Chen Qi, Espey Michael Graham, Sun Andrew Y, Pooput Chaya, Kirk Kenneth L, Krishna Murali C, Khosh Deena Beneda, Drisko Jeanne, Levine Mark
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11105-9. doi: 10.1073/pnas.0804226105. Epub 2008 Aug 4.
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 glioblastoma 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.
抗坏血酸是一种通常被视为抗氧化剂的必需营养素。在本研究中，我们表明，药理浓度的抗坏血酸盐是一种促氧化剂，在体外对多种癌细胞产生依赖过氧化氢的细胞毒性，而不会对正常细胞产生不利影响。为了在体内测试这种作用，通过肠外给予抗坏血酸盐绕过了正常的口服严格控制。对携带胶质母细胞瘤异种移植物的小鼠进行实时微透析采样显示，单剂量药理抗坏血酸盐可在肿瘤间质液中选择性地产生持续的抗坏血酸自由基和过氧化氢，而在血液中则不会。此外，每日药理抗坏血酸治疗方案显著降低了在小鼠中建立的卵巢癌（P < 0.005）、胰腺癌（P < 0.05）和胶质母细胞瘤（P < 0.001）的生长速度。静脉给予抗坏血酸的人类也很容易达到类似的药理浓度。这些数据表明，抗坏血酸盐作为前药可能对预后不良且治疗选择有限的癌症有益。
