Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death.
Mn porphyrin in combination with ascorbate acts as a pro-oxidant and mediates caspase-independent cancer cell death.
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DOI：
10.1016/j.freeradbiomed.2013.11.031
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发表时间：
2014-03
影响因子：
7.4
通讯作者：
Devi, Gayathri R.
中科院分区：
文献类型：
--
作者：
Evans, Myron K.;Tovmasyan, Artak;Batinic-Haberle, Ines;Devi, Gayathri R.
关键词：
炎症性乳腺癌（IBC）是一种侵袭性且独特的乳腺癌亚型，对治疗介导的细胞凋亡的抵抗最近归因于超氧化物歧化酶（SOD）表达、谷胱甘肽（GSH）的增加和活性物质积累的减少。在本研究中，我们证明了两种基于 Mn(III) N-取代吡啶基卟啉 (MnP) 的 SOD 模拟物（MnTE-2-PyP5+ 和 MnTnBuOE-2-PyP5+）催化抗坏血酸氧化的独特能力，导致过量过氧化物的产生，进而导致细胞死亡。 MnP + 抗坏血酸处理导致的过氧化物积累可通过施用外源过氧化氢酶而完全逆转，这表明 ROS 对于细胞死亡至关重要。 MnP/抗坏血酸作用导致的细胞死亡与 GSH 水平、促生存信号（pNF-κB、pERK1/2）和 X 连锁凋亡蛋白抑制剂 (XIAP)（最有效的 caspase 抑制剂）表达的降低相对应。尽管观察到了经典细胞凋亡的标志物，包括 PARP 裂解和膜联蛋白 V 染色，但给予泛半胱天冬酶抑制剂 QVD-OPh 并没有逆转观察到的细胞毒性。 MnP + 抗坏血酸处理的细胞显示凋亡诱导因子 (AIF) 的核易位，表明可能存在不依赖 caspase 的细胞死亡机制。药理学抗坏血酸已经在最近完成的一期临床试验中显示出前景，其中内源性金属蛋白催化其氧化和随后的过氧化物形成。通过优化的金属基催化剂（例如锰卟啉）催化抗坏血酸氧化，作为单独的抗癌剂或与其他方式（例如放射疗法和化学疗法）组合具有巨大的治疗潜力。
Resistance to therapy-mediated apoptosis in inflammatory breast cancer (IBC), an aggressive and distinct subtype of breast cancer, was recently attributed to increased superoxide dismutase (SOD) expression, glutathione (GSH), and decreased accumulation of reactive species. In the present study, we demonstrate the unique ability of two Mn(III) N-substituted pyridylporphyrin (MnP)-based SOD mimics (MnTE-2-PyP5+ and MnTnBuOE-2-PyP5+) to catalyze oxidation of ascorbate, leading to the production of excessive levels of peroxide and in turn cell death. The accumulation of peroxide, as a consequence of MnP + ascorbate treatment, was fully reversed by the administration of exogenous catalase showing that ROS was essential for cell death. Cell death as a consequence of the action of MnP/ascorbate corresponded with decreases in GSH levels, pro-survival signaling (pNF-κB, pERK1/2), and in expression of X-linked inhibitor of apoptosis protein (XIAP), the most potent caspase inhibitor. Although markers of classical apoptosis were observed, including PARP cleavage and Annexin V staining, administration of a pan-caspase inhibitor, QVD-OPh, did not reverse the observed cytotoxicity. MnP + ascorbate treated cells showed nuclear translocation of apoptosis inducing factor (AIF), suggesting the possibility of a mechanism of caspase-independent cell death. Pharmacological ascorbate has already shown promise in recently completed Phase I Clinical Trials, where its oxidation and subsequent peroxide formation was catalyzed by endogenous metalloproteins. The catalysis of ascorbate oxidation by an optimized metal-based catalyst (such as Mn porphyrin) carries a large therapeutic potential as a sole anticancer agent or in combination with other modalities such as radio- and chemo- therapy.
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影响因子：
5.7
作者：
Aird, Katherine M.;Ding, Xiuyun;Devi, Gayathri R.
通讯作者：
Devi, Gayathri R.
影响因子：
7.4
作者：
Barbouti, A;Doulias, PT;Galaris, D
通讯作者：
Galaris, D
影响因子：
7.1
作者：
DI MASCIO, P;MURPHY, ME;SIES, H
通讯作者：
SIES, H
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：
4.5
作者：
Fang, J.;Nakamura, H.;Iyer, A. K.
通讯作者：
Iyer, A. K.