Naslov
Radioprotection of the brain white matter by Mn(III) N-butoxyethylpyridylporphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5+

Autori
Weitzel, DH ; Tovmasyan, Artak ; Ashcraft, KA ; Rajic, Zrinka ; Weitner, Tin ; Liu, C ; Li, W ; Buckley, AF ; Prasad, MR ; Young, KH ; Rodriguiz, RM ; Wetsel, WC ; Peters, KB ; Spasojevic, Ivan ; Herndon II, JE ; Batinic Haberle, Ines ; Dewhirst, MW

Izvornik
Molecular cancer therapeutics (1535-7163) 14 (2015); 70-79

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Mn porphyrin ; MnTnBuOE-2-PyP5+ ; brain tumor ; radiation therapy

Sažetak
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- PyP5þ(Mn(III) meso-tetrakis(Nn- butoxyethylpyridinium-2-yl)porphyrin), to provide longterm 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-PyP5þ before and after RT and evaluated threemonths later. At this time point, drug concentration in the brain was 25 nmol/L. Mice treated with MnTnBuOE-2-PyP5+/ 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- PyP5+/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-PyP5þ/RT. Our data demonstrate that MnTnBuOE-2-PyP5+ is neuroprotective for oxidative stress damage caused by radiation exposure. In addition, glioblastoma cells were not protected by MnTnBuOE-2-PyP5+ combination with radiation in vitro. Likewise, the combination of MnTnBuOE-2-PyP5+ with radiation inhibited tumor growth more than RT alone in flank tumors. In summary, MnTnBuOE-2-PyP5+ 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti, Farmacija

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