Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor.
Antiangiogenic action of redox-modulating Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP(5+), via suppression of oxidative stress in a mouse model of breast tumor.
复制标题
氧化还原调节Mn（III）中曲霉（N-乙基吡啶-2-基）卟啉MNTE-2-PYP（5+）的抗血管生成作用，通过抑制乳腺肿瘤小鼠模型中的氧化应激。
DOI：
10.1016/j.freeradbiomed.2009.07.001
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发表时间：
2009-10-01
影响因子：
7.4
通讯作者：
Batinic-Haberle, Ines
中科院分区：
文献类型：
--
作者：
Rabbani, Zahid N.;Spasojevic, Ivan;Zhang, Xiuwu;Moeller, Benjamin J.;Haberle, Sinisa;Vasquez-Vivar, Jeannette;Dewhirst, Mark W.;Vujaskovic, Zeljko;Batinic-Haberle, Ines
关键词：
MnTE-2-PyP 5+是活性氧和氮物质的有效催化清除剂，主要是超氧化物和过氧亚硝酸盐。因此，它不仅减弱了原发性氧化损伤，而且被发现调节基于氧化还原的信号传导途径（HIF-1α、NF-κB、SP-1和AP-1），因此也反过来调节继发性氧化损伤。癌症被广泛认为是一种氧化应激状态。本研究的目的是证明催化SOD模拟物/过氧亚硝酸根清除剂是否以及为什么会发挥抗癌作用;即评估MnTE-2-PyP 5+对氧化应激的减弱是否可以抑制4 T1小鼠乳腺肿瘤模型中的肿瘤生长。将肿瘤细胞植入Balb/C小鼠侧腹。研究了三组小鼠（n=25）：对照（PBS）、2 mg/kg/天和15 mg/kg/天的MnTE-2-PyP 5+，当肿瘤平均200 mm 3时开始每天两次皮下给予（直到它们达到初始体积的约5倍）。检测肿瘤内缺氧（pimonidazole，carbonic anhydrase，CAIX）、HIF-1α、VEGF、增殖毛细血管指数（CD 105）、微血管密度（CD 31）、蛋白质硝化、DNA氧化（8-OHdG）、NADPH氧化酶（Nox-4）、细胞凋亡（CD 31）、巨噬细胞浸润（CD 68）和肿瘤药物水平。在2 mg/kg/天剂量下观察到肿瘤生长延迟的趋势，在15 mg/kg/天剂量下具有显著性。药物剂量增加7.5倍，伴随着药物肿瘤水平的相似（6倍）增加。通过DNA损伤、蛋白质3-硝基酪氨酸、巨噬细胞浸润和NADPH氧化酶水平的降低，观察到氧化应激大大减弱。此外，缺氧显著降低，HIF-1α和VEGF水平也显著降低。因此，观察到血管生成的抑制;微血管密度和内皮细胞增殖均显著降低。我们的研究首次表明MnTE-2-PyP 5+本身具有抗癌活性。通过HIF/VEGF途径的抗癌活性可能来自于药物对氧化应激的影响。因此，通过抗氧化剂催化清除ROS/RNS，从而抑制细胞转录活性，可能是抗癌治疗的适当策略。通过优化给药方案、利用更多的生物可利用的锰卟啉（MnP）以及将MnP治疗与辐射、热疗和化疗相结合可以实现抗癌效果的增强。与其他抗癌药物相比，Mn卟啉可能是有利的，这是由于它们对正常组织的辐射保护以及通过预防慢性吗啡耐受来提供疼痛管理的能力。
MnTE-2-PyP5+ is a potent catalytic scavenger of reactive oxygen and nitrogen species, primarily superoxide and peroxynitrite. It therefore not only attenuates primary oxidative damage, but was found to modulate redox-based signaling pathways (HIF-1α, NF-κB, SP-1 and AP-1), and thus in turn secondary oxidative injury also. Cancer has been widely considered as an oxidative stress condition. The goal of the present study was to prove if and why a catalytic SOD mimic/peroxynitrite scavenger would exert anti-cancer effects; i.e. to evaluate whether the attenuation of the oxidative stress by MnTE-2-PyP5+ could suppress tumor growth in a 4T1 mouse breast tumor model. Tumor cells were implanted into Balb/C mouse flanks. Three groups of mice (n=25) were studied: control (PBS), 2 mg/kg/day and 15 mg/kg/day of MnTE-2-PyP5+ given subcutaneously twice daily starting when the tumors averaged 200 mm3 (until they reached ~5-fold of initial volum). Intratumoral hypoxia (pimonidazole, carbonic anhydrase, CAIX), HIF-1α, VEGF, proliferating capillary index (CD105), microvessel density (CD31), protein nitration, DNA oxidation (8-OHdG) NADPH oxidase (Nox-4), apoptosis (CD31), macrophage infiltration (CD68) and tumor drug levels were assessed. With 2 mg/kg/day a trend toward tumor growth delay was observed and was significant with 15 mg/kg/day. The 7.5-fold increase in drug dose was accompanied by similar (6-fold) increase in drug tumor levels. Oxidative stress was largely attenuated as was observed through the decreased levels of DNA damage, protein 3-nitrotyrosine, macrophage infiltration and NADPH oxidase. Further, hypoxia was significantly decreased as were the levels of HIF-1α and VEGF. Consequently, suppression of angiogenesis was observed; both the microvessel density and the endothelial cell proliferation were markedly decreased. Our study indicates for the first time that MnTE-2-PyP5+ has anti-cancer activity in its own right. The anti-cancer activity via HIF/VEGF pathways probably arises from the impact of the drug on the oxidative stress. Therefore, the catalytic scavenging of ROS/RNS by antioxidants, which in turn suppresses cellular transcriptional activity, could be an appropriate strategy for anti-cancer therapy. Enhancement of the anti-cancer effects may be achieved by optimizing the dosing regime, utilizing more bioavailable Mn porphyrins (MnP), and combining MnP treatment with irradiation, hyperthermia and chemotherapy. Mn porphyrins may be advantageous compared to other anti-cancer drugs, due to their radioprotection of normal tissue and the ability to afford pain management via prevention of chronic morphine tolerance.
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影响因子：
4.1
作者：
Ferrer-Sueta, G;Batinic-Haberle, I;Radi, R
通讯作者：
Radi, R
影响因子：
2.9
作者：
Brar, SS;Kennedy, TP;Hoidal, JR
通讯作者：
Hoidal, JR
影响因子：
7.4
作者：
Batinic-Haberle, I;Spasojevic, I;Fridovich, I
通讯作者：
Fridovich, I
影响因子：
11.2
作者：
Connor, Kip M.;Hempel, Nadine;Melendez, J. Andres
通讯作者：
Melendez, J. Andres
影响因子：
4.8
作者：
Batinic-Haberle, I;Benov, L;Fridovich, I
通讯作者：
Fridovich, I