OKN-007 decreases free radical levels in a preclinical F98 rat glioma model

作者：de Souza Patricia Coutinho; Smith Nataliya; Atolagbe Oluwatomisin; Ziegler Jadith; Njoku Charity; Lerner Megan; Ehrenshaft Marilyn; Mason Ronald P; Meek Bill; Plafker Scott M; Saunders Debra; Mamedova Nadezda; Towner Rheal A^*

来源：Free Radical Biology and Medicine, 2015, 87: 157-168.

DOI：10.1016/j.freeradbiomed.2015.06.026

• Molecular magnetic resonance imaging
• Glioma
• Free radical
• Immuno-spin-trapping
• OKN-007
• In vivo
• F98 glioma
• Nuclear factor erythroid 2-related factor 2 (NrF2)
• Inducible nitric oxide synthase (iNOS)
• 3-nitrotyrosine (3-NT)
• Malondialdehyde (MDA)

Free radicals are associated with glioma tumors. Here, we report on the ability of an anticancer nitrone compound, OKN-007 [Oklahoma Nitrone 007; a clisulfonyl derivative of ci-phenyl-tert-butyl nitrone (PBN)] to decrease free radical levels in F98 rat gliomas using combined molecular magnetic resonance imaging (mMRI) and immunospin-trapping (1ST) 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-Gcl-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 eiythroid 2-related factor 2, inducible nitric oxide synthase, 3-nitrotymsine, 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 FLISA. The results indicate that OKN-007 effectively decreases free radicals associated with glioma rumor growth. Furthermore, this method can potentially be applied toward other types of cancers for the in vivo detection of rnacromolecular free radicals and the assessment of antioxidants.

• 出版日期2015-10