NAD(P)H:Quinone oxidoreductase activity is the principal determinant of beta-lapachone cytotoxicity.
NAD(P)H:Quinone oxidoreductase activity is the principal determinant of beta-lapachone cytotoxicity.
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发表时间：
2000
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通讯作者：
J. Pink;S. Planchon;C. Tagliarino;M. Varnes;D. Siegel;D. Boothman
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作者：
J. Pink;S. Planchon;C. Tagliarino;M. Varnes;D. Siegel;D. Boothman
β - lapachone在许多细胞系中激活了一种新的凋亡反应。我们证明了NAD(P)H：醌氧化还原酶（NQO1）大大增强了β -lapachone的毒性。在一组乳腺癌细胞系中，NQO1的表达与对4小时β -lapachone脉冲的敏感性直接相关，而NQO1抑制剂双oumarol可显著保护表达NQO1的细胞免受β -lapachone毒性的影响。用NQO1表达质粒稳定转染缺乏NQO1的细胞系MDA-MB-468，可增加β -lapachone暴露后的凋亡反应和致死性。双甾体酚可抑制细胞凋亡反应和致死性。生化研究表明，NQO1对β -lapachone的还原会导致醌和对苯二酚之间的无效循环，并伴随减少的NAD(P)H的损失。此外，在β -lapachone处理后，观察到半胱氨酸蛋白酶的活化，其特征与中性钙依赖性蛋白酶calpain一致。这是肿瘤细胞中β -lapachone细胞内靶标的首次明确阐明。NQO1可以用于基因治疗、放疗和/或化学预防干预，因为该酶在许多肿瘤类型（如乳腺癌和肺癌）和肿瘤转化过程中升高。
beta-Lapachone activates a novel apoptotic response in a number of cell lines. We demonstrate that the enzyme NAD(P)H:quinone oxidoreductase (NQO1) substantially enhances the toxicity of beta-lapachone. NQO1 expression directly correlated with sensitivity to a 4-h pulse of beta-lapachone in a panel of breast cancer cell lines, and the NQO1 inhibitor, dicoumarol, significantly protected NQO1-expressing cells from all aspects of beta-lapachone toxicity. Stable transfection of the NQO1-deficient cell line, MDA-MB-468, with an NQO1 expression plasmid increased apoptotic responses and lethality after beta-lapachone exposure. Dicoumarol blocked both the apoptotic responses and lethality. Biochemical studies suggest that reduction of beta-lapachone by NQO1 leads to a futile cycling between the quinone and hydroquinone forms, with a concomitant loss of reduced NAD(P)H. In addition, the activation of a cysteine protease, which has characteristics consistent with the neutral calcium-dependent protease, calpain, is observed after beta-lapachone treatment. This is the first definitive elucidation of an intracellular target for beta-lapachone in tumor cells. NQO1 could be exploited for gene therapy, radiotherapy, and/or chemopreventive interventions, since the enzyme is elevated in a number of tumor types (i.e. breast and lung) and during neoplastic transformation.