Ascorbate/menadione-induced oxidative stress kills cancer cells that express normal or mutated forms of the oncogenic protein Bcr-Abl. An in vitro and in vivo mechanistic study
Ascorbate/menadione-induced oxidative stress kills cancer cells that express normal or mutated forms of the oncogenic protein Bcr-Abl. An in vitro and in vivo mechanistic study
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DOI：
10.1007/s10637-010-9441-3
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发表时间：
2011-10-01
影响因子：
3.4
通讯作者：
Verrax, Julien
中科院分区：
文献类型：
--
作者：
Beck, Raphael;Pedrosa, Rozangela Curi;Verrax, Julien
大量研究表明，氧化应激的产生可能对癌症治疗有用。在这项研究中，我们在体外和体内评估了抗坏血酸/甲萘二酮(ASC/MEN)诱导的氧化应激(ASC/MEN)的抗肿瘤潜力。这种还原剂(抗坏血酸)和氧化还原活性苯二酮(甲萘二酮)的组合会产生氧化还原循环，从而形成活性氧物种(ROS)。ASC/MEN在几种细胞类型上进行了检测，包括K562细胞(稳定的人源性白血病细胞系)、新鲜分离的慢性粒细胞白血病患者的白细胞、转bcr-Abl的BaF3细胞(小鼠前B细胞系)和来自健康献血者的外周血白细胞。尽管后者对ASC/MEN耐药，但所有其他细胞系的存活率显著降低，包括表达野生型或突变bcr-Abl的BaF3细胞。在标准的皮下肿瘤移植模型中，ASC/MEN可显著延缓K562和表达突变BCR-Abl T315I的BaF3细胞的增殖。体外实验表明，将这些细胞注入小鼠的血液中，没有观察到ASC/MEN的作用，很可能是因为红细胞具有很高的抗氧化能力。我们推测，癌细胞对ASC/MEN比健康细胞更敏感，因为它们缺乏抗氧化酶，主要是过氧化氢酶。这种细胞毒性的机制涉及Hsp90的氧化裂解，随后失去其伴侣功能，从而导致野生型和突变的bcr-Abl蛋白的降解。
Numerous studies suggest that generation of oxidative stress could be useful in cancer treatment. In this study, we evaluated, in vitro and in vivo, the antitumor potential of oxidative stress induced by ascorbate/menadione (asc/men). This combination of a reducing agent (ascorbate) and a redox active quinone (menadione) generates redox cycling leading to formation of reactive oxygen species (ROS). Asc/men was tested in several cell types including K562 cells (a stable human-derived leukemia cell line), freshly isolated leukocytes from patients with chronic myeloid leukemia, BaF3 cells (a murine pro-B cell line) transfected with Bcr-Abl and peripheral blood leukocytes derived from healthy donors. Although these latter cells were resistant to asc/men, survival of all the other cell lines was markedly reduced, including the BaF3 cells expressing either wild-type or mutated Bcr-Abl. In a standard in vivo model of subcutaneous tumor transplantation, asc/men provoked a significant delay in the proliferation of K562 and BaF3 cells expressing the T315I mutated form of Bcr-Abl. No effect of asc/men was observed when these latter cells were injected into blood of mice most probably because of the high antioxidant potential of red blood cells, as shown by in vitro experiments. We postulate that cancer cells are more sensitive to asc/men than healthy cells because of their lack of antioxidant enzymes, mainly catalase. The mechanism underlying this cytotoxicity involves the oxidative cleavage of Hsp90 with a subsequent loss of its chaperone function thus leading to degradation of wild-type and mutated Bcr-Abl protein.