Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction.
Artemisinin dimer anticancer activity correlates with heme-catalyzed reactive oxygen species generation and endoplasmic reticulum stress induction.
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DOI：
10.1002/ijc.24496
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发表时间：
2009-09-15
影响因子：
6.4
通讯作者：
Newton, Dianne L.
中科院分区：
文献类型：
--
作者：
Stockwin, Luke H.;Han, Bingnan;Yu, Sherry X.;Hollingshead, Melinda G.;ElSohly, Mahmoud A.;Gul, Waseem;Slade, Desmond;Galal, Ahmed M.;Newton, Dianne L.
治疗疟疾的类似物青蒿素在体外和体内都具有抗癌活性。本研究对两个二聚体青蒿素(NSC724910和735847)进行了研究，以确定其作用机制。二聚体的活性是单体的1000倍，治疗与增加活性氧(ROS)和诱导细胞凋亡有关。抗氧化剂L-NaC、铁络合剂去铁胺和外源氯化高铁对二聚体活性有抑制作用。类似地，CoPPIX诱导HMOX活性抑制，而SnPPIX抑制HMOX活性增强。这些结果强调了铁、血红素和ROS在活动中的重要性。二聚体处理细胞的微阵列分析确定DNA损伤、铁/血红素和半胱氨酸/蛋氨酸代谢、抗氧化反应和内质网(ER)应激是受影响的途径。检测内质网应激反应是相关的，因为在疟疾中，青蒿素抑制pfATP6，这是哺乳动物内质网驻留的SERCA钙-ATPase的原虫同源物。NSC735847与SERCA特异性抑制剂和内质网应激诱导剂thapsigargin的比较研究显示，NSC735847在转录变化、内源性SERCA诱导和内质网钙动员方面表现出相似的行为。但是，thapsigargin对ROS的产生影响不大，对不同的内质网应激蛋白有调节作用，并且对纯化的SERCA1有更强的抑制作用。此外，NSC735847的一个缺乏内过氧化的非活性衍生物对纯化的SERCA1具有相同的抑制活性，这表明直接抑制SERCA对整体细胞毒性几乎没有影响。综上所述，这些数据暗示间接的内质网应激诱导是青蒿素二聚体活性的中心机制。
Analogs of the malaria therapeutic, artemisinin, possess in vitro and in vivo anti-cancer activity. In this study, two dimeric artemisinins (NSC724910 and 735847) were studied to determine their mechanism of action. Dimers were >1000 fold more active than monomer and treatment was associated with increased reactive oxygen species (ROS) and apoptosis induction. Dimer activity was inhibited by the anti-oxidant L-NAC, the iron chelator desferroxamine, and exogenous hemin. Similarly, induction of heme oxygenase (HMOX) with CoPPIX inhibited activity while inhibition of HMOX with SnPPIX enhanced it. These results emphasize the importance of iron, heme and ROS in activity. Microarray analysis of dimer treated cells identified DNA damage; iron/heme and cysteine/methionine metabolism, antioxidant response, and endoplasmic reticulum (ER) stress as affected pathways. Detection of an ER-stress response was relevant because in malaria, artemisinin inhibits pfATP6, the plasmodium orthologue of mammalian ER-resident SERCA Ca2+-ATPases. A comparative study of NSC735847 with thapsigargin, a specific SERCA inhibitor and ER-stress inducer showed similar behavior in terms of transcriptomic changes, induction of endogenous SERCA and ER calcium mobilization. However, thapsigargin had little effect on ROS production, modulated different ER-stress proteins and had greater potency against purified SERCA1. Furthermore, an inactive derivative of NSC735847 that lacked the endoperoxide had identical inhibitory activity against purified SERCA1, suggesting that direct inhibition of SERCA has little inference on overall cytotoxicity. In summary, these data implicate indirect ER-stress induction as a central mechanism of artemisinin dimer activity.
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影响因子：
64.8
作者：
Eckstein-Ludwig, U;Webb, RJ;Krishna, S
通讯作者：
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影响因子：
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