title: Mechanism of the Antitumor and Radiosensitizing Effects of a Manganese Porphyrin, MnHex-2-PyP.
abstract: OBJECTIVE
  Cationic manganese (Mn)-substituted N-pyridylporphyrin-based potent mimics of the family of superoxide dismutases (SODs) protect normal tissues from injury related to ionizing radiation (IR) by reducing levels of reactive oxygen and nitrogen species (ROS/RNS). Furthermore, Mn-porphyrins have demonstrated antitumor and radiosensitizing effects on cancer cells by promoting IR-induced tumor vasculature damage and apoptotic processes. In this study, we explored the underlying mechanisms of Mn-porphyrin-mediated tumor radiosensitization using murine mammary carcinoma 4T1 and melanoma B16 cells in vitro and in vivo.
  
  
  RESULTS
  Combination treatment with MnTnHex-2-PyP and IR substantially reduced cell viability, clonogenic cell survival, and DNA damage repair and synergistically increased IR-induced apoptosis of 4T1 and B16 cells. MnTnHex-2-PyP in combination with IR caused a significant delay in growth of 4T1 and B16 xenograft tumors. MnTnHex-2-PyP dose-dependently enhanced IR-mediated production of H2O2-derived species, but not superoxide. Catalase overexpression reversed MnTnHex-2-PyP-enhanced ROS production and apoptosis. Demonstrated suppression of phosphorylation of several mitogen-activated protein (MAP) kinases and activation of NF-κB by MnTnHex-2-PyP/IR, which presumably inhibited activation of the antiapoptotic pathway, are in agreement with our other data on the apoptosis of cancer cells. Innovation and Conclusions: MnTnHex-2-PyP exerted a radiosensitizing effect on 4T1 and B16 tumor models in vitro and in vivo via pro-oxidative actions and therefore bears a large therapeutic potential. When combined with IR, it attenuated DNA damage repair and triggered a shift from prosurvival pathways to apoptotic cell death, likely due to increased ROS production and disturbed cellular redox balance, acting at the level of nuclear factor κB (NF-κB). Antioxid. Redox Signal. 27, 1067-1082.
authors.affiliation: 1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.|2 Sungkyunkwan University School of Medicine , Seoul, Republic of Korea.
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Shin
authors.affiliation: 1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.
authors.forename: Changhoon
authors.initials: C
authors.lastname: Choi
authors.affiliation: 1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.
authors.forename: Ga-Haeng
authors.initials: GH
authors.lastname: Lee
authors.affiliation: 1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.
authors.forename: Arang
authors.initials: A
authors.lastname: Son
authors.affiliation: 1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.
authors.forename: Su-Hyeon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: 1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.|2 Sungkyunkwan University School of Medicine , Seoul, Republic of Korea.
authors.forename: Hee Chul
authors.initials: HC
authors.lastname: Park
authors.affiliation: 3 Department of Radiation Oncology, Duke University School of Medicine , Durham, North Carolina.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.affiliation: 1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.|2 Sungkyunkwan University School of Medicine , Seoul, Republic of Korea.
authors.forename: Won
authors.initials: W
authors.lastname: Park
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008546:Melanoma, Experimental / Q000378:metabolism / Q000628:therapy*; D008665:Metalloporphyrins / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D008665:Metalloporphyrins; C521294:Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin; D011838:Radiation-Sensitizing Agents
keywords: MnTnHex-2-PyP; SOD mimic; manganese porphyrin; radiation therapy; radiosensitization; reactive oxygen species