A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo.
A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo.
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DOI：
10.1016/j.freeradbiomed.2010.10.696
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发表时间：
2011-01-01
影响因子：
7.4
通讯作者：
Newton, Dianne L.
中科院分区：
文献类型：
--
作者：
Hancock, Chad N.;Stockwin, Luke H.;Han, Bingnan;Divelbiss, Raymond D.;Jun, Jung Ho;Malhotra, Sanjay V.;Hollingshead, Melinda G.;Newton, Dianne L.
在本研究中，我们评价了新型缩氨基硫脲NSC 689534的Cu2+络合物的体内外抗癌活性。结果表明，铜络合可使NSC-689534活性(低微米范围)提高4-5倍，而铁可使其完全减弱。重要的是，一旦形成，NSC 689534/Cu2+复合体在存在额外的铁或含铁生物分子的情况下仍具有活性。Nsc 689534/Cu2+主要通过诱导细胞内ROS，消耗细胞内谷胱甘肽和蛋白硫醇来介导其作用。细胞用抗氧化剂L-NaC预处理后活性减弱，而Nsc 689534/Cu2+与谷胱甘肽生物合成抑制剂丁硫氨酸亚硫胺有有效的协同作用。对NSC 689534/Cu2+处理的细胞进行的微阵列分析强调了参与氧化和内质网应激/UPR、自噬和金属代谢的通路的激活。对内质网应激和自噬作用的进一步研究表明，Nsc 689534/Cu2+诱导的细胞死亡是内质网应激依赖性和自噬非依赖性的。最后，Nsc 689534/Cu2+在HL60异种移植模型中显示了活性。这些数据表明，NSC 689534/Cu2+是一种有效的氧化应激诱导剂，值得进一步的临床前研究。
In this study, a Cu2+ chelate of the novel thiosemicarbazone NSC 689534 was evaluated for in vitro and in vivo anti-cancer activity. Results demonstrated that NSC 689534 activity (low µM range) was enhanced 4–5 fold by copper chelation and completely attenuated by iron. Importantly, once formed, the NSC 689534/Cu2+ complex retained activity in the presence of additional iron or iron-containing biomolecules. NSC 689534/Cu2+ mediated its effects primarily through the induction of ROS, with depletion of cellular glutathione and protein thiols. Pre-treatment of cells with the antioxidant L-NAC impaired activity, whereas NSC 689534/Cu2+ effectively synergized with the glutathione biosynthesis inhibitor, buthionine sulphoximine. Microarray analysis of NSC 689534/Cu2+-treated cells highlighted activation of pathways involved in oxidative and ER-stress/UPR, autophagy and metal metabolism. Further scrutiny of the role of ER-stress and autophagy indicated that NSC 689534/Cu2+ -induced cell death was ER-stress dependent and autophagy-independent. Lastly, NSC 689534/Cu2+ was shown to have activity in an HL60 xenograft model. These data suggest that NSC 689534/Cu2+ is a potent oxidative stress inducer worthy of further preclinical investigation.
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影响因子：
11.2
作者：
Fels DR;Ye J;Segan AT;Kridel SJ;Spiotto M;Olson M;Koong AC;Koumenis C
通讯作者：
Koumenis C
影响因子：
5.8
作者：
CORY, JG;CORY, AH;SARTORELLI, AC
通讯作者：
SARTORELLI, AC
影响因子：
2.3
作者：
Gómez-Saiz, P;Gil-García, R;García-Tojal, J
通讯作者：
García-Tojal, J
影响因子：
2.9
作者：
AREZZO, F
通讯作者：
AREZZO, F
影响因子：
8.2
作者：
Li, Jing-jing;Tang, Qiang;Xiang, Ji-zhou
通讯作者：
Xiang, Ji-zhou