Baader S L, Bruchelt G, Trautner M C, Boschert H, Niethammer D
Children's Hospital, Department of Hematology and Oncology, University of Tuebingen, Germany.
Anticancer Res. 1994 Jan-Feb;14(1A):221-7.
Ascorbic acid (AA) was found to be cytotoxic to neuroblastoma cells in vitro and in vivo. In the present, study we investigated whether the reduced--(AA) or oxidized form (dehydroascorbic acid, DhAA) and its rapidly formed metabolites were the main cytotoxic agents. In neuroblastoma SK-N-SH cells, AA was found to be more cytotoxic than DhAA, although considerably higher amounts of [14C]DhAA than of [14C]AA were incorporated. In contrast, SK-N-LO cells derived from neuroectodermal tissue in fact showed a similar uptake but were much less injured by both substances. We observed that uptake of [14C]AA and [14C]DhAA was impaired in the presence of dithiothreitol and glutathione. Once inside the cell, [14C]DhAA was partially reduced to [14C]AA. From these data we conclude first that at least part of AA is oxidized prior to its uptake, and second that the reduced form of AA and perhaps ascorbyl radicals but not DhAA or its metabolites are the most important forms in mediating cytotoxic reactions in neuroblastoma cells. Furthermore, the results strengthen the previous assumption that AA acts as a pro-oxidant in neuroblastoma cells and supports its use in the treatment of neuroblastoma, especially in combination with existing chemotherapeutics.
体外和体内实验均发现抗坏血酸（AA）对神经母细胞瘤细胞具有细胞毒性。在本研究中，我们调查了还原型（AA）或氧化型（脱氢抗坏血酸，DhAA）及其快速形成的代谢产物是否为主要的细胞毒性剂。在神经母细胞瘤SK-N-SH细胞中，发现AA比DhAA的细胞毒性更大，尽管[14C]DhAA的掺入量比[14C]AA高得多。相比之下，源自神经外胚层组织的SK-N-LO细胞实际上显示出相似的摄取量，但两种物质对其造成的损伤要小得多。我们观察到，在二硫苏糖醇和谷胱甘肽存在的情况下，[14C]AA和[14C]DhAA的摄取受到损害。一旦进入细胞内，[14C]DhAA会部分还原为[14C]AA。从这些数据我们首先得出结论，至少部分AA在摄取之前就被氧化了，其次，AA的还原形式以及可能的抗坏血酸自由基而非DhAA或其代谢产物是介导神经母细胞瘤细胞细胞毒性反应的最重要形式。此外，这些结果强化了先前的假设，即AA在神经母细胞瘤细胞中作为促氧化剂起作用，并支持其在神经母细胞瘤治疗中的应用，特别是与现有化疗药物联合使用时。
