Radioprotection of the brain white matter by Mn(III) n-Butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5

• Published in: Molecular cancer therapeutics 2015-01, Vol.14 (1), p.70-79
• Main Authors: Weitzel, Douglas H, Tovmasyan, Artak, Ashcraft, Kathleen A, Rajic, Zrinka, Weitner, Tin, Liu, Chunlei, Li, Wei, Buckley, Anne F, Prasad, Mark R, Young, Kenneth H, Rodriguiz, Ramona M, Wetsel, William C, Peters, Katherine B, Spasojevic, Ivan, Herndon, 2nd, James E, Batinic-Haberle, Ines, Dewhirst, Mark W
• Format: Article
• Language: English
• Subjects: Animals; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Cell Line, Tumor; Corpus Callosum - radiation effects; Glioblastoma - drug therapy; Glioblastoma - pathology; Glioblastoma - radiotherapy; Humans; Metalloporphyrins - administration & dosage; Metalloporphyrins - pharmacology; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Motor Activity - radiation effects; Oxidative Stress - drug effects; Radiation-Protective Agents - administration & dosage; Radiation-Protective Agents - pharmacology; White Matter - pathology; White Matter - radiation effects
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-14-0343

Cranial irradiation is a standard therapy for primary and metastatic brain tumors. A major drawback of radiotherapy (RT), however, is long-term cognitive loss that affects quality of life. Radiation-induced oxidative stress in normal brain tissue is thought to contribute to cognitive decline. We evaluated the effectiveness of a novel mimic of superoxide dismutase enzyme (SOD), MnTnBuOE-2-PyP(5+)(Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin), to provide long-term neuroprotection following 8 Gy of whole brain irradiation. Long-term RT damage can only be assessed by brain imaging and neurocognitive studies. C57BL/6J mice were treated with MnTnBuOE-2-PyP(5+) before and after RT and evaluated three months later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP(5+)/RT exhibited MRI evidence for myelin preservation in the corpus callosum compared with saline/RT treatment. Corpus callosum histology demonstrated a significant loss of axons in the saline/RT group that was rescued in the MnTnBuOE-2-PyP(5+)/RT group. In addition, the saline/RT groups exhibited deficits in motor proficiency as assessed by the rotorod test and running wheel tests. These deficits were ameliorated in groups treated with MnTnBuOE-2-PyP(5+)/RT. Our data demonstrate that MnTnBuOE-2-PyP(5+) is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP(5+) combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP(5+) with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP(5+) has dual activity as a neuroprotector and a tumor radiosensitizer. Thus, it is an attractive candidate for adjuvant therapy with RT in future studies with patients with brain cancer.