Antimelanoma activity of the redox dye DCPIP (2,6-dichlorophenolindophenol) is antagonized by NQO1.
Antimelanoma activity of the redox dye DCPIP (2,6-dichlorophenolindophenol) is antagonized by NQO1.
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DOI：
10.1016/j.bcp.2009.04.016
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发表时间：
2009-08-15
影响因子：
5.8
通讯作者：
Wondrak, Georg T.
中科院分区：
文献类型：
--
作者：
Cabello, Christopher M.;Bair, Warner B., III;Bause, Alexandra S.;Wondrak, Georg T.
参与控制癌细胞存活和增殖信号的氧化还原稳态的改变代表了一种化学脆弱性，可以通过促氧化剂氧化还原干预来靶向。在这里，我们证明了氧化还原染料2，6-二氯苯酚(DCPIP)在体外和体内都可以作为一种针对人黑色素瘤细胞的促氧化化疗药物。在人黑色素瘤细胞系A375和G361中观察到的DCPIP-凋亡性与NAD(P)H：QO1的表达水平呈负相关。在NQO1活性较低的A375细胞中，DCPIP通过原天冬氨酸氨基转移酶-3和PARP裂解诱导细胞凋亡，而表达高水平酶活性NQO1的G361细胞对DCPIP细胞毒作用具有抵抗力。NQO1的遗传(SiRNA)或药理(双香豆酚)拮抗作用使G361细胞对DCPIP具有强烈的促凋亡活性。在A375和NQO1调节的G361细胞中，DCPIP-细胞毒性与诱导氧化应激和谷胱甘肽的快速耗竭有关。表达谱分析显示DCPIP诱导了A375细胞的应激反应，免疫检测进一步证实了编码Hsp70B‘(HSPA6)、Hsp70(HSPA1A)、血红素加氧酶-1(Hmox1)和早期生长反应蛋白1(Egr1)的基因大量上调。在A375小鼠异种移植模型中，DCPIP系统给药显示出显著的抗黑色素瘤活性。这些发现表明，使用DCPIP靶向显示低NQO1酶活性的肿瘤是可行的。
Altered redox homeostasis involved in the control of cancer cell survival and proliferative signaling represents a chemical vulnerability that can be targeted by prooxidant redox intervention. Here, we demonstrate that the redox dye 2,6-dichlorophenolindophenol (DCPIP) may serve as a prooxidant chemotherapeutic targeting human melanoma cells in vitro and in vivo. DCPIP-apoptogenicity observed in the human melanoma cell lines A375 and G361 was inversely correlated with NAD(P)H:quinone oxidoreductase (NQO1) expression levels. In A375 cells displaying low NQO1 activity, DCPIP induced apoptosis with procaspase-3 and PARP cleavage, whereas G361 cells expressing high levels of enzymatically active NQO1 were resistant to DCPIP-cytotoxicity. Genetic (siRNA) or pharmacological (dicoumarol) antagonism of NQO1 strongly sensitized G361 cells to DCPIP apoptogenic activity. DCPIP-cytotoxicity was associated with the induction of oxidative stress and rapid depletion of glutathione in A375 and NQO1-modulated G361 cells. Expression array analysis revealed a DCPIP-induced stress response in A375 cells with massive up-regulation of genes encoding Hsp70B’ (HSPA6), Hsp70 (HSPA1A), heme oxygenase-1 (HMOX1), and early growth response protein 1 (EGR1) further confirmed by immunodetection. Systemic administration of DCPIP displayed significant antimelanoma activity in the A375 murine xenograft model. These findings suggest feasibility of targeting tumors that display low NQO1 enzymatic activity using DCPIP.
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影响因子：
7.4
作者：
Cabello, Christopher M.;Bair, Warner B., III;Lamore, Sarah D.;Ley, Stephanie;Bause, Alexandra S.;Azimian, Sara;Wondrak, Georg T.
通讯作者：
Wondrak, Georg T.
影响因子：
3.8
作者：
Chow, Ari M.;Brown, Ian R.
通讯作者：
Brown, Ian R.
影响因子：
30.8
作者：
Fagerholm, Rainer;Hofstetter, Barbara;Nevanlinna, Heli
通讯作者：
Nevanlinna, Heli
影响因子：
11.5
作者：
Fruehauf, John P.;Meyskens, Frank L., Jr.
通讯作者：
Meyskens, Frank L., Jr.
影响因子：
3
作者：
Hileman, EO;Liu, JS;Huang, P
通讯作者：
Huang, P