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.