title: OKN-007 decreases free radical levels in a preclinical F98 rat glioma model.
abstract: Free radicals are associated with glioma tumors. Here, we report on the ability of an anticancer nitrone compound, OKN-007 [Oklahoma Nitrone 007; a disulfonyl derivative of α-phenyl-tert-butyl nitrone (PBN)] to decrease free radical levels in F98 rat gliomas using combined molecular magnetic resonance imaging (mMRI) and immunospin-trapping (IST) methodologies. Free radicals are trapped with the spin-trapping agent, 5,5-dimethyl-1-pyrroline N-oxide (DMPO), to form DMPO macromolecule radical adducts, and then further tagged by immunospin trapping by an antibody against DMPO adducts. In this study, we combined mMRI with a biotin-Gd-DTPA-albumin-based contrast agent for signal detection with the specificity of an antibody for DMPO nitrone adducts (anti-DMPO probe), to detect in vivo free radicals in OKN-007-treated rat F98 gliomas. OKN-007 was found to significantly decrease (P < 0.05) free radical levels detected with an anti-DMPO probe in treated animals compared to untreated rats. Immunoelectron microscopy was used with gold-labeled antibiotin to detect the anti-DMPO probe within the plasma membrane of F98 tumor cells from rats administered anti-DMPO in vivo. OKN-007 was also found to decrease nuclear factor erythroid 2-related factor 2, inducible nitric oxide synthase, 3-nitrotyrosine, and malondialdehyde in ex vivo F98 glioma tissues via immunohistochemistry, as well as decrease 3-nitrotyrosine and malondialdehyde adducts in vitro in F98 cells via ELISA. The results indicate that OKN-007 effectively decreases free radicals associated with glioma tumor growth. Furthermore, this method can potentially be applied toward other types of cancers for the in vivo detection of macromolecular free radicals and the assessment of antioxidants.
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA; Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Coutinho de Souza
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Smith
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.
authors.forename: Oluwatomisin
authors.initials: O
authors.lastname: Atolagbe
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.
authors.forename: Jadith
authors.initials: J
authors.lastname: Ziegler
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.
authors.forename: Charity
authors.initials: C
authors.lastname: Njoku
authors.affiliation: Department of Surgery Research Laboratory, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Lerner
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Ehrenshaft
authors.affiliation: Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Mason
authors.affiliation: Center for Health Sciences, Oklahoma State University, Tulsa, OK, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Meek
authors.affiliation: Free Radical Biology & Aging, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Plafker
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.
authors.forename: Debra
authors.initials: D
authors.lastname: Saunders
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA.
authors.forename: Nadezda
authors.initials: N
authors.lastname: Mamedova
authors.affiliation: Advanced Magnetic Resonance Center, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104, USA; Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, USA. Electronic address: Rheal-Towner@omrf.org.
authors.forename: Rheal A
authors.initials: RA
authors.lastname: Towner
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001557:Benzenesulfonates / Q000008:administration & dosage*; D003287:Contrast Media / Q000737:chemistry; D003497:Cyclic N-Oxides / Q000737:chemistry; D004195:Disease Models, Animal; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007097:Imines / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D008297:Male; D008315:Malondialdehyde / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D019097:Spin Trapping
chemical_list: D000975:Antioxidants; D001557:Benzenesulfonates; D003287:Contrast Media; D003497:Cyclic N-Oxides; D005609:Free Radicals; D007097:Imines; C552724:OKN 007; D008315:Malondialdehyde; C017245:5,5-dimethyl-1-pyrroline-1-oxide
keywords: 3-nitrotyrosine (3-NT); F98 glioma; Free radical; Glioma; Immuno-spin-trapping; In vivo; Inducible nitric oxide synthase (iNOS); Malondialdehyde (MDA); Molecular magnetic resonance imaging; Nuclear factor erythroid 2-related factor 2 (Nrf2); OKN-007