Shin Sung-Won, Choi Changhoon, Lee Ga-Haeng, Son Arang, Kim Su-Hyeon, Park Hee Chul, Batinic-Haberle Ines, Park Won
1 Department of Radiation Oncology, Samsung Medical Center , Seoul, Republic of Korea.
2 Sungkyunkwan University School of Medicine , Seoul, Republic of Korea.
Antioxid Redox Signal. 2017 Nov 10;27(14):1067-1082. doi: 10.1089/ars.2016.6889. Epub 2017 Mar 30.
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.
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 HO-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.
阳离子锰（Mn）取代的基于N-吡啶基卟啉的超氧化物歧化酶（SOD）家族的有效模拟物，通过降低活性氧和氮物种（ROS/RNS）水平，保护正常组织免受电离辐射（IR）相关损伤。此外，锰卟啉通过促进IR诱导的肿瘤血管损伤和凋亡过程，对癌细胞表现出抗肿瘤和放射增敏作用。在本研究中，我们在体外和体内使用小鼠乳腺癌4T1和黑色素瘤B16细胞，探索了锰卟啉介导的肿瘤放射增敏的潜在机制。
MnTnHex-2-PyP与IR联合治疗显著降低了细胞活力、克隆细胞存活率和DNA损伤修复能力，并协同增加了IR诱导的4T1和B16细胞凋亡。MnTnHex-2-PyP与IR联合使用导致4T1和B16异种移植肿瘤的生长显著延迟。MnTnHex-2-PyP剂量依赖性地增强了IR介导的羟基衍生物种的产生，但不增强超氧化物的产生。过氧化氢酶过表达逆转了MnTnHex-2-PyP增强的ROS产生和凋亡。MnTnHex-2-PyP/IR对几种丝裂原活化蛋白（MAP）激酶磷酸化的抑制作用以及NF-κB的激活，推测抑制了抗凋亡途径的激活，这与我们关于癌细胞凋亡的其他数据一致。创新与结论：MnTnHex-2-PyP通过促氧化作用在体外和体内对4T1和B16肿瘤模型发挥放射增敏作用，因此具有巨大的治疗潜力。当与IR联合使用时，它减弱了DNA损伤修复，并引发了从促生存途径到凋亡细胞死亡的转变，这可能是由于ROS产生增加和细胞氧化还原平衡紊乱，作用于核因子κB（NF-κB）水平。《抗氧化与氧化还原信号》第27卷，第1067 - 1082页。
