Metabolomic Profiles on Antiblastic Cardiotoxicity: New Perspectives for Early Diagnosis and Cardioprotection
Abstract
:1. Introduction
2. What’s Metabolomics?
- Sample collection and storage;
- Sample analysis, using nuclear magnetic resonance spectroscopy and mass spectrometry techniques;
- Data analysis using multivariate statistical tools.
3. Until 2019: Early Detection of Drug-Induced Cardiotoxicity in Animal Studies
4. Step Ahead: The Human Model
4.1. In Vitro
4.2. In Vivo
5. Conclusions
Funding
Conflicts of Interest
Abbreviations
CTX | Cardiotoxicity |
ATP | Adenosine TriPhosphate |
MRI | Magnetic Resonance Imaging |
TCA | Tricarboxylic acid |
PCr | Phosphocreatine |
YWPC | Yellow Wine Polyphenolic Compound |
NEFA | Non Esterified Fatty Acids |
HF | Heart Failure |
GY | Grey |
ADP | Adenosine DiPhosphate |
AMP | Adenosine MonoPhosphate |
AMPK | Adenosine-MonoPhosphate Kinase |
NMR | Nuclear Magnetic Resonance |
MS | Mass Spectrometry |
GC | Gas Chromatography |
LC | Liquid Chromatograph |
DOX | Doxorubicine |
iNOS | inducible Nitric Oxide Synthases |
eNOS | endothelial Nitric Oxide Synthases |
THP | pirarubicin |
L-THP | Liposome pirarubicin |
F-THP | Free pirarubicin |
UPLC–Q-TOF-MS | Ultra-Performance Liquid Chromatography–Quadrupole Time-of-Flight MS |
H-NMR | Hydrogen NMR |
hiPSC-CMs | Human induced Pluripotent Stem Cell-Derived CardioMyocytes |
DZR | Dexrazoxane |
TKIs | Tyrosine Kinase Inhibitors |
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Reference | Species | Biofluid/Tissue | Metabolites/Metabolism Discrimination |
---|---|---|---|
Andreadu et al., 2009 [4] | Wistar rats | Aqueous myocardial extracts | Increased levels of acetate and succinate, decreased levels of branched-chain amino acids |
Andreadu et al., 2014 [5] | Wistar rats | Aqueous myocardial extracts | Perturbations of energy metabolism |
Tan et al., 2011 [6] | ICR mice | Myocardial tissue | Increased levels of L-alanine, phosphate, glycine, succinate, malate, proline, threonic acid, glutamine, phenylalanine, dihydroxyacetonephosphate (DHAP), glycerol-3-phosphate (G-3-P), fructose, glucose, stearic acid, myo-inositol and cholesterol; decreased levels of lactate, β-hydroxybutyric acid, l-valine, isoleucine, threonine, citrate, linoleic acid, arachidonic acid |
Cong et al., 2012 [7] | Sprague-Dawley rats | Urine | Metabolites involved in metabolic process related to myocardial energy metabolism: tricarboxylic acid cycle (citrate), glycolysis (lactate), pentose phosphate pathway (d-gluconate-1-phosphate) and amino acid metabolism (N-acetylglutamine and N-acetyl-dl-tryptophan) |
Li et al., 2015 [8] | Wistar rats | Plasma | l-carnitine, 19-hydroxydioxycortic acid, LPC (14:0) and LPC (20:2) |
Schnackenberg et al., 2016 [9] | B6C3F1 mice | Heart tissue, Plasma | Myocardial specimens: altered levels of 18 amino acids and acetylornithine, kynurenine, putrescine and serotonin, decreased levels of 5 acylcarnitines. Plasma samples: altered levels of 16 amino acids and acetylornithine and hydroxyproline, increased levels of 16 acylcarnitines |
Yin et al., 2016 [10] | Wistar rats | Plasma | l-carnitine, proline, 19-hydroxydeoxycorticosterone, phuyoshingosine, cholic acid, LPC (14:0), LPC (18:3), LPC (16:1), LPE (18:2), LPC (22:5), LPC (22:6), linoleic acid, LPC (22:4), LPC (20:2), LPE (18:0), LPC (20:3) |
Chaudhari et al., 2017 [11] | Human-induced pluripotent stem cell-derived cardiomyocytes | Culture medium | Reduction in the utilisation of pyruvate and acetate, and accumulation of formate |
QuanJun et al., 2017 [12] | BALB/c mice | Serum | DOX administration: increase in 5-hydroxylisine, 2-hydroxybutyrate, 2-oxoglutarate, 3-hydroxybutyrate decrease in glucose, glutamate, cysteine, acetone, methionine, asparate, isoleucine and glycylproline. DZR treatment: increase in lactate, 3-hydroxybutyrate, glutamate, alanine; decrease in glucose, trimethylamine N-oxide and carnosine levels |
Yun et al., 2021 [13] | C57BL/6 mice | Myocardial tissue | Periplocymarin reduced cardiomyocyte apoptosis protecting myocytes from DOX-induced CTX |
Timm et al., 2020 [14] | Wistar rats | Myocardial tissue, Plasma | DOX administration: decrease of the tricarboxylic acid (TCA) cycle intermediate malate, TCA cycle-related glutamate, total carnitine, acetyl carnitine, NAD, AMP, ADP, ATP |
Timm et al., 2022 [15] | Wistar rats | Liver tissue | DOX administration: increase in several acyl-carnitine species as well as increases in high energy phosphates, citrate and markers of oxidative stress |
Geng et al., 2020 [16] | Sprague-Dawley rats | Serum, heart, liver, kidney, and brain tissue | DOX administration: the altered metabolites in the heart were 3-methyl-1-pentanol, cholesterol, d-glucose, d-lactic acid, glycerol, glycine, l-alanine, l-valine, palmitic acid, phenol, propanoic acid, and stearic acid |
Gramatyka et al., 2020 [17] | C57Bl/6NCrl mice | Heart tissue | Ionizing radiation with 2 Gy: high levels of pantothenate and glutamate and decreased levels of alanine, malonate, acetylcarnitine, glycine and adenosine |
Zhou et al., 2020 [18] | C57BL/6 J mice | Feces, urine, plasma | Nintedanib metabolic pathways majorly included were hydroxylation, demethylation, glucuronidation, and acetylation reactions |
Lin et al., 2021 [19] | Sprague-Dawley rats | Serum | YWPC influences the levels of metabolites altered by DOX (decreased levels of arachidonic and linoleic acid, increased levels of tryptophan) |
Abdelgail et al., 2020 [20] | Wistar rats | Serum, heart tissue | Some metabolites were associated with sorafenib-induced CTX, particularly glycin and lattic acid; the coadministration of Losartan reverted these changes |
Alhazzani et al.,2021 [21] | Sprague-Dawley rats | Serum | DOX monotherapy reduced concentrations of several amino acids, in contrast the combination therapy reverses these metabolic pathways |
Reference | Species | Biofluid/Tissue | Metabolites/Metabolism Discrimination |
---|---|---|---|
Chin Yoon et al., [22] | Human cardiomyocyte cell line (AC 16) and human breast cancer cell line (MCF-7) | Culture medium | Spinochrome D (SpD) influenced glutathione metabolism in AC16 cells and and increased ATP production and the oxygen consumption rate in D-galactose-treated AC16 cells. SpD protected these cells from DOX-induced CTX, reducing the mitochondrial damage of DOX |
Palmer et al., 2020 [23] | Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) | Culture medium | Arachidonic acid, lactic acid, 2′-deoxycytidine and thymidine have important roles in modulating oxidative stress, mitochondrial function and replication resulted associated with CTX |
Draguet et al., 2021 [24] | MDA-MB-231 (ATCC® HTB-26TM) and MCF-7 (ATCC® HTB-22TM) cell lines | Culture medium | The combination of CB-839 (glutaminase inhibitor) and Oxamate (lactate dehydrogenase inhibitor) and the combination of CB-839/Oxamate/D609 (a phosphatidylcholine-specific phospholipase C inhibitor) caused significant cell mortality in two breast cancer cell lines (MDA-MB-231 and MCF-7) and were able to improve DOX-efficacy on the same cell lines |
Dionisio et al., 2022 [25] | Human cardiac proliferative and differentiated AC16 cells | Culture medium | 4-hydroxycyclophosphamide and acrolein induced mitochondrial and lysosomal dysfunction: increased in sugar levels within the cells and a perturbed levels of some metabolites of the Krebs cycle and altered levels of amino acid |
Unger et et al., 2020 [26] | Sprague-Dawley rats; Patients receiving radiation therapy for esophageal cancer | Heart Tissue; Plasma | Radiation therapy CTX: SM(d18:1/16:0), PC(16:0/14:0), SM(d18:1/18:0), PE(16:0/20:4), 1-(1,2-Dihexanoylphosphatidyl) inositol-4,5-bisphosphate and Gly-Arg-Gly-Asp-Asn-Pro were upregulated |
Asnani et al., 2020 [27] | Women with breast cancer treated with anthracyclines and trastuzumab | Plasma | Changes in citric acid and aconitic acid that differentiated patients who developed CTX |
Cocco et al., 2020 [28] | Human population of breast cancer patient | Plasma | In patients with CTX were identified a higher prevalence of Krebs cycle intermediates (fumarate and succinate) and fatty acid (e.g., linoleic acid). |
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Fazzini, L.; Caggiari, L.; Deidda, M.; Onnis, C.; Saba, L.; Mercuro, G.; Cadeddu Dessalvi, C. Metabolomic Profiles on Antiblastic Cardiotoxicity: New Perspectives for Early Diagnosis and Cardioprotection. J. Clin. Med. 2022, 11, 6745. https://doi.org/10.3390/jcm11226745
Fazzini L, Caggiari L, Deidda M, Onnis C, Saba L, Mercuro G, Cadeddu Dessalvi C. Metabolomic Profiles on Antiblastic Cardiotoxicity: New Perspectives for Early Diagnosis and Cardioprotection. Journal of Clinical Medicine. 2022; 11(22):6745. https://doi.org/10.3390/jcm11226745
Chicago/Turabian StyleFazzini, Luca, Ludovica Caggiari, Martino Deidda, Carlotta Onnis, Luca Saba, Giuseppe Mercuro, and Christian Cadeddu Dessalvi. 2022. "Metabolomic Profiles on Antiblastic Cardiotoxicity: New Perspectives for Early Diagnosis and Cardioprotection" Journal of Clinical Medicine 11, no. 22: 6745. https://doi.org/10.3390/jcm11226745