Elesclomol induces cancer cell apoptosis through oxidative stress

氧化应激 细胞凋亡 活性氧 癌症研究 DNA损伤 癌症 程序性细胞死亡 癌细胞 化学 药理学 生物 生物化学 遗传学 DNA
作者
Jessica R. Kirshner,Suqin He,Vishwasenani Balasubramanyam,Jane Kepros,Chin‐Yu Yang,Mei Zhang,Zhenjian Du,James Barsoum,John Bertin
出处
期刊:Molecular Cancer Therapeutics [American Association for Cancer Research]
卷期号:7 (8): 2319-2327 被引量:311
标识
DOI:10.1158/1535-7163.mct-08-0298
摘要

Abstract Elesclomol (formerly STA-4783) is a novel small molecule undergoing clinical evaluation in a pivotal phase III melanoma trial (SYMMETRY). In a phase II randomized, double-blinded, controlled, multi-center trial in 81 patients with stage IV metastatic melanoma, treatment with elesclomol plus paclitaxel showed a statistically significant doubling of progression-free survival time compared with treatment with paclitaxel alone. Although elesclomol displays significant therapeutic activity in the clinic, the mechanism underlying its anticancer activity has not been defined previously. Here, we show that elesclomol induces apoptosis in cancer cells through the induction of oxidative stress. Treatment of cancer cells in vitro with elesclomol resulted in the rapid generation of reactive oxygen species (ROS) and the induction of a transcriptional gene profile characteristic of an oxidative stress response. Inhibition of oxidative stress by the antioxidant N-acetylcysteine blocked the induction of gene transcription by elesclomol. In addition, N-acetylcysteine blocked drug-induced apoptosis, indicating that ROS generation is the primary mechanism responsible for the proapoptotic activity of elesclomol. Excessive ROS production and elevated levels of oxidative stress are critical biochemical alterations that contribute to cancer cell growth. Thus, the induction of oxidative stress by elesclomol exploits this unique characteristic of cancer cells by increasing ROS levels beyond a threshold that triggers cell death. [Mol Cancer Ther 2008;7(8):2319–27]
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