O(2)(⋅-) and H(2)O(2)-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.
O(2)(⋅-) and H(2)O(2)-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate.
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DOI：
10.1016/j.ccell.2017.02.018
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发表时间：
2017-04-10
期刊：
影响因子：
50.3
通讯作者：
Allen BG
中科院分区：
文献类型：
--
作者：
Schoenfeld JD;Sibenaller ZA;Mapuskar KA;Wagner BA;Cramer-Morales KL;Furqan M;Sandhu S;Carlisle TL;Smith MC;Abu Hejleh T;Berg DJ;Zhang J;Keech J;Parekh KR;Bhatia S;Monga V;Bodeker KL;Ahmann L;Vollstedt S;Brown H;Shanahan Kauffman EP;Schall ME;Hohl RJ;Clamon GH;Greenlee JD;Howard MA;Schultz MK;Smith BJ;Riley DP;Domann FE;Cullen JJ;Buettner GR;Buatti JM;Spitz DR;Allen BG
药理抗坏血酸已被认为是一种潜在的抗癌药物，当与放射和化疗相结合时。抗坏血酸的抗癌作用被假设为包括抗坏血酸的自氧化导致H_2O_2的稳态水平增加；然而，癌细胞选择性毒性的机制(S)仍不清楚。目前的研究表明，癌细胞线粒体氧化代谢的改变导致O2·−和H_2O_2水平的增加，能够扰乱细胞内的铁代谢，从而选择性地敏化非小细胞肺癌和胶质母细胞瘤细胞，通过氧化还原活性活化铁和H_2O_2的促氧化化学作用而产生抗坏血酸。此外，临床前研究和临床试验证明了抗坏血酸在GBM和NSCLC治疗中的可行性、选择性毒性、耐受性和潜在疗效。Schoenfeld等人的研究成果。表明癌细胞由于其氧化还原活性铁代谢的改变而对抗坏血酸选择性敏感。他们提供了临床前和临床数据，证明了抗坏血酸药物治疗胶质母细胞瘤和肺癌的可行性、耐受性和潜在疗效。
Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2•− and H2O2 are capable of disrupting intracellular iron metabolism thereby selectively sensitizing non-small cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy. Schoenfeld et al. show that cancer cells are selectively sensitive to ascorbate due to their altered redox active iron metabolism. They present preclinical and clinical data demonstrating the feasibility, tolerability, and potential efficacy of pharmacological ascorbate for treating glioblastoma and lung cancer.