title: Elesclomol induces cancer cell apoptosis through oxidative stress.
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.
authors: Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USA.
authors: Jessica R
authors: JR
authors: Kirshner
authors: Suqin
authors: S
authors: He
authors: Vishwasenani
authors: V
authors: Balasubramanyam
authors: Jane
authors: J
authors: Kepros
authors: Chin-Yu
authors: CY
authors: Yang
authors: Mei
authors: M
authors: Zhang
authors: Zhenjian
authors: Z
authors: Du
authors: James
authors: J
authors: Barsoum
authors: John
authors: J
authors: Bertin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D020869:Gene Expression Profiling; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; D006834:Hydrazines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C512195:elesclomol