Mechanism of the Antitumor and Radiosensitizing Effects of a Manganese Porphyrin, MnHex-2-PyP.
AIMS
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.
['Shin|Sung-Won|SW|', 'Choi|Changhoon|C|', 'Lee|Ga-Haeng|GH|', 'Son|Arang|A|', 'Kim|Su-Hyeon|SH|', 'Park|Hee Chul|HC|', 'Batinic-Haberle|Ines|I|', 'Park|Won|W|']
D000818:Animals D001943:Breast Neoplasms D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D020935:MAP Kinase Signaling System D008546:Melanoma, Experimental D008665:Metalloporphyrins D051379:Mice D010766:Phosphorylation D011838:Radiation-Sensitizing Agents D023041:Xenograft Model Antitumor Assays
radiosensitization manganese porphyrin MnTnHex-2-PyP SOD mimic radiation therapy reactive oxygen species