title: Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells.
abstract: OBJECTIVE
  Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox-active nitroxide group. TEMPO-aspirin (TEMPO-ASA) and TEMPO-indomethacin (TEMPO-IND) were synthesized and evaluated in the lung cancer cell line A549.
  
  
  METHODS
  We evaluated physico-chemical properties of TEMPO-ASA and TEMPO-IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase-like properties was assayed by measuring cytochrome c reduction and anti-inflammatory effects were assayed by measuring production of prostaglandin E(2) (PGE(2) ) and leukotriene B(4) (LTB(4) ). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo.
  
  
  RESULTS
  MTD were: TEMPO (140 mg·kg(-1) ), ASA (100 mg·kg(-1) ), indomethacin (5 mg·kg(-1) ), TEMPO-ASA (100 mg·kg(-1) ) and TEMPO-IND (40 mg·kg(-1) ). While TEMPO-ASA was as well tolerated as ASA, TEMPO-IND showed an eightfold improvement over indomethacin. TEMPO-IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO-ASA and TEMPO-IND inhibited production of PGE(2) and LTB(4) in A549 cells with maximum effects at 100 µg·mL(-1) or 10 µg·mL(-1) respectively.
  
  
  CONCLUSIONS
  The nitroxide-NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti-inflammatory effects, inhibiting cyclooxygenase and 5-lipoxygenase enzymes. These redox-modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID-associated toxicity.
authors.affiliation: Radiation Biology Branch National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Wilmarie
authors.initials: W
authors.lastname: Flores-Santana
authors.forename: Terry
authors.initials: T
authors.lastname: Moody
authors.forename: Weibin
authors.initials: W
authors.lastname: Chen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gorczynski
authors.forename: Mai E
authors.initials: ME
authors.lastname: Shoman
authors.forename: Carlos
authors.initials: C
authors.lastname: Velázquez
authors.forename: Angela
authors.initials: A
authors.lastname: Thetford
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Murali K
authors.initials: MK
authors.lastname: Cherukuri
authors.forename: S Bruce
authors.initials: SB
authors.lastname: King
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002351:Carrageenan; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007975:Leukotriene B4 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D003497:Cyclic N-Oxides; D007975:Leukotriene B4; D002351:Carrageenan; D013482:Superoxide Dismutase; D015232:Dinoprostone; D001241:Aspirin; C003959:TEMPO; D007213:Indomethacin