TY - JOUR
T1 - OKN-007 decreases free radical levels in a preclinical F98 rat glioma model
AU - Coutinho De Souza, Patricia
AU - Smith, Nataliya
AU - Atolagbe, Oluwatomisin
AU - Ziegler, Jadith
AU - Njoku, Charity
AU - Lerner, Megan
AU - Ehrenshaft, Marilyn
AU - Mason, Ronald P.
AU - Meek, Bill
AU - Plafker, Scott M.
AU - Saunders, Debra
AU - Mamedova, Nadezda
AU - Towner, Rheal A.
N1 - Publisher Copyright:
© 2015 Published by Elsevier Inc.
PY - 2015/6/17
Y1 - 2015/6/17
N2 - 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.
AB - 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.
KW - (Nrf2)
KW - 3-nitrotyrosine(3-NT)
KW - F98 glioma
KW - Freeradical
KW - Glioma
KW - Immuno-spin-trapping
KW - In vivo
KW - Inducible nitric oxide synthase (iNOS)
KW - Malondialdehyde (MDA)
KW - Molecular magneticresonanceimaging
KW - Nuclear factor erythroid2-related factor 2
KW - OKN-007
UR - http://www.scopus.com/inward/record.url?scp=84940049564&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2015.06.026
DO - 10.1016/j.freeradbiomed.2015.06.026
M3 - Article
C2 - 26119786
AN - SCOPUS:84940049564
SN - 0891-5849
VL - 87
SP - 157
EP - 168
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
M1 - FRBMD1500130
ER -