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Leukemia Jan 2022While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these... (Review)
Review
While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.
Topics: Animals; Antineoplastic Agents; Energy Metabolism; Humans; Leukemia, Myeloid, Acute; Mitochondria; Neoplastic Stem Cells; Oxidative Phosphorylation
PubMed: 34561557
DOI: 10.1038/s41375-021-01416-w -
Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.International Journal of Molecular... Sep 2022Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically... (Review)
Review
Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy-metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.
Topics: Glycolysis; Hexokinase; Humans; Neoplasms; Phosphofructokinase-1; Phosphoglycerate Kinase; Phosphoglycerate Mutase; Pyruvates; Tumor Microenvironment
PubMed: 36077431
DOI: 10.3390/ijms231710037 -
Seminars in Perinatology Apr 2020Pregnant women frequently take prescription and over the counter medications. The efficacy of medications is affected by the many physiological changes during pregnancy,... (Review)
Review
Pregnant women frequently take prescription and over the counter medications. The efficacy of medications is affected by the many physiological changes during pregnancy, and these events may be further impacted by genetic factors. Research on pharmacogenomic and pharmacokinetic influences on drug disposition during pregnancy has lagged behind other fields. Clinical investigators have demonstrated altered activity of several drug metabolizing enzymes during pregnancy. Emerging evidence also supports the influence of pharmacogenomic variability in drug response for many important classes of drugs commonly used in pregnancy. Prescribing medications during pregnancy requires an understanding of the substantial dynamic physiologic and metabolic changes that occur during gestation. Pharmacogenomics also contributes to the inter-individual variability in response to many medications, and more research is needed to understand how best to manage drug therapy in pregnant women.
Topics: Analgesics, Opioid; Antidepressive Agents; Antiemetics; Antihypertensive Agents; Cytochrome P-450 Enzyme System; Drug Elimination Routes; Female; Humans; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomic Variants; Pharmacokinetics; Pregnancy
PubMed: 32081407
DOI: 10.1016/j.semperi.2020.151222 -
Journal of Medicinal Chemistry Jun 2020
Topics: Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Pharmaceutical Preparations; Toxicology
PubMed: 32484351
DOI: 10.1021/acs.jmedchem.0c00874 -
Drug Metabolism Reviews Feb 2021Drug metabolizing enzymes catalyze the biotransformation of many of drugs and chemicals. The drug metabolizing enzymes are distributed among several evolutionary... (Review)
Review
Drug metabolizing enzymes catalyze the biotransformation of many of drugs and chemicals. The drug metabolizing enzymes are distributed among several evolutionary families and catalyze a range of detoxication reactions, including oxidation/reduction, conjugative, and hydrolytic reactions that serve to detoxify potentially toxic compounds. This detoxication function requires that drug metabolizing enzymes exhibit substrate promiscuity. In addition to their catalytic functions, many drug metabolizing enzymes possess functions unrelated to or in addition to catalysis. Such proteins are termed 'moonlighting proteins' and are defined as proteins with multiple biochemical or biophysical functions that reside in a single protein. This review discusses the diverse moonlighting functions of drug metabolizing enzymes and the roles they play in physiological functions relating to reproduction, vision, cell signaling, cancer, and transport. Further research will likely reveal new examples of moonlighting functions of drug metabolizing enzymes.
Topics: Biotransformation; Humans; Oxidation-Reduction
PubMed: 33264039
DOI: 10.1080/03602532.2020.1858857 -
Drug Metabolism and Disposition: the... Mar 2023
Topics: Precision Medicine; Inactivation, Metabolic; Metabolic Clearance Rate
PubMed: 36849441
DOI: 10.1124/dmd.122.001243 -
Drug Metabolism and Disposition: the... Jul 2022
Topics: Inactivation, Metabolic; Metabolic Clearance Rate
PubMed: 35817440
DOI: 10.1124/dmd.122.000925 -
Xenobiotica; the Fate of Foreign... May 2020Metabolism and transport of many drugs oscillate with times of the day (solar time), resulting in circadian time-dependent drug exposure and...
Metabolism and transport of many drugs oscillate with times of the day (solar time), resulting in circadian time-dependent drug exposure and pharmacokinetics.Time-dependent pharmacokinetics (also known as chronopharmacokinetics) is associated with time-varying drug effects and toxicity.This review summarizes drug-metabolizing enzymes and transporters with rhythmic expressions in the liver, intestine and/or kidney. Correlations of these diurnal proteins with circadian variations in drug exposure and effects/toxicity are covered. We also discuss the molecular mechanisms for circadian control of enzymes and transporters.Mechanism-based chronopharmacokinetics would facilitate a better understanding of chronopharmacology and the design of time-specific drug delivery systems, ultimately leading to improved drug efficacy and minimized toxicity.
Topics: Circadian Clocks; Circadian Rhythm; Drug Delivery Systems; Humans; Inactivation, Metabolic; Kidney; Liver; Membrane Transport Proteins; Metabolic Clearance Rate; Pharmaceutical Preparations
PubMed: 31544568
DOI: 10.1080/00498254.2019.1672120 -
Drug Metabolism and Disposition: the... May 2022
Topics: Inactivation, Metabolic; Liver; Metabolic Clearance Rate
PubMed: 35562120
DOI: 10.1124/dmd.122.000869 -
Human Genomics May 2021UDP-glucuronosyltransferases (UGTs) are the main phase II drug-metabolizing enzymes mediating the most extensive glucuronidation-binding reaction in the human body. The... (Review)
Review
UDP-glucuronosyltransferases (UGTs) are the main phase II drug-metabolizing enzymes mediating the most extensive glucuronidation-binding reaction in the human body. The UGT1A family is involved in more than half of glucuronidation reactions. However, significant differences exist in the distribution of UGT1As in vivo and the expression of UGT1As among individuals, and these differences are related to the occurrence of disease and differences in metabolism. In addition to genetic polymorphisms, there is now interest in the contribution of epigenetics and noncoding RNAs (especially miRNAs) to this differential change. Epigenetics regulates UGT1As pretranscriptionally through DNA methylation and histone modification, and miRNAs are considered the key mechanism of posttranscriptional regulation of UGT1As. Both epigenetic inheritance and miRNAs are involved in the differences in sex expression and in vivo distribution of UGT1As. Moreover, epigenetic changes early in life have been shown to affect gene expression throughout life. Here, we review and summarize the current regulatory role of epigenetics in the UGT1A family and discuss the relationship among epigenetics and UGT1A-related diseases and treatment, with references for future research.
Topics: Epigenesis, Genetic; Glucuronosyltransferase; Humans; Inactivation, Metabolic; MicroRNAs; Multigene Family
PubMed: 34034810
DOI: 10.1186/s40246-021-00331-6