs Development
7. Avoiding Difficulties and Performing Successful Plant Metabolomic Analyses
8. Challenges of Plant Metabolomics-Based Anticancer Drug Development and Possible Solutions
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Plant | Altered Metabolic Pathway | Cancer Type | Study |
---|---|---|---|
Aloe vera (leaves) | Protein biosynthesis, catecholamine biosynthesis, mitochondria transport chain, and pentose phosphate pathway. | Raji cell lines (cancerous lymphoma cells) | [150] |
American ginseng (Panax quinquefolius L.) | Amino acid, lipids, and carbohydrates metabolism. Metabolites involved in inflammation and oxidation. | Colon carcinogenesis | [129] |
Xanthium strumarium | Tyrosine metabolism, nucleotide metabolism, fatty acid biosynthesis, and glycerolipid metabolism. | Ovarian cancer cell line (A2780cp) | [103] |
Xanthium strumarium | Aminoacyl-tRNA synthesis, glycerolipid metabolism, fatty acid biosynthesis, and biotin metabolism. | Epithelial ovarian cancer cell line (SK-OV-3) | [151] |
Procedure standardization | To consider | The metabolomics procedure including sample preparation, measurement and data analysis should be standardized [67]. |
Benefit | Standardization of all the steps facilitates the direct comparison of data obtained in different laboratories (inter/intra-laboratory exchanges). This helps to ensure reproducibility [172], and broaden the identification of key metabolites; it also permits the building of comprehensive metabolomics databases [173]. | |
Plant collection, sample size, preparation and extraction | To consider | - Plant samples should be quickly collected [174]. - The season and the tissue from which the bioactive compounds are to be isolated should be carefully chosen [20,175]. |
Benefit | - Avoiding activity loss and change in metabolites’ composition [130,175,176]. - Obtaining the highest activity of metabolites. | |
To consider | Samples should be immediately frozen in liquid nitrogen and stored at − 80˚ C or lyophilized. | |
Benefit | Avoiding any significant changes in plant composition [20]. | |
To consider | The sample size should be considered. | |
Benefit | Avoiding non-reliable results [177]. | |
To consider | Quality assurance (QA) (the measures implemented by the laboratory to ensure that quality standards will be fulfilled) and quality control (QC) samples (the quality of untargeted data is ensured by preparing various types of mixtures) should be used in untargeted metabolomics studies. | |
Benefit | - Acquiring high-quality publishable data. - Avoiding batch variations [178,179,180]. | |
To consider | An efficient extraction method using a solvent system with the proper solvent and solvent-to-sample ratio should be used. Attention should be paid to the extraction duration. | |
Benefit | An effective extraction method enables the extraction of the maximum quantity of metabolites and provides access to low abundant compounds that are difficult to extract. It also helps in achieving reproducible quantification of metabolites [20,181,182,183]. | |
Combining metabolomics studies and anticancer activity bioassays | To consider | Metabolomics results should be compared to data from biological assays. |
Benefit | - Achieving reliable correlations between the identified phytochemicals and the biological activity of the extract. - Achieving good discrimination between the different samples based on their activity, in correlation with metabolites identification [184]. | |
MS-based metabolomics analysis | To consider | Metabolomics approach involving experimental deconvolution of the tandem mass spectrometry (MS/MS) data acquired in a broad MS isolation window (ex. 9 Da) is recommended (For more details, see reference) [185,186]. Direct analysis of the samples using quadrupole (Q) time of flight-mass spectrometry (TOF-MS) [187] or a Fourier transform ion cyclotron MS (FT-MS) [188] or direct infusion of the samples using direct infusion mass spectrometry (DIMS) and flow infusion mass spectrometry (FIMS) is highly useful [189]. |
Benefit | - The experimental deconvolution of MS/MS data acquired in a broad MS isolation window permits to obtain high quality spectra and the identification of novel metabolite [185,186]. - TOF instruments provides high mass accuracy and high resolution, and allows to detect large diversity of masses [187]. - Fourier transform ion cyclotron MS (FT-MS) eliminates any need for chromatography prior to analysis [188]. - Direct infusion mass spectrometry provides reduced instrument cycle times, reduced sample pretreatment and high-throughput screening (analysis of more than 1000 samples/week) [189]. | |
NMR-based metabolomics analysis | To consider | The use of NMR analysis for metabolomics studies is highly recommended. |
Benefit | Quantification of metabolites [190]. | |
Combining analytical platforms (MS-NMR) | To consider | The integration of different analytical platforms (mass spectrometry (MS) and NMR techniques) in a metabolomics study is highly recommended. [191,192]. |
Benefit | Obtaining broader metabolome coverage and high-quality data using hyphenated separation platforms [191,192]. | |
Sample analysis by MS-based targeted metabolomics | To consider | - Ultra-high-performance liquid chromatography coupled to a triple quadrupole MS (UPLCQqQ-MS), which is operated in MRM (Multiple Reaction Monitoring) mode is an ideal technique to be used in targeted metabolomics [193,194]. Attention to false positives is necessary [177]. False positives might be observed as a result of isomeric metabolites having similar product ion used to detect the target compounds, but are inadequately separated by liquid chromatography [193,194]. |
Benefit | - UPLCQqQ-MS is sensitive, reproducible, characterizes a wide range of compounds, and allows for robust quantification [193,194]. - Avoiding false metabolic data [177]. | |
To consider | Metabolomics data standards are useful. | |
Benefit | Ensure reproducible research [195]. | |
Integrated metabolomics analysis | To consider | Metabolomics studies should be integrated with other Omics studies including genomics, proteomics, transcriptomics, and metabolomics is highly recommended. |
Benefit | - Obtaining a comprehensive picture of cancer metabolism [196]. - Revealing biosynthetic pathways and mechanisms of action of active metabolites [78]. | |
Data normalization | To consider | Metabolomics data should be normalized. |
Benefit | - Minimizing batch-to-batch variations. - Important for large-scale metabolomics analyses [197]. | |
Metabolomic profiling in relation to previous studies | To consider | Metabolic profiling of plants previously reported to have anticancer activity is highly useful. |
Benefit | - The generation of a database will allow for robust differentiation of active extracts and for the selection of target bioactive metabolites. - Speeding up drug discovery from anticancer plants [91]. | |
Assessing response to treatment | To consider | Analysis of the biological sample (cells/tissues) following treatment with plant extracts/extracted plant compounds is useful. |
Benefit | - Validation of the effectiveness of the extract/extracted bioactive compounds. - Elucidation of the metabolic alterations induced in the host cell upon treatment. - Understanding the impact of the treatment on cancer metabolism [198,199]. |
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Dabbousy, R.; Rima, M.; Roufayel, R.; Rahal, M.; Legros, C.; Sabatier, J.-M.; Fajloun, Z. Plant Metabolomics: The Future of Anticancer Drug Discovery. Pharmaceuticals 2024, 17, 1307. https://doi.org/10.3390/ph17101307
Dabbousy R, Rima M, Roufayel R, Rahal M, Legros C, Sabatier J-M, Fajloun Z. Plant Metabolomics: The Future of Anticancer Drug Discovery. Pharmaceuticals. 2024; 17(10):1307. https://doi.org/10.3390/ph17101307
Chicago/Turabian StyleDabbousy, Ranin, Mohamad Rima, Rabih Roufayel, Mohamad Rahal, Christian Legros, Jean-Marc Sabatier, and Ziad Fajloun. 2024. "Plant Metabolomics: The Future of Anticancer Drug Discovery" Pharmaceuticals 17, no. 10: 1307. https://doi.org/10.3390/ph17101307