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Inflammation and cancer: chemical approaches to mechanisms, imaging, and treatment.

Marnett LJ - J. Org. Chem. (2012)

Bottom Line: Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease.The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer.In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

View Article: PubMed Central - PubMed

Affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. larry.marnett@vanderbilt.edu

ABSTRACT
The inflammatory response represents a first line of defense against invading pathogens and is important to human health. Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease. The chemistry of the inflammatory response is complex and involves the generation of highly reactive oxidants and electrophiles designed to kill the pathogen as well as the release of small molecule and protein mediators of intercellular signaling, chemotaxis, vasoconstriction, and wound-healing. Oxidation of unsaturated fatty acids--either nonenzymatic or enzymatic--contributes to the inflammatory response and associated cellular pathologies. The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer. In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

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Polyunsaturatedfatty acids and lipid peroxidation.
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fig2: Polyunsaturatedfatty acids and lipid peroxidation.

Mentions: Most cellular constituents can be oxidized, nitrated,or chlorinated by the species in Figure 1,but membrane constituents are particularly sensitive to reaction.This is due to the ubiquity of membranes throughout cells combinedwith the presence of monounsaturated or polyunsaturated fatty acidsat the sn-2 position of every glycerophospholipidmolecule of every membrane.28 Unsaturatedfatty acid groups are prone to oxidation because of the presence ofallylic H atoms. The bis-allylic H atoms in polyunsaturated fattyacids are even more sensitive to oxidation, and the reactivity increaseswith the number of double bonds.29 Thequantitatively and biologically most significant polyunsaturated fattyacids are linoleic acid (18:2) and arachidonic acid (20:4) (Figure 2). Removal of the allylic H atom produces a carbon-centeredradical that couples to O2 to form a peroxyl radical. Peroxylradicals are reasonably strong oxidants and can oxidize neighboringpolyunsaturated fatty acid residues in phospholipid membranes. Theseradical cascades can exhibit long chain lengths. For example, it isestimated that some 200 molecules of 20:4 can be oxidized per initialoxidation event.30 Vitamin E serves asthe principal membrane-bound antioxidant that interrupts these chains,terminating autoxidation and protecting membranes from further degradation.31 The vitamin E phenoxyl radical produced by reductionof lipid peroxyl radicals decays to quinone or epoxide products thatprevent propagation of lipid oxidation.32


Inflammation and cancer: chemical approaches to mechanisms, imaging, and treatment.

Marnett LJ - J. Org. Chem. (2012)

Polyunsaturatedfatty acids and lipid peroxidation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3375764&req=5

fig2: Polyunsaturatedfatty acids and lipid peroxidation.
Mentions: Most cellular constituents can be oxidized, nitrated,or chlorinated by the species in Figure 1,but membrane constituents are particularly sensitive to reaction.This is due to the ubiquity of membranes throughout cells combinedwith the presence of monounsaturated or polyunsaturated fatty acidsat the sn-2 position of every glycerophospholipidmolecule of every membrane.28 Unsaturatedfatty acid groups are prone to oxidation because of the presence ofallylic H atoms. The bis-allylic H atoms in polyunsaturated fattyacids are even more sensitive to oxidation, and the reactivity increaseswith the number of double bonds.29 Thequantitatively and biologically most significant polyunsaturated fattyacids are linoleic acid (18:2) and arachidonic acid (20:4) (Figure 2). Removal of the allylic H atom produces a carbon-centeredradical that couples to O2 to form a peroxyl radical. Peroxylradicals are reasonably strong oxidants and can oxidize neighboringpolyunsaturated fatty acid residues in phospholipid membranes. Theseradical cascades can exhibit long chain lengths. For example, it isestimated that some 200 molecules of 20:4 can be oxidized per initialoxidation event.30 Vitamin E serves asthe principal membrane-bound antioxidant that interrupts these chains,terminating autoxidation and protecting membranes from further degradation.31 The vitamin E phenoxyl radical produced by reductionof lipid peroxyl radicals decays to quinone or epoxide products thatprevent propagation of lipid oxidation.32

Bottom Line: Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease.The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer.In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

View Article: PubMed Central - PubMed

Affiliation: A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. larry.marnett@vanderbilt.edu

ABSTRACT
The inflammatory response represents a first line of defense against invading pathogens and is important to human health. Chronic inflammation contributes to the etiology of multiple diseases, especially those associated with aging, such as cancer and cardiovascular disease. The chemistry of the inflammatory response is complex and involves the generation of highly reactive oxidants and electrophiles designed to kill the pathogen as well as the release of small molecule and protein mediators of intercellular signaling, chemotaxis, vasoconstriction, and wound-healing. Oxidation of unsaturated fatty acids--either nonenzymatic or enzymatic--contributes to the inflammatory response and associated cellular pathologies. The current perspective summarizes our research on unsaturated fatty acid oxidation in the context of inflammation and cancer. In addition to understanding the consequences of DNA and protein modification by lipid electrophiles, our research has focused on the development of molecularly targeted agents to image and treat cancer.

Show MeSH
Related in: MedlinePlus