Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice
Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice
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DOI：
10.1073/pnas.0804226105
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发表时间：
2008-08-12
影响因子：
11.1
通讯作者：
Levine, Mark
中科院分区：
文献类型：
--
作者：
Chen, Qi;Espey, Michael Graham;Levine, Mark
抗坏血酸是一种必需的营养素，通常被认为是一种抗氧化剂。在这项研究中，我们表明，抗坏血酸在药理浓度是一种促氧化剂，产生过氧化氢依赖性细胞毒性对各种癌细胞在体外没有不利影响正常细胞。为了测试这种作用在体内，正常的口服严格控制绕过肠胃外抗坏血酸给药。实时微透析采样的小鼠荷胶质母细胞瘤异种移植物显示，一个单一的药理剂量的抗坏血酸产生持续的抗坏血酸自由基和过氧化氢的形成选择性的肿瘤间质液，但不是在血液中。此外，每日抗坏血酸药物治疗方案显著降低了小鼠卵巢（P < 0.005）、胰腺（P < 0.05）和胶质母细胞瘤（P < 0.001）肿瘤的生长速率。在静脉注射抗坏血酸的人体中，很容易达到类似的药理学浓度。这些数据表明，抗坏血酸作为前药可能对预后不良和治疗选择有限的癌症有好处。
Ascorbic acid is an essential nutrient commonly regarded as an antioxidant. In this study, we showed that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Real-time microdialysis sampling in mice bearing gliobiastoma xenografts showed that a single pharmacologic dose of ascorbate produced sustained ascorbate radical and hydrogen peroxide formation selectively within interstitial fluids of tumors but not in blood. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. Similar pharmacologic concentrations were readily achieved in humans given ascorbate intravenously. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.