Antimetabolites and cancer: emerging data with a focus on antifolates

Scagliotti, Giorgio V.; Selvaggi, Giovanni

doi:10.1517/13543776.16.2.189

Cited by 15 publications

(10 citation statements)

References 58 publications

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“…The approach has yielded many successes, including antimetabolites such a folate derivatives used in cancer therapy [39] and the nucleoside analog prodrugs used for antiviral therapy [40]. With the recent availability of databases of metabolites and metabolic reactions, we have gained a wealth of information regarding the interaction of small molecules with biological systems.…”

Section: Metabolomics In Drug Discovery and Polypharmacology Studiesmentioning

confidence: 99%

Navigating the Human Metabolome for Biomarker Identification and Design of Pharmaceutical Molecules

Panagiotou

2010

BioMed Research International

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Metabolomics is a rapidly evolving discipline that involves the systematic study of endogenous small molecules that characterize the metabolic pathways of biological systems. The study of metabolism at a global level has the potential to contribute significantly to biomedical research, clinical medical practice, as well as drug discovery. In this paper, we present the most up-to-date metabolite and metabolic pathway resources, and we summarize the statistical, and machine-learning tools used for the analysis of data from clinical metabolomics. Through specific applications on cancer, diabetes, neurological and other diseases, we demonstrate how these tools can facilitate diagnosis and identification of potential biomarkers for use within disease diagnosis. Additionally, we discuss the increasing importance of the integration of metabolomics data in drug discovery. On a case-study based on the Human Metabolome Database (HMDB) and the Chinese Natural Product Database (CNPD), we demonstrate the close relatedness of the two data sets of compounds, and we further illustrate how structural similarity with human metabolites could assist in the design of novel pharmaceuticals and the elucidation of the molecular mechanisms of medicinal plants.

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Section: Metabolomics In Drug Discovery and Polypharmacology Studiesmentioning

confidence: 99%

Navigating the Human Metabolome for Biomarker Identification and Design of Pharmaceutical Molecules

Panagiotou

2010

BioMed Research International

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“…Antimetabolites typically affect the S phase of the cell cycle by inhibiting the assembly of nucleic acids 14 . Antimetabolites can be classified as: (1) antifolates, (2) purine analogues, (3) pyrimidine analogues and (4) nucleoside (sugar-modified) analogues 14 . Antifolates such as Methotrexate interfere with cell activity by targeting folate-dependent enzymes 14 .…”

Section: Introductionmentioning

confidence: 99%

“…Antimetabolites can be classified as: (1) antifolates, (2) purine analogues, (3) pyrimidine analogues and (4) nucleoside (sugar-modified) analogues 14 . Antifolates such as Methotrexate interfere with cell activity by targeting folate-dependent enzymes 14 . Pyrimidine analogues, such as Gemcitabine, are known to prevent DNA synthesis and repair by exhausting deoxynucleoside triphosphates.…”

Section: Introductionmentioning

confidence: 99%

“…Gemcitabine has been shown to induce radiosensitization in cells when administered 24 hours before radiation therapy, with lasting effects for up to 48 hours 1 . Nucleoside analogues such as 5-fluorouracil (5-FU) prevent nucleic acid production 14 . This mechanism of action relies on cleavage into the DNA and RNA, resulting in disrupted DNA synthesis and transcription, thus affecting protein synthesis 14 .…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic agents and radiation therapy: mechanisms of action and clinical applications

Marrone

Tran

2014

J Radiother Pract

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BackgroundThe combination of radiation therapy and chemotherapy is rooted in its ability to help achieve locoregional and systemic control, therefore increasing the overall disease-free survival of patients. Understanding the mechanistic actions of cytotoxic agents and their targets on the cell cycle, as well as the governing pharmacokinetic principles can improve treatment delivery. The adjuvant treatment setting can overcome barriers such as hypoxia and genetically driven treatment resistance.PurposeThe purpose of this review is to present theoretical frameworks behind the chemoradiation paradigm and to describe current chemoradiation practices in radiation oncology.MethodologyA review was conducted using the US National Library of Medicine, National Institutes of Health database (PubMed) using the following search keywords: chemoradiation, spatial cooperation, chemotherapeutic agents, pharmacokinetics, anti-vascular agents, tumour vasculature and tumour hypoxia.Results and conclusionsCurrent research has reported several rationales for the beneficial combination of radiation and chemotherapy to eradicate oncological diseases. Mechanisms of action and biological approaches are showing that concurrent treatments, as well as novel agents such as anti-vascular and anti-angiogenic agents may benefit improved treatment outcomes by reducing micro hypoxic environments in tumours. In addition, chemotherapy administered in tandem with radiation enhances cell-killing effects by targeting the cell cycle.

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“…Although frequently associated with inhibiting cancer progression (60,65), metabolic regulation is relatively unexploited but promising in the context of autoreactivity. Both innate and adaptive immune cells depend on specific metabolic pathways for survival.…”

Section: Introductionmentioning

confidence: 99%

Mn Porphyrin Regulation of Aerobic Glycolysis: Implications on the Activation of Diabetogenic Immune Cells

Delmastro-Greenwood

Votyakova

Goetzman

et al. 2013

Antioxidants & Redox Signaling

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Aims: The immune system is critical for protection against infections and cancer, but requires scrupulous regulation to limit self-reactivity and autoimmunity. Our group has utilized a manganese porphyrin catalytic antioxidant (MnTE-2-PyP 5+ , MnP) as a potential immunoregulatory therapy for type 1 diabetes. MnP has previously been shown to modulate diabetogenic immune responses through decreases in proinflammatory cytokine production from antigen-presenting cells and T cells and to reduce diabetes onset in nonobese diabetic mice. However, it is unclear whether or not MnP treatment can act beyond the reported inflammatory mediators. Therefore, the hypothesis that MnP may be affecting the redox-dependent bioenergetics of diabetogenic splenocytes was investigated. Results: MnP treatment enhanced glucose oxidation, reduced fatty acid oxidation, but only slightly decreased overall oxidative phosphorylation. These alterations occurred because of increased tricarboxylic acid cycle aconitase enzyme efficiency and were not due to changes in mitochondrial abundance. MnP treatment also displayed decreased aerobic glycolysis, which promotes activated immune cell proliferation, as demonstrated by reduced lactate production and glucose transporter 1 (Glut1) levels and inactivation of key signaling molecules, such as mammalian target of rapamycin, c-myc, and glucose-6-phosphate dehydrogenase. Innovation: This work highlights the importance of redox signaling by demonstrating that modulation of reactive oxygen species can supplant complex downstream regulation, thus affecting metabolic programming toward aerobic glycolysis. Conclusion: MnP treatment promotes metabolic quiescence, impeding diabetogenic autoimmune responses by restricting the metabolic pathways for energy production and affecting anabolic processes necessary for cell proliferation.

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Antimetabolites and cancer: emerging data with a focus on antifolates

Cited by 15 publications

References 58 publications

Navigating the Human Metabolome for Biomarker Identification and Design of Pharmaceutical Molecules

Navigating the Human Metabolome for Biomarker Identification and Design of Pharmaceutical Molecules

Cytotoxic agents and radiation therapy: mechanisms of action and clinical applications

Mn Porphyrin Regulation of Aerobic Glycolysis: Implications on the Activation of Diabetogenic Immune Cells

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