Cellular Redox Modulator, ortho Mn(III) meso-tetrakis(N-n-Hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+ in the Treatment of Brain Tumors

Abstract

Despite intensive efforts to improve multimodal treatment of brain tumors, survival remains limited. Current therapy consists of a combination of surgery, irradiation and chemotherapy with predisposition to long-term complications. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. This study explores the utility of a manganese porphyrin in a brain tumor model. The compound used is ortho isomer, manganese(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+. It is a powerful SOD mimic and peroxynitrite scavenger and a potent modulator of redox-based cellular transcriptional activity, able to suppress excessive immune and inflammatory responses and in turn proliferative pathways. It is further one of the most lipophilic compounds among cationic Mn(III) N-alkylpyridylporphyrins, and thus accumulates predominantly in mitochondria relative to cytosol. In mitochondria, MnTnHex-2-PyP5+ could mimic our key antioxidant system, mitochondrial superoxide dismutase, MnSOD, whose overexpression has been widely shown to suppress tumor growth. Importantly, MnTnHex-2-PyP5+ crosses blood brain barrier in sufficient amounts to demonstrate efficacy in treating CNS injuries. For those reasons we elected to test its effects in inhibiting brain tumor growth. This study is the first report of the antitumor properties of MnTnHex-2-PyP5+ as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED), and is the first case where a redox-able metal complex has been used in glioma therapy. When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex-2-PyP5+ caused a significant (P ≤ 0.001) growth delay in D-245 MG, D-256 MG, D-341 MED, and D-456 MG tumors. Growth delay for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MED. With mice bearing intracranial xenografts, MnTnHex-2-PyP5+ increases median survival by 33% in adult glioblastoma multiforme (D-256 MG; P ≤ 0.001) and 173% in pediatric medulloblastoma (D-341 MED, ≤0.001). The beneficial effects of MnTnHex-2-PyP5+ are presumably achieved either (1) indirectly via elimination of signaling reactive oxygen and nitrogen species (in particular superoxide and peroxynitrite) which in turn would prevent activation of transcription factors; or (2) directly by coupling with cellular reductants and redox-sensitive signaling proteins. The former action is antioxidative while the latter action is presumably pro-oxidative in nature. Our findings suggest that the use of Mn porphyrin-based SOD mimics, and in particular lipophilic analogues such as MnTnHex-2-PyP5+, is a promising approach for brain tumor therapy.

Radioprotection of the Brain White Matter by Mn(III) N-Butoxyethylpyridylporphyrin–Based Superoxide Dismutase Mimic MnTnBuOE-2-PyP5+

“…In general, tumor cells have higher oxidative stress level than normal cells due to an imbalance between antioxidant capacity and ROS levels (18, 19) and, therefore, may respond more robustly to antioxidant therapies. As described above, however, our previous porphyrin analogues did not preserve tumor cell growth in vitro or in vivo but, in fact, they did sensitize tumors to radiation in vivo (8, 9, 11, 20–22). Treatment of tumor cells or tumors with MnTnBuOn-2-PyP 5+ likewise demonstrated no protective advantage and, like the earlier analogues, sensitized flank tumors to radiation.…”

“…MnTnHex-2-PyP 5+ treatment alone increased the survival of mice with intracranial tumors (pediatric medulloblastoma and glioblastoma multiforme; ref. 22) and decreased the tumor growth rate in a breast cancer model (11). In addition, MnTE-2-PyP 5+ significantly enhanced radiation effects on breast and prostate tumor growth delay in mice (8, 21, 23).…”

Manganese superoxide dismutase, MnSOD and its mimics

“…The hydrophilic MnTE-2-PyP 5+ was up to 120-fold less efficacious at 6 to 15 mg/kg single or multiple doses (ip, iv, sc, icv) in animal models, and from ~20 to 50 μM in cellular models [44, 46]. MnTnHex-2-PyP 5+ was remarkably efficacious in stroke and hemorrhage rodent models [112, 150], rabbit cerebral palsy [163, 191], brain glioma study [192], organotypic hyppocampal slice model of oxygen glucose deprivation [190], rat eye hypertension [193], rat lung radiation [194], rat renal ischemia reperfusion model [144, 195], E. coli model [116], and ataxia telangiectasia radiation cellular model [196]. The most remarkable efficacy of MnTnHex-2-PyP 5+ was found in the rabbit cerebral palsy model (see below under Cerebral palsy ).…”

Design, Synthesis, Selective Recognition Properties and Targeted Drug Delivery Application

“…Manganese porphyrins catalytically neutralize oxidative stress stimulated molecules such as superoxide, peroxynitrite, carbonate radical and nitric oxide. [276][277][278][279][280][281][282][283] Lower the level of oxidative stress suppress secreation of angiogenic cytokine and other important tumorogenic factors such as hypoxia-inducible factor-1α (HIF-1α), interleukin-2 and VEGF 284,285 and expression of antiangiogenic factors such as interleukin-4. 286 In accordance with these facts, combination of radiotherapy with administration of manganese porphyrins can lead to strong inhibition of tumor growth.…”